Cutis

Originating in 1968, the dermatologic surgery fellowship is as young as many dermatologists in practice today. Not surprisingly, the blossoming fellowship has undergone its fair share of both growth and growing pains over the last 5 decades. 

A Brief History

The first dermatologic surgery fellowship was born in 1968 when Dr. Perry Robins established a program at the New York University Medical Center for training in chemosurgery.¹ The fellowship quickly underwent notable change with the rising popularity of the fresh tissue technique, which was first performed by Dr. Fred Mohs in 1953 and made popular following publication of a series of landmark articles on the technique by Drs. Sam Stegman and Theodore Tromovitch in the late 1960s and early 1970s. The fellowship correspondingly saw a rise in fresh tissue technique training, accompanied by a decline in chemosurgery training. In 1974, Dr. Daniel Jones coined the term micrographic surgery to describe the favored technique, and at the 1985 annual meeting of the American College of Chemosurgery, the name of the technique was changed to Mohs micrographic surgery.¹

By 1995, the fellowship was officially named Procedural Dermatology, and programs were exclusively accredited by the American College of Mohs Surgery (ACMS). A 1-year Procedural Dermatology fellowship gained accreditation by the Accreditation Council for Graduate Medical Education (ACGME) in 2003.² Beginning in July 2013, all fellowship programs in the United States fell under the governance of the ACGME; however, the ACMS has remained the sponsor of the matching process.³ In 2014, the ACGME changed the name of the fellowship to Micrographic Surgery and Dermatologic Oncology (MSDO).² Fellowship training today is centered on the core elements of cutaneous oncologic surgery, cutaneous reconstructive surgery, and dermatologic oncology; however, the scope of training in technologies and techniques offered has continued to broaden.⁴ Many programs now offer additional training in cosmetic and other procedural dermatology. To date, there are 76 accredited MSDO fellowship training programs in the United States and more than 1500 fellowship-trained micrographic surgeons.^2,4

Trends in Program and Match Statistics

As the role of dermatologic surgery within the field of dermatology continues to expand, the MSDO fellowship has become increasingly popular over the last decade. From 2005 to 2018, applicants participating in the fellowship match increased by 34%.³ Despite the fellowship’s growing popularity, programs participating in the match have remained largely stable from 2005 to 2018, with 50 positions offered in 2005 and 58 in 2018. The match rate has correspondingly decreased from 66.2% in 2005 to 61.1% in 2018.³ 

Changes in the Match Process

The fellowship match is processed by the SF Match and sponsored by the ACMS. Over the last decade, programs have increasingly opted for exemptions from participation in the SF Match. In 2005, there were 8 match exemptions. In 2018, there were 20.⁴ Despite the increasing popularity of match exemptions, in October 2018 the ACMS Board of Directors approved a new policy that eliminated match exemptions, with the exception of applicants on active military duty and international (non-Canadian) applicants. All other applicants applying for a fellowship position for the 2020-2021 academic year must participate in the match.⁴ This new policy attempts to ensure a fair match process, especially for applicants who have trained at a program without an affiliated MSDO fellowship. 

The Road to Board Certification

Further growth during the fellowship’s mid-adult years centered on the long-contested debate on subspecialty board certification. In 2009, an American Society for Dermatologic Surgery membership survey demonstrated an overwhelming majority in opposition. In 2014, the debate resurfaced. At the 2016 American Society for Dermatologic Surgery annual meeting, former American Academy of Dermatology presidents Brett Coldiron, MD, and Darrell S. Rigel, MD, MS, conveyed opposing positions, after which an audience survey demonstrated a 69% opposition rate. Proponents continued to argue that board certification would decrease divisiveness in the specialty, create a better brand, help to obtain a Medicare specialty designation that could help prevent exclusion of Mohs surgeons from insurance networks, give allopathic dermatologists the same opportunity for certification as osteopathic counterparts, and demonstrate competence to the public. Those in opposition argued that the term dermatologic oncology erroneously suggests general dermatologists are not experts in the treatment of skin cancers, practices may be restricted by carriers misusing the new credential, and subspecialty certification would actually create division among practicing dermatologists.⁵

Following years of debate, the American Board of Dermatology’s proposal to offer subspecialty certification in Micrographic Dermatologic Surgery was submitted to the American Board of Medical Specialties and approved on October 26, 2018. The name of the new subspecialty (Micrographic Dermatologic Surgery) is different than that of the fellowship (Micrographic Surgery and Dermatologic Oncology), a decision reached in response to diplomats indicating discomfort with the term oncology potentially misleading the public that general dermatologists do not treat skin cancer. Per the American Board of Dermatology official website, the first certification examination likely will take place in about 2 years. A maintenance of certification examination for the subspecialty will be required every 10 years.⁶

Final Thoughts 

During its short history, the MSDO fellowship has undergone a notable evolution in recognition, popularity among residents, match process, and board certification, which attests to its adaptability over time and growing prominence.

Originating in 1968, the dermatologic surgery fellowship is as young as many dermatologists in practice today. Not surprisingly, the blossoming fellowship has undergone its fair share of both growth and growing pains over the last 5 decades. 

A Brief History

The first dermatologic surgery fellowship was born in 1968 when Dr. Perry Robins established a program at the New York University Medical Center for training in chemosurgery.¹ The fellowship quickly underwent notable change with the rising popularity of the fresh tissue technique, which was first performed by Dr. Fred Mohs in 1953 and made popular following publication of a series of landmark articles on the technique by Drs. Sam Stegman and Theodore Tromovitch in the late 1960s and early 1970s. The fellowship correspondingly saw a rise in fresh tissue technique training, accompanied by a decline in chemosurgery training. In 1974, Dr. Daniel Jones coined the term micrographic surgery to describe the favored technique, and at the 1985 annual meeting of the American College of Chemosurgery, the name of the technique was changed to Mohs micrographic surgery.¹

By 1995, the fellowship was officially named Procedural Dermatology, and programs were exclusively accredited by the American College of Mohs Surgery (ACMS). A 1-year Procedural Dermatology fellowship gained accreditation by the Accreditation Council for Graduate Medical Education (ACGME) in 2003.² Beginning in July 2013, all fellowship programs in the United States fell under the governance of the ACGME; however, the ACMS has remained the sponsor of the matching process.³ In 2014, the ACGME changed the name of the fellowship to Micrographic Surgery and Dermatologic Oncology (MSDO).² Fellowship training today is centered on the core elements of cutaneous oncologic surgery, cutaneous reconstructive surgery, and dermatologic oncology; however, the scope of training in technologies and techniques offered has continued to broaden.⁴ Many programs now offer additional training in cosmetic and other procedural dermatology. To date, there are 76 accredited MSDO fellowship training programs in the United States and more than 1500 fellowship-trained micrographic surgeons.^2,4

Trends in Program and Match Statistics

As the role of dermatologic surgery within the field of dermatology continues to expand, the MSDO fellowship has become increasingly popular over the last decade. From 2005 to 2018, applicants participating in the fellowship match increased by 34%.³ Despite the fellowship’s growing popularity, programs participating in the match have remained largely stable from 2005 to 2018, with 50 positions offered in 2005 and 58 in 2018. The match rate has correspondingly decreased from 66.2% in 2005 to 61.1% in 2018.³ 

Changes in the Match Process

The fellowship match is processed by the SF Match and sponsored by the ACMS. Over the last decade, programs have increasingly opted for exemptions from participation in the SF Match. In 2005, there were 8 match exemptions. In 2018, there were 20.⁴ Despite the increasing popularity of match exemptions, in October 2018 the ACMS Board of Directors approved a new policy that eliminated match exemptions, with the exception of applicants on active military duty and international (non-Canadian) applicants. All other applicants applying for a fellowship position for the 2020-2021 academic year must participate in the match.⁴ This new policy attempts to ensure a fair match process, especially for applicants who have trained at a program without an affiliated MSDO fellowship. 

The Road to Board Certification

Further growth during the fellowship’s mid-adult years centered on the long-contested debate on subspecialty board certification. In 2009, an American Society for Dermatologic Surgery membership survey demonstrated an overwhelming majority in opposition. In 2014, the debate resurfaced. At the 2016 American Society for Dermatologic Surgery annual meeting, former American Academy of Dermatology presidents Brett Coldiron, MD, and Darrell S. Rigel, MD, MS, conveyed opposing positions, after which an audience survey demonstrated a 69% opposition rate. Proponents continued to argue that board certification would decrease divisiveness in the specialty, create a better brand, help to obtain a Medicare specialty designation that could help prevent exclusion of Mohs surgeons from insurance networks, give allopathic dermatologists the same opportunity for certification as osteopathic counterparts, and demonstrate competence to the public. Those in opposition argued that the term dermatologic oncology erroneously suggests general dermatologists are not experts in the treatment of skin cancers, practices may be restricted by carriers misusing the new credential, and subspecialty certification would actually create division among practicing dermatologists.⁵

Following years of debate, the American Board of Dermatology’s proposal to offer subspecialty certification in Micrographic Dermatologic Surgery was submitted to the American Board of Medical Specialties and approved on October 26, 2018. The name of the new subspecialty (Micrographic Dermatologic Surgery) is different than that of the fellowship (Micrographic Surgery and Dermatologic Oncology), a decision reached in response to diplomats indicating discomfort with the term oncology potentially misleading the public that general dermatologists do not treat skin cancer. Per the American Board of Dermatology official website, the first certification examination likely will take place in about 2 years. A maintenance of certification examination for the subspecialty will be required every 10 years.⁶

Final Thoughts 

During its short history, the MSDO fellowship has undergone a notable evolution in recognition, popularity among residents, match process, and board certification, which attests to its adaptability over time and growing prominence.

Originating in 1968, the dermatologic surgery fellowship is as young as many dermatologists in practice today. Not surprisingly, the blossoming fellowship has undergone its fair share of both growth and growing pains over the last 5 decades. 

A Brief History

The first dermatologic surgery fellowship was born in 1968 when Dr. Perry Robins established a program at the New York University Medical Center for training in chemosurgery.¹ The fellowship quickly underwent notable change with the rising popularity of the fresh tissue technique, which was first performed by Dr. Fred Mohs in 1953 and made popular following publication of a series of landmark articles on the technique by Drs. Sam Stegman and Theodore Tromovitch in the late 1960s and early 1970s. The fellowship correspondingly saw a rise in fresh tissue technique training, accompanied by a decline in chemosurgery training. In 1974, Dr. Daniel Jones coined the term micrographic surgery to describe the favored technique, and at the 1985 annual meeting of the American College of Chemosurgery, the name of the technique was changed to Mohs micrographic surgery.¹

By 1995, the fellowship was officially named Procedural Dermatology, and programs were exclusively accredited by the American College of Mohs Surgery (ACMS). A 1-year Procedural Dermatology fellowship gained accreditation by the Accreditation Council for Graduate Medical Education (ACGME) in 2003.² Beginning in July 2013, all fellowship programs in the United States fell under the governance of the ACGME; however, the ACMS has remained the sponsor of the matching process.³ In 2014, the ACGME changed the name of the fellowship to Micrographic Surgery and Dermatologic Oncology (MSDO).² Fellowship training today is centered on the core elements of cutaneous oncologic surgery, cutaneous reconstructive surgery, and dermatologic oncology; however, the scope of training in technologies and techniques offered has continued to broaden.⁴ Many programs now offer additional training in cosmetic and other procedural dermatology. To date, there are 76 accredited MSDO fellowship training programs in the United States and more than 1500 fellowship-trained micrographic surgeons.^2,4

Trends in Program and Match Statistics

As the role of dermatologic surgery within the field of dermatology continues to expand, the MSDO fellowship has become increasingly popular over the last decade. From 2005 to 2018, applicants participating in the fellowship match increased by 34%.³ Despite the fellowship’s growing popularity, programs participating in the match have remained largely stable from 2005 to 2018, with 50 positions offered in 2005 and 58 in 2018. The match rate has correspondingly decreased from 66.2% in 2005 to 61.1% in 2018.³ 

Changes in the Match Process

The fellowship match is processed by the SF Match and sponsored by the ACMS. Over the last decade, programs have increasingly opted for exemptions from participation in the SF Match. In 2005, there were 8 match exemptions. In 2018, there were 20.⁴ Despite the increasing popularity of match exemptions, in October 2018 the ACMS Board of Directors approved a new policy that eliminated match exemptions, with the exception of applicants on active military duty and international (non-Canadian) applicants. All other applicants applying for a fellowship position for the 2020-2021 academic year must participate in the match.⁴ This new policy attempts to ensure a fair match process, especially for applicants who have trained at a program without an affiliated MSDO fellowship. 

The Road to Board Certification

Further growth during the fellowship’s mid-adult years centered on the long-contested debate on subspecialty board certification. In 2009, an American Society for Dermatologic Surgery membership survey demonstrated an overwhelming majority in opposition. In 2014, the debate resurfaced. At the 2016 American Society for Dermatologic Surgery annual meeting, former American Academy of Dermatology presidents Brett Coldiron, MD, and Darrell S. Rigel, MD, MS, conveyed opposing positions, after which an audience survey demonstrated a 69% opposition rate. Proponents continued to argue that board certification would decrease divisiveness in the specialty, create a better brand, help to obtain a Medicare specialty designation that could help prevent exclusion of Mohs surgeons from insurance networks, give allopathic dermatologists the same opportunity for certification as osteopathic counterparts, and demonstrate competence to the public. Those in opposition argued that the term dermatologic oncology erroneously suggests general dermatologists are not experts in the treatment of skin cancers, practices may be restricted by carriers misusing the new credential, and subspecialty certification would actually create division among practicing dermatologists.⁵

Following years of debate, the American Board of Dermatology’s proposal to offer subspecialty certification in Micrographic Dermatologic Surgery was submitted to the American Board of Medical Specialties and approved on October 26, 2018. The name of the new subspecialty (Micrographic Dermatologic Surgery) is different than that of the fellowship (Micrographic Surgery and Dermatologic Oncology), a decision reached in response to diplomats indicating discomfort with the term oncology potentially misleading the public that general dermatologists do not treat skin cancer. Per the American Board of Dermatology official website, the first certification examination likely will take place in about 2 years. A maintenance of certification examination for the subspecialty will be required every 10 years.⁶

Final Thoughts 

During its short history, the MSDO fellowship has undergone a notable evolution in recognition, popularity among residents, match process, and board certification, which attests to its adaptability over time and growing prominence.

If by now you have not had a patient ask, “Doctor, what sunscreen should I use NOW?” you will soon.

The US Food and Drug Administration (FDA) recently published a press release detailing a proposed rule on how manufacturers will be required to test and label sunscreens in the United States.^1,2 Although the press release was complicated and contained much information, the media specifically latched onto the FDA’s consideration of only 2 active sunscreen ingredients—zinc oxide and titanium dioxide—as generally recognized as safe and effective (GRASE). In response, some patients may assume that most sunscreens on the market are dangerous.

How did this new proposed rule come about? To understand the process, it takes some explanation of the history of the FDA’s regulation of sunscreens.

How are sunscreens regulated by the FDA?

The regulatory process for sunscreens in the United States is complicated. The FDA regulates sunscreens as over-the-counter (OTC) drugs rather than as cosmetics, which is how they are regulated in most of the rest of the world.

The US sunscreen regulation process began in 1978 with an advance notice of proposed rulemaking from the FDA that included recommendations from an advisory review panel on the safe and effective use of OTC sunscreen products.³ At that time, 21 active sunscreen ingredients and their maximum use concentrations were listed and determined to be safe, or GRASE. It also gave manufacturers guidance on how to test for efficacy with the methodology for determining the sun protection factor (SPF) as well as various labeling requirements. Over the years, the FDA has issued a number of other sunscreen guidelines, such as removing padimate A and adding avobenzone and zinc oxide to the list of GRASE ingredients in the 1990s.^4,5

In 1999, the FDA issued a final rule that listed 16 active sunscreen ingredients and concentrations as GRASE.⁶ There were some restrictions as to certain combinations of ingredients that could not be used in a finished product. Labeling requirements, including a maximum SPF of 30, also were put in place. This final rule established a final sunscreen monograph that was supposed to have been effective by 2002; however, in 2001 the agency delayed the effective date indefinitely because they had not yet established broad-spectrum (UVA) protection testing and labeling.⁷

The FDA published a proposed rule in 2007 as well as a final rule in 2011 that again listed the same 16 ingredients as GRASE and specified labeling and testing methods for establishing SPF, broad-spectrum protection, and water-resistance claims.^8,9 The final rule limited product labels to a maximum SPF of 50+; provided directions for use with regard to other labeling elements (eg, warnings); and identified specific claims that would not be allowed on product labels, such as “waterproof” and “all-day protection.”⁹

Nevertheless, an effective final OTC monograph for sunscreen products has not yet been published.

What is the Sunscreen Innovation Act?

In 2014, the US Congress enacted the Sunscreen Innovation Act¹⁰ primarily to mandate that the FDA develop a more efficient way to determine the safety and efficacy of new active sunscreen ingredients that were commonly used in Europe and other parts of the world at the time. Many of these agents were thought to be more protective in the UVA and/or UVB spectrum, and if added to the list of GRASE ingredients available to US manufacturers, they would lead to the development of products that would improve the protection offered by sunscreens marketed to US consumers. The time and extent application (TEA) was established, a method that allowed manufacturers to apply for FDA approval of specific agents. The TEA also suggested allowing data generated in other countries where these agents were already in use for years to be considered in the FDA’s evaluation of the agents as GRASE. In addition, Congress mandated that a final monograph on OTC sunscreens be published by the end of 2019. A number of manufacturers have submitted TEAs for new active sunscreen ingredients, and so far, all have been rejected.

Why is the FDA interested in more safety data?

Since then, the FDA has become concerned not only with the safety and efficacy of newly proposed agents through the TEA but also with the original 16 active sunscreen ingredients listed as GRASE in the 2011 final rule. In the 1970s and 1980s, sunscreen use was limited to beach vacations or outdoor sporting events, but sun-protective behaviors have changed dramatically since that time, with health care providers now becoming cognizant of the growing threats of skin cancer and melanoma as well as the cosmetic concerns of photoaging, thereby recommending daily sunscreen use to their patients. In addition, the science behind sunscreens with higher concentrations of active ingredients intended to achieve higher and higher SPFs and their respective penetration of the skin has evolved, leading to new concerns about systemic toxicity. Early limited research frequently touted by the lay media has suggested that some of these agents might lead to hormonal changes, reproductive toxicity, and carcinogenicity.

In November 2016, the FDA issued a guidance for manufacturers that outlined the safety data that would be required to establish an OTC sunscreen active ingredient as GRASE.¹¹ It also provided detailed information about both clinical and nonclinical safety testing, including human irritation and sensitization studies as well as human photosafety studies. In vitro dermal and systemic carcinogenicity studies and animal developmental and reproductive toxicity studies also were required as well studies regarding safety in children.

Many of these recommendations were already being utilized by manufacturers; however, one important change was the requirement for human absorption studies by a maximal usage trial, which more accurately addresses the absorption of sunscreen agents according to actual use. Such studies will be required at the highest allowable concentration of an agent in multiple vehicles and over large body surface areas for considerable exposure times.

This guidance to sunscreen manufacturers was announced to the public in a press release in May 2018.¹²

What are the new regulations?

All of this has culminated in the recent proposed rule, which includes several important proposals²:

• Of the 16 currently marketed active sunscreen ingredients, only 2—zinc oxide and titanium dioxide—are considered GRASE. Two ingredients—trolamine salicylate and para-aminobenzoic acid—are considered non-GRASE, but there is not enough information at this time to determine if the remaining 12 ingredients are GRASE. The FDA is working with manufacturers to obtain sufficient information to make this determination.

• Approved dosage formulations include sprays, oils, lotions, creams, gels, butters, pastes, ointments, and sticks. Further information is needed regarding powders before they can be considered.

• The maximum SPF will be increased from 50+ to 60+.

• Sunscreens with an SPF of 15 or higher are required to provide broad-spectrum protection commensurate with the SPF, expanding on critical wavelength testing.

• There are new labeling changes, including a requirement that active ingredients be listed on the front of the packaging.
• Sunscreen products that contain insect repellents are considered non-GRASE.

What’s next?

The process for the proposed final rule has now entered a 90-day public comment period that will end on May 27, 2019; however, it is unlikely that a final monograph as mandated by Congress will be produced by the end of this year.

Sunscreen manufacturers currently are coordinating a response to the proposed rule through the Personal Care Products Council and the Consumer Healthcare Products Association Sunscreen Task Force. It is likely that the new required testing will be costly, with estimates exceeding tens or even hundreds of millions of dollars. In all likelihood, the number of active ingredients that the industry will agree to support with costly testing will be fewer than the 12 that are now on the list. It also is likely that this process will lead to fewer sunscreen products for consumers to choose from and almost certainly at a higher cost.

What do we tell patients in the meantime?

According to the FDA’s rules, it was necessary that this process was made public, but it will almost certainly concern our patients as to the safety of the sunscreen products they have been using. We should be concerned that some of our patients may limit their use of sunscreens because of safety concerns.

There is no question that, as physicians, we want to “first, do no harm,” so we should all be interested in assuring our patients that our sunscreen recommendations are safe and we support the FDA proposal for additional data. The good news is that when this process is completed, a large number of agents will likely be found to be GRASE. When the FDA finally gives its imprimatur to sunscreens, it will hopefully help to silence those naysayers who report that sunscreens are dangerous for consumers; however, it has been suggested by some in industry that the new testing required may take at least 5 years.

What should dermatologists do when we are asked, “What sunscreen should I use NOW?” For most patients, I would explain the regulatory process and assure them that the risk-benefit ratio at this point suggests they should continue using the same sunscreens that they are currently using. For special situations such as pregnant women and children, it may be best to suggest products that contain only the 2 GRASE inorganic agents.

If by now you have not had a patient ask, “Doctor, what sunscreen should I use NOW?” you will soon.

The US Food and Drug Administration (FDA) recently published a press release detailing a proposed rule on how manufacturers will be required to test and label sunscreens in the United States.^1,2 Although the press release was complicated and contained much information, the media specifically latched onto the FDA’s consideration of only 2 active sunscreen ingredients—zinc oxide and titanium dioxide—as generally recognized as safe and effective (GRASE). In response, some patients may assume that most sunscreens on the market are dangerous.

How did this new proposed rule come about? To understand the process, it takes some explanation of the history of the FDA’s regulation of sunscreens.

How are sunscreens regulated by the FDA?

The regulatory process for sunscreens in the United States is complicated. The FDA regulates sunscreens as over-the-counter (OTC) drugs rather than as cosmetics, which is how they are regulated in most of the rest of the world.

The US sunscreen regulation process began in 1978 with an advance notice of proposed rulemaking from the FDA that included recommendations from an advisory review panel on the safe and effective use of OTC sunscreen products.³ At that time, 21 active sunscreen ingredients and their maximum use concentrations were listed and determined to be safe, or GRASE. It also gave manufacturers guidance on how to test for efficacy with the methodology for determining the sun protection factor (SPF) as well as various labeling requirements. Over the years, the FDA has issued a number of other sunscreen guidelines, such as removing padimate A and adding avobenzone and zinc oxide to the list of GRASE ingredients in the 1990s.^4,5

In 1999, the FDA issued a final rule that listed 16 active sunscreen ingredients and concentrations as GRASE.⁶ There were some restrictions as to certain combinations of ingredients that could not be used in a finished product. Labeling requirements, including a maximum SPF of 30, also were put in place. This final rule established a final sunscreen monograph that was supposed to have been effective by 2002; however, in 2001 the agency delayed the effective date indefinitely because they had not yet established broad-spectrum (UVA) protection testing and labeling.⁷

The FDA published a proposed rule in 2007 as well as a final rule in 2011 that again listed the same 16 ingredients as GRASE and specified labeling and testing methods for establishing SPF, broad-spectrum protection, and water-resistance claims.^8,9 The final rule limited product labels to a maximum SPF of 50+; provided directions for use with regard to other labeling elements (eg, warnings); and identified specific claims that would not be allowed on product labels, such as “waterproof” and “all-day protection.”⁹

Nevertheless, an effective final OTC monograph for sunscreen products has not yet been published.

What is the Sunscreen Innovation Act?

In 2014, the US Congress enacted the Sunscreen Innovation Act¹⁰ primarily to mandate that the FDA develop a more efficient way to determine the safety and efficacy of new active sunscreen ingredients that were commonly used in Europe and other parts of the world at the time. Many of these agents were thought to be more protective in the UVA and/or UVB spectrum, and if added to the list of GRASE ingredients available to US manufacturers, they would lead to the development of products that would improve the protection offered by sunscreens marketed to US consumers. The time and extent application (TEA) was established, a method that allowed manufacturers to apply for FDA approval of specific agents. The TEA also suggested allowing data generated in other countries where these agents were already in use for years to be considered in the FDA’s evaluation of the agents as GRASE. In addition, Congress mandated that a final monograph on OTC sunscreens be published by the end of 2019. A number of manufacturers have submitted TEAs for new active sunscreen ingredients, and so far, all have been rejected.

Why is the FDA interested in more safety data?

Since then, the FDA has become concerned not only with the safety and efficacy of newly proposed agents through the TEA but also with the original 16 active sunscreen ingredients listed as GRASE in the 2011 final rule. In the 1970s and 1980s, sunscreen use was limited to beach vacations or outdoor sporting events, but sun-protective behaviors have changed dramatically since that time, with health care providers now becoming cognizant of the growing threats of skin cancer and melanoma as well as the cosmetic concerns of photoaging, thereby recommending daily sunscreen use to their patients. In addition, the science behind sunscreens with higher concentrations of active ingredients intended to achieve higher and higher SPFs and their respective penetration of the skin has evolved, leading to new concerns about systemic toxicity. Early limited research frequently touted by the lay media has suggested that some of these agents might lead to hormonal changes, reproductive toxicity, and carcinogenicity.

In November 2016, the FDA issued a guidance for manufacturers that outlined the safety data that would be required to establish an OTC sunscreen active ingredient as GRASE.¹¹ It also provided detailed information about both clinical and nonclinical safety testing, including human irritation and sensitization studies as well as human photosafety studies. In vitro dermal and systemic carcinogenicity studies and animal developmental and reproductive toxicity studies also were required as well studies regarding safety in children.

Many of these recommendations were already being utilized by manufacturers; however, one important change was the requirement for human absorption studies by a maximal usage trial, which more accurately addresses the absorption of sunscreen agents according to actual use. Such studies will be required at the highest allowable concentration of an agent in multiple vehicles and over large body surface areas for considerable exposure times.

This guidance to sunscreen manufacturers was announced to the public in a press release in May 2018.¹²

What are the new regulations?

All of this has culminated in the recent proposed rule, which includes several important proposals²:

• Of the 16 currently marketed active sunscreen ingredients, only 2—zinc oxide and titanium dioxide—are considered GRASE. Two ingredients—trolamine salicylate and para-aminobenzoic acid—are considered non-GRASE, but there is not enough information at this time to determine if the remaining 12 ingredients are GRASE. The FDA is working with manufacturers to obtain sufficient information to make this determination.

• Approved dosage formulations include sprays, oils, lotions, creams, gels, butters, pastes, ointments, and sticks. Further information is needed regarding powders before they can be considered.

• The maximum SPF will be increased from 50+ to 60+.

• Sunscreens with an SPF of 15 or higher are required to provide broad-spectrum protection commensurate with the SPF, expanding on critical wavelength testing.

• There are new labeling changes, including a requirement that active ingredients be listed on the front of the packaging.
• Sunscreen products that contain insect repellents are considered non-GRASE.

What’s next?

The process for the proposed final rule has now entered a 90-day public comment period that will end on May 27, 2019; however, it is unlikely that a final monograph as mandated by Congress will be produced by the end of this year.

Sunscreen manufacturers currently are coordinating a response to the proposed rule through the Personal Care Products Council and the Consumer Healthcare Products Association Sunscreen Task Force. It is likely that the new required testing will be costly, with estimates exceeding tens or even hundreds of millions of dollars. In all likelihood, the number of active ingredients that the industry will agree to support with costly testing will be fewer than the 12 that are now on the list. It also is likely that this process will lead to fewer sunscreen products for consumers to choose from and almost certainly at a higher cost.

What do we tell patients in the meantime?

According to the FDA’s rules, it was necessary that this process was made public, but it will almost certainly concern our patients as to the safety of the sunscreen products they have been using. We should be concerned that some of our patients may limit their use of sunscreens because of safety concerns.

There is no question that, as physicians, we want to “first, do no harm,” so we should all be interested in assuring our patients that our sunscreen recommendations are safe and we support the FDA proposal for additional data. The good news is that when this process is completed, a large number of agents will likely be found to be GRASE. When the FDA finally gives its imprimatur to sunscreens, it will hopefully help to silence those naysayers who report that sunscreens are dangerous for consumers; however, it has been suggested by some in industry that the new testing required may take at least 5 years.

What should dermatologists do when we are asked, “What sunscreen should I use NOW?” For most patients, I would explain the regulatory process and assure them that the risk-benefit ratio at this point suggests they should continue using the same sunscreens that they are currently using. For special situations such as pregnant women and children, it may be best to suggest products that contain only the 2 GRASE inorganic agents.

If by now you have not had a patient ask, “Doctor, what sunscreen should I use NOW?” you will soon.

The US Food and Drug Administration (FDA) recently published a press release detailing a proposed rule on how manufacturers will be required to test and label sunscreens in the United States.^1,2 Although the press release was complicated and contained much information, the media specifically latched onto the FDA’s consideration of only 2 active sunscreen ingredients—zinc oxide and titanium dioxide—as generally recognized as safe and effective (GRASE). In response, some patients may assume that most sunscreens on the market are dangerous.

How did this new proposed rule come about? To understand the process, it takes some explanation of the history of the FDA’s regulation of sunscreens.

How are sunscreens regulated by the FDA?

The regulatory process for sunscreens in the United States is complicated. The FDA regulates sunscreens as over-the-counter (OTC) drugs rather than as cosmetics, which is how they are regulated in most of the rest of the world.

The US sunscreen regulation process began in 1978 with an advance notice of proposed rulemaking from the FDA that included recommendations from an advisory review panel on the safe and effective use of OTC sunscreen products.³ At that time, 21 active sunscreen ingredients and their maximum use concentrations were listed and determined to be safe, or GRASE. It also gave manufacturers guidance on how to test for efficacy with the methodology for determining the sun protection factor (SPF) as well as various labeling requirements. Over the years, the FDA has issued a number of other sunscreen guidelines, such as removing padimate A and adding avobenzone and zinc oxide to the list of GRASE ingredients in the 1990s.^4,5

In 1999, the FDA issued a final rule that listed 16 active sunscreen ingredients and concentrations as GRASE.⁶ There were some restrictions as to certain combinations of ingredients that could not be used in a finished product. Labeling requirements, including a maximum SPF of 30, also were put in place. This final rule established a final sunscreen monograph that was supposed to have been effective by 2002; however, in 2001 the agency delayed the effective date indefinitely because they had not yet established broad-spectrum (UVA) protection testing and labeling.⁷

The FDA published a proposed rule in 2007 as well as a final rule in 2011 that again listed the same 16 ingredients as GRASE and specified labeling and testing methods for establishing SPF, broad-spectrum protection, and water-resistance claims.^8,9 The final rule limited product labels to a maximum SPF of 50+; provided directions for use with regard to other labeling elements (eg, warnings); and identified specific claims that would not be allowed on product labels, such as “waterproof” and “all-day protection.”⁹

Nevertheless, an effective final OTC monograph for sunscreen products has not yet been published.

What is the Sunscreen Innovation Act?

In 2014, the US Congress enacted the Sunscreen Innovation Act¹⁰ primarily to mandate that the FDA develop a more efficient way to determine the safety and efficacy of new active sunscreen ingredients that were commonly used in Europe and other parts of the world at the time. Many of these agents were thought to be more protective in the UVA and/or UVB spectrum, and if added to the list of GRASE ingredients available to US manufacturers, they would lead to the development of products that would improve the protection offered by sunscreens marketed to US consumers. The time and extent application (TEA) was established, a method that allowed manufacturers to apply for FDA approval of specific agents. The TEA also suggested allowing data generated in other countries where these agents were already in use for years to be considered in the FDA’s evaluation of the agents as GRASE. In addition, Congress mandated that a final monograph on OTC sunscreens be published by the end of 2019. A number of manufacturers have submitted TEAs for new active sunscreen ingredients, and so far, all have been rejected.

Why is the FDA interested in more safety data?

Since then, the FDA has become concerned not only with the safety and efficacy of newly proposed agents through the TEA but also with the original 16 active sunscreen ingredients listed as GRASE in the 2011 final rule. In the 1970s and 1980s, sunscreen use was limited to beach vacations or outdoor sporting events, but sun-protective behaviors have changed dramatically since that time, with health care providers now becoming cognizant of the growing threats of skin cancer and melanoma as well as the cosmetic concerns of photoaging, thereby recommending daily sunscreen use to their patients. In addition, the science behind sunscreens with higher concentrations of active ingredients intended to achieve higher and higher SPFs and their respective penetration of the skin has evolved, leading to new concerns about systemic toxicity. Early limited research frequently touted by the lay media has suggested that some of these agents might lead to hormonal changes, reproductive toxicity, and carcinogenicity.

In November 2016, the FDA issued a guidance for manufacturers that outlined the safety data that would be required to establish an OTC sunscreen active ingredient as GRASE.¹¹ It also provided detailed information about both clinical and nonclinical safety testing, including human irritation and sensitization studies as well as human photosafety studies. In vitro dermal and systemic carcinogenicity studies and animal developmental and reproductive toxicity studies also were required as well studies regarding safety in children.

Many of these recommendations were already being utilized by manufacturers; however, one important change was the requirement for human absorption studies by a maximal usage trial, which more accurately addresses the absorption of sunscreen agents according to actual use. Such studies will be required at the highest allowable concentration of an agent in multiple vehicles and over large body surface areas for considerable exposure times.

This guidance to sunscreen manufacturers was announced to the public in a press release in May 2018.¹²

What are the new regulations?

All of this has culminated in the recent proposed rule, which includes several important proposals²:

• Of the 16 currently marketed active sunscreen ingredients, only 2—zinc oxide and titanium dioxide—are considered GRASE. Two ingredients—trolamine salicylate and para-aminobenzoic acid—are considered non-GRASE, but there is not enough information at this time to determine if the remaining 12 ingredients are GRASE. The FDA is working with manufacturers to obtain sufficient information to make this determination.

• Approved dosage formulations include sprays, oils, lotions, creams, gels, butters, pastes, ointments, and sticks. Further information is needed regarding powders before they can be considered.

• The maximum SPF will be increased from 50+ to 60+.

• Sunscreens with an SPF of 15 or higher are required to provide broad-spectrum protection commensurate with the SPF, expanding on critical wavelength testing.

• There are new labeling changes, including a requirement that active ingredients be listed on the front of the packaging.
• Sunscreen products that contain insect repellents are considered non-GRASE.

What’s next?

The process for the proposed final rule has now entered a 90-day public comment period that will end on May 27, 2019; however, it is unlikely that a final monograph as mandated by Congress will be produced by the end of this year.

Sunscreen manufacturers currently are coordinating a response to the proposed rule through the Personal Care Products Council and the Consumer Healthcare Products Association Sunscreen Task Force. It is likely that the new required testing will be costly, with estimates exceeding tens or even hundreds of millions of dollars. In all likelihood, the number of active ingredients that the industry will agree to support with costly testing will be fewer than the 12 that are now on the list. It also is likely that this process will lead to fewer sunscreen products for consumers to choose from and almost certainly at a higher cost.

What do we tell patients in the meantime?

According to the FDA’s rules, it was necessary that this process was made public, but it will almost certainly concern our patients as to the safety of the sunscreen products they have been using. We should be concerned that some of our patients may limit their use of sunscreens because of safety concerns.

There is no question that, as physicians, we want to “first, do no harm,” so we should all be interested in assuring our patients that our sunscreen recommendations are safe and we support the FDA proposal for additional data. The good news is that when this process is completed, a large number of agents will likely be found to be GRASE. When the FDA finally gives its imprimatur to sunscreens, it will hopefully help to silence those naysayers who report that sunscreens are dangerous for consumers; however, it has been suggested by some in industry that the new testing required may take at least 5 years.

What should dermatologists do when we are asked, “What sunscreen should I use NOW?” For most patients, I would explain the regulatory process and assure them that the risk-benefit ratio at this point suggests they should continue using the same sunscreens that they are currently using. For special situations such as pregnant women and children, it may be best to suggest products that contain only the 2 GRASE inorganic agents.

Sézary syndrome (SS) is an advanced leukemic form of cutaneous T-cell lymphoma (CTCL) that is characterized by generalized erythroderma and T-cell leukemia. Skin changes can include erythroderma, keratosis pilaris–like lesions, keratoderma, ectropion, alopecia, and nail changes.¹ Nail changes in SS patients frequently are overlooked and underreported; they vary greatly from patient to patient, and their incidence has not been widely evaluated in the literature.

In this retrospective study, we reviewed medical records from a previously collected CTCL clinic database at the University of Texas MD Anderson Cancer Center (Houston, Texas) and found nail abnormalities in 36 of 83 (43.4%) patients with a diagnosis of SS. Findings for 2 select cases are described in more detail; they were compared to prior case reports from the literature to establish a comprehensive list of nail irregularities that have been associated with SS.

Methods

We examined records from a previously collected CTCL clinic database at the University of Texas MD Anderson Cancer Center. This database was part of an institutional review board–approved protocol to prospectively collect data from patients with CTCL. Our search yielded 83 patients with SS who were seen between 2007 and 2014.

Results

Of the 83 cases reviewed from the CTCL database, 36 (43.4%) SS patients reported at least 1 nail abnormality on the fingernails or toenails. Patients ranged in age from 59 to 85 years and included 27 (75%) men and 9 (25%) women. Nail irregularities noted on physical examination are summarized in Table 1. More than half of the patients presented with nail thickening (58.3% [21/36]), dystrophy (55.6% [20/36]), or yellowing (55.6% [20/36]) of 1 or more nails. Other findings included 15 (41.7%) patients with subungual hyperkeratosis, 3 (8.3%) with Beau lines, and 1 (2.8%) with multiple oil spots consistent with salmon patches. Five (13.9%) patients had only 1 reported nail irregularity, and 1 (2.8%) patient had 6 irregularities. The average number of nail abnormalities per patient was 2.88 (range, 1–6). We selected 2 patients with extensive nail findings who represent the spectrum of nail findings in patients with SS.

Patient 1
A 71-year-old white man presented with a papular rash of 30 years’ duration. The eruption first occurred on the soles of the feet but progressed to generalized erythroderma. He was found to be colonized with methicillin-resistant Staphylococcus aureus. Over the next 9 months, the patient was diagnosed with SS at an outside institution and was treated with cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, gemcitabine, etoposide, methylprednisolone, cytarabine, cisplatin, topical steroids, and intravenous methotrexate with no apparent improvement. At presentation to our institution, physical examination revealed pruritus; alopecia; generalized lymphadenopathy; erythroderma; and irregular nail findings, including yellowing, thickened fingernails and toenails with subungual debris, and splinter hemorrhage (Figure 1). A thick plaque with perioral distribution as well as erosions on the face and feet were noted. The total body surface area (BSA) affected was 100% (patches, 91%; plaques, 9%).

At diagnosis at our institution, the patient’s white blood cell (WBC) count was 17,800/µL (reference range, 4000–11,000/µL), with 11% Sézary cells noted. Biopsy of a lymph node from the inguinal area indicated T-cell lymphoma with clonal T-cell receptor (TCR) β gene rearrangement. Biopsy of lesional skin in the right groin area showed an atypical T-cell lymphocytic infiltrate with a CD4:CD8 ratio of 2.9:1 and partial loss of CD7 expression, consistent with mycosis fungoides (MF)/SS stage IVA. At presentation to our institution, the WBC count was 12,700/µL with a neutrophil count of 47% (reference range, 42%–66%), lymphocyte count of 36% (reference range, 24%–44%), monocyte count of 4% (reference range, 2%–7%), platelet count of 427,000/µL (reference range, 150,000–350,000/µL), hemoglobin of 9.9 g/dL (reference range, 14.0–17.5 g/dL), and lactate dehydrogenase of 733 U/L (reference range, 135–214 U/L). Lymphocytes were positive for CD2, CD3, CD4, CD5, CD25, CD52, TCRα, TCRβ, and TCR VB17; partial for CD26; and negative for CD7, CD8, and CD57. At follow-up 1 month later, the CD4⁺CD26⁻ T-cell population was 56%, which was consistent with SS T-cell lymphoma.

Skin scrapings from the generalized keratoderma on the patient’s feet were positive for fungal hyphae under potassium hydroxide examination. Nail clippings showed compact keratin with periodic acid–Schiff–positive small yeast forms admixed with bacterial organisms, consistent with onychomycosis. At our institution, the patient received extracorporeal photopheresis, whirlpool therapy (a type of hydrotherapy), steroid wet wraps, and intravenous vancomycin for methicillin-resistant S aureus. He also received bexarotene, levothyroxine sodium, and fenofibrate. After antibiotics and 2 sessions of photopheresis, the total BSA improved from 100% to 33%. The feet and nails were treated with ciclopirox gel and terbinafine, but neither the keratoderma nor the nails improved.

Patient 2
An 84-year-old white man with B-cell chronic lymphocytic leukemia also was diagnosed with SS at an outside institution. One year later, he presented to our institution with mild pruritus and swelling of the lower left leg, which was diagnosed as deep vein thrombosis. There was bilateral scaling of the palms, with fissures present on the left palm. The fingernails showed dystrophy with Beau lines, and the toenails were dystrophic with onycholysis on the bilateral great toes (Figure 2). Patches were noted on most of the body, including the feet, with plaques limited to the hands; the total BSA affected was 80%. Flow cytometry showed an elevated Sézary cell count (CD4⁺CD26⁻) of 4700 cells/µL. Complete blood cell count with differential included a hemoglobin level of 11.4 g/dL, hematocrit level of 35.3% (reference range, 37%–47%), a platelet count of 217,000/µL, and a WBC count of 17,700/µL, of which 29% were neutrophils, 63% were lymphocytes, 6% were monocytes, and 2% were eosinophils. The lactate dehydrogenase level was elevated at 829 U/L. The patient had not been treated for chronic lymphocytic leukemia in the last 11 months due to adverse reactions to rituximab after 2 cycles of fludarabine, cyclophosphamide, and rituximab chemotherapy. First-line therapy for the patient was photopheresis for SS.

Comment

Nail changes are found in many cases of advanced-stage SS but rarely have been reported in the literature. A literature review of PubMed articles indexed for MEDLINE was conducted using the search terms Sézary, nail, onychodystrophy, cutaneous T-cell lymphoma, and CTCL. All results were reviewed for original reported cases of SS with at least 1 reported nail finding. A total of 7 reports^2-8 met these requirements with a total of 43 SS patients with reported nail findings, which are summarized in Tables 2 and 3.

Our findings are generally consistent with those previously described in the literature. Nail thickening, yellowing, subungual hyperkeratosis, dystrophy, and onycholysis are consistently some of the most common nail findings in patients with SS. In 2012, Martin and Duvic⁹ found that 52.9% (45/85) of SS patients with keratoderma on physical examination were positive for dermatophyte hyphae when skin scrapings were done under potassium hydroxide examination, a considerably greater incidence than in the general population (10%–20%). The nail changes seen in our SS patients were identical to those found in dermatophyte infections, including discoloration, subungual debris, nail thickening, onycholysis, and dystrophy.¹⁰ In patient 1, nail clippings were positive for onychomycosis, a common nail condition that is especially prevalent in older or immunocompromised patients.^9,10

Interestingly, findings not observed in the literature included salmon patches and Beau lines. Beau lines are horizontal depressions in the nail plate and often are indicative of temporary interruption of nail growth, such as due to an underlying disease process, severe illness, and/or chemotherapy.^11,12 In our review, patient 2 had clinical findings of Beau lines. Because the average time for fingernail regrowth is 3 to 6 months,¹³ it is reasonable to assume that physical findings associated with fludarabine, cyclophosphamide, and rituximab chemotherapy treatment would no longer be demonstrated 11 months after completion of therapy. On the other hand, paronychia was frequently observed by Damasco et al⁸ (63.2% [12/19] of their cases), yet it was not found in our database or the other literature reports we reviewed. Perhaps these differences are due to differences in patient populations and/or available therapies, lack of documentation, or small sample size and limited reports in the literature.

A common question is: Are the nail irregularities caused by the physical symptoms of advanced CTCL or by the underlying disease process in response to the atypical T cells? Erythroderma has been speculated to cause many of the clinical findings of nail abnormalities found in CTCL patients.^2,3 However, Fleming et al¹⁴ described an MF patient who experienced onychomadesis without erythroderma, which suggests that a different mechanism may cause these nail changes. The wide range of nail abnormalities in CTCL can cause problems with diagnosing the specific cause underlying the nail alteration.

To further complicate the issue, numerous therapies for CTCL also may cause nail changes, such as the previously described Beau lines. In 2010, Parmentier et al⁴ reported a patient with nail alterations that had been present for more than 1 year, with 9 of 10 fingernails demonstrating anonychia, onychomadesis, subungual distal hyperkeratosis, and onycholysis. In this case report, the authors were able to exclude phototherapy as the cause of onycholysis (visible separation of the nail plate from the nail bed) and other clinical nail findings in the SS patient based on the onset of nail changes prior to beginning psoralen plus UVA therapy and complete sparing of 1 finger.⁴ The findings in our patient 1, who had no history of psoralen plus UVA therapy at the time the irregular nail findings presented, supports this observation. Total skin electron beam therapy for MF also has been reported to cause temporary nail stasis and thus must be taken into account when considering nail changes in patients with MF/SS.¹⁵

A nail matrix biopsy may provide clues to the definitive cause of the clinically observed nail changes; however, this procedure typically is not performed due to patient concerns of postoperative complications including pain and nail dystrophy.¹⁶ Histopathology features were similar in reported nail biopsies of 2 SS patients.^3,4 Tosti et al³ reported that longitudinal biopsy showed a dense lymphocytic infiltrate of atypical lymphocytes with involuted nuclei and notable epidermotropism. Parmentier et al⁴ reported a longitudinal nail biopsy in an SS patient that presented with atypical lymphocytes, epidermotropism, and Pautrier microabscess formation. Immunostaining showed CD3 positivity within the distal nail matrix, nail bed, and hyponychium. One-third of the cells stained positive for CD4, while the majority stained positive for CD8. Most notably, the skin, nails, and blood showed identical clonal rearrangement of TCRγ.⁴ Nail matrix biopsies in MF patients rarely have been reported in the literature, but those that are available show similar features to those seen in SS patients. Harland et al¹⁷ summarized the findings of 4 case reports of CTCL patients that included nail biopsies by stating, “[a]ll histopathologic findings from nail biopsies showed a dense subepithelial infiltrate of lymphocytes with marked epitheliotropism.” These histopathologic abnormalities are akin to skin biopsies in MF patients, thus providing an essential link to the disease state of MF and the nail abnormalities found within SS patients.

Treatment of the nail problems found within SS is challenging due to limited research. Parmentier et al⁴ noted an SS patient who was treated with topical mechlorethamine applied directly to the nail. In this case, topical mechlorethamine was effective at treating onychomadesis, subungual distal hyperkeratosis, and onycholysis within 6 months.⁴ Another SS patient, who presented with thickening and yellowing of the nail, had reported a proximal nail plate that resolved after chemotherapy. The patient did not survive long enough to note complete improvement of the nail.³ In our study, patient 1 was treated with ciclopirox gel and terbinafine, which did not result in nail improvement. Nail treatments in SS patients have yet to show much improvement and thus need more research and focus in the literature.

Conclusion

Sézary syndrome is a rare CTCL that can present with clinical features that may be mistaken for other diseases. Nail abnormalities in SS patients may be related to fungal involvement, medical therapy, or the underlying disease process of SS. We report one of the largest populations of SS patients with specific reported nail abnormalities, thus expanding the possibilities of nail changes that accompany the disease. Continued research and studies involving SS can provide a better understanding of nail involvement and successful treatment of these clinical findings.

Sézary syndrome (SS) is an advanced leukemic form of cutaneous T-cell lymphoma (CTCL) that is characterized by generalized erythroderma and T-cell leukemia. Skin changes can include erythroderma, keratosis pilaris–like lesions, keratoderma, ectropion, alopecia, and nail changes.¹ Nail changes in SS patients frequently are overlooked and underreported; they vary greatly from patient to patient, and their incidence has not been widely evaluated in the literature.

In this retrospective study, we reviewed medical records from a previously collected CTCL clinic database at the University of Texas MD Anderson Cancer Center (Houston, Texas) and found nail abnormalities in 36 of 83 (43.4%) patients with a diagnosis of SS. Findings for 2 select cases are described in more detail; they were compared to prior case reports from the literature to establish a comprehensive list of nail irregularities that have been associated with SS.

Methods

We examined records from a previously collected CTCL clinic database at the University of Texas MD Anderson Cancer Center. This database was part of an institutional review board–approved protocol to prospectively collect data from patients with CTCL. Our search yielded 83 patients with SS who were seen between 2007 and 2014.

Results

Of the 83 cases reviewed from the CTCL database, 36 (43.4%) SS patients reported at least 1 nail abnormality on the fingernails or toenails. Patients ranged in age from 59 to 85 years and included 27 (75%) men and 9 (25%) women. Nail irregularities noted on physical examination are summarized in Table 1. More than half of the patients presented with nail thickening (58.3% [21/36]), dystrophy (55.6% [20/36]), or yellowing (55.6% [20/36]) of 1 or more nails. Other findings included 15 (41.7%) patients with subungual hyperkeratosis, 3 (8.3%) with Beau lines, and 1 (2.8%) with multiple oil spots consistent with salmon patches. Five (13.9%) patients had only 1 reported nail irregularity, and 1 (2.8%) patient had 6 irregularities. The average number of nail abnormalities per patient was 2.88 (range, 1–6). We selected 2 patients with extensive nail findings who represent the spectrum of nail findings in patients with SS.

Patient 1
A 71-year-old white man presented with a papular rash of 30 years’ duration. The eruption first occurred on the soles of the feet but progressed to generalized erythroderma. He was found to be colonized with methicillin-resistant Staphylococcus aureus. Over the next 9 months, the patient was diagnosed with SS at an outside institution and was treated with cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, gemcitabine, etoposide, methylprednisolone, cytarabine, cisplatin, topical steroids, and intravenous methotrexate with no apparent improvement. At presentation to our institution, physical examination revealed pruritus; alopecia; generalized lymphadenopathy; erythroderma; and irregular nail findings, including yellowing, thickened fingernails and toenails with subungual debris, and splinter hemorrhage (Figure 1). A thick plaque with perioral distribution as well as erosions on the face and feet were noted. The total body surface area (BSA) affected was 100% (patches, 91%; plaques, 9%).

At diagnosis at our institution, the patient’s white blood cell (WBC) count was 17,800/µL (reference range, 4000–11,000/µL), with 11% Sézary cells noted. Biopsy of a lymph node from the inguinal area indicated T-cell lymphoma with clonal T-cell receptor (TCR) β gene rearrangement. Biopsy of lesional skin in the right groin area showed an atypical T-cell lymphocytic infiltrate with a CD4:CD8 ratio of 2.9:1 and partial loss of CD7 expression, consistent with mycosis fungoides (MF)/SS stage IVA. At presentation to our institution, the WBC count was 12,700/µL with a neutrophil count of 47% (reference range, 42%–66%), lymphocyte count of 36% (reference range, 24%–44%), monocyte count of 4% (reference range, 2%–7%), platelet count of 427,000/µL (reference range, 150,000–350,000/µL), hemoglobin of 9.9 g/dL (reference range, 14.0–17.5 g/dL), and lactate dehydrogenase of 733 U/L (reference range, 135–214 U/L). Lymphocytes were positive for CD2, CD3, CD4, CD5, CD25, CD52, TCRα, TCRβ, and TCR VB17; partial for CD26; and negative for CD7, CD8, and CD57. At follow-up 1 month later, the CD4⁺CD26⁻ T-cell population was 56%, which was consistent with SS T-cell lymphoma.

Skin scrapings from the generalized keratoderma on the patient’s feet were positive for fungal hyphae under potassium hydroxide examination. Nail clippings showed compact keratin with periodic acid–Schiff–positive small yeast forms admixed with bacterial organisms, consistent with onychomycosis. At our institution, the patient received extracorporeal photopheresis, whirlpool therapy (a type of hydrotherapy), steroid wet wraps, and intravenous vancomycin for methicillin-resistant S aureus. He also received bexarotene, levothyroxine sodium, and fenofibrate. After antibiotics and 2 sessions of photopheresis, the total BSA improved from 100% to 33%. The feet and nails were treated with ciclopirox gel and terbinafine, but neither the keratoderma nor the nails improved.

Patient 2
An 84-year-old white man with B-cell chronic lymphocytic leukemia also was diagnosed with SS at an outside institution. One year later, he presented to our institution with mild pruritus and swelling of the lower left leg, which was diagnosed as deep vein thrombosis. There was bilateral scaling of the palms, with fissures present on the left palm. The fingernails showed dystrophy with Beau lines, and the toenails were dystrophic with onycholysis on the bilateral great toes (Figure 2). Patches were noted on most of the body, including the feet, with plaques limited to the hands; the total BSA affected was 80%. Flow cytometry showed an elevated Sézary cell count (CD4⁺CD26⁻) of 4700 cells/µL. Complete blood cell count with differential included a hemoglobin level of 11.4 g/dL, hematocrit level of 35.3% (reference range, 37%–47%), a platelet count of 217,000/µL, and a WBC count of 17,700/µL, of which 29% were neutrophils, 63% were lymphocytes, 6% were monocytes, and 2% were eosinophils. The lactate dehydrogenase level was elevated at 829 U/L. The patient had not been treated for chronic lymphocytic leukemia in the last 11 months due to adverse reactions to rituximab after 2 cycles of fludarabine, cyclophosphamide, and rituximab chemotherapy. First-line therapy for the patient was photopheresis for SS.

Comment

Nail changes are found in many cases of advanced-stage SS but rarely have been reported in the literature. A literature review of PubMed articles indexed for MEDLINE was conducted using the search terms Sézary, nail, onychodystrophy, cutaneous T-cell lymphoma, and CTCL. All results were reviewed for original reported cases of SS with at least 1 reported nail finding. A total of 7 reports^2-8 met these requirements with a total of 43 SS patients with reported nail findings, which are summarized in Tables 2 and 3.

Our findings are generally consistent with those previously described in the literature. Nail thickening, yellowing, subungual hyperkeratosis, dystrophy, and onycholysis are consistently some of the most common nail findings in patients with SS. In 2012, Martin and Duvic⁹ found that 52.9% (45/85) of SS patients with keratoderma on physical examination were positive for dermatophyte hyphae when skin scrapings were done under potassium hydroxide examination, a considerably greater incidence than in the general population (10%–20%). The nail changes seen in our SS patients were identical to those found in dermatophyte infections, including discoloration, subungual debris, nail thickening, onycholysis, and dystrophy.¹⁰ In patient 1, nail clippings were positive for onychomycosis, a common nail condition that is especially prevalent in older or immunocompromised patients.^9,10

Interestingly, findings not observed in the literature included salmon patches and Beau lines. Beau lines are horizontal depressions in the nail plate and often are indicative of temporary interruption of nail growth, such as due to an underlying disease process, severe illness, and/or chemotherapy.^11,12 In our review, patient 2 had clinical findings of Beau lines. Because the average time for fingernail regrowth is 3 to 6 months,¹³ it is reasonable to assume that physical findings associated with fludarabine, cyclophosphamide, and rituximab chemotherapy treatment would no longer be demonstrated 11 months after completion of therapy. On the other hand, paronychia was frequently observed by Damasco et al⁸ (63.2% [12/19] of their cases), yet it was not found in our database or the other literature reports we reviewed. Perhaps these differences are due to differences in patient populations and/or available therapies, lack of documentation, or small sample size and limited reports in the literature.

A common question is: Are the nail irregularities caused by the physical symptoms of advanced CTCL or by the underlying disease process in response to the atypical T cells? Erythroderma has been speculated to cause many of the clinical findings of nail abnormalities found in CTCL patients.^2,3 However, Fleming et al¹⁴ described an MF patient who experienced onychomadesis without erythroderma, which suggests that a different mechanism may cause these nail changes. The wide range of nail abnormalities in CTCL can cause problems with diagnosing the specific cause underlying the nail alteration.

To further complicate the issue, numerous therapies for CTCL also may cause nail changes, such as the previously described Beau lines. In 2010, Parmentier et al⁴ reported a patient with nail alterations that had been present for more than 1 year, with 9 of 10 fingernails demonstrating anonychia, onychomadesis, subungual distal hyperkeratosis, and onycholysis. In this case report, the authors were able to exclude phototherapy as the cause of onycholysis (visible separation of the nail plate from the nail bed) and other clinical nail findings in the SS patient based on the onset of nail changes prior to beginning psoralen plus UVA therapy and complete sparing of 1 finger.⁴ The findings in our patient 1, who had no history of psoralen plus UVA therapy at the time the irregular nail findings presented, supports this observation. Total skin electron beam therapy for MF also has been reported to cause temporary nail stasis and thus must be taken into account when considering nail changes in patients with MF/SS.¹⁵

A nail matrix biopsy may provide clues to the definitive cause of the clinically observed nail changes; however, this procedure typically is not performed due to patient concerns of postoperative complications including pain and nail dystrophy.¹⁶ Histopathology features were similar in reported nail biopsies of 2 SS patients.^3,4 Tosti et al³ reported that longitudinal biopsy showed a dense lymphocytic infiltrate of atypical lymphocytes with involuted nuclei and notable epidermotropism. Parmentier et al⁴ reported a longitudinal nail biopsy in an SS patient that presented with atypical lymphocytes, epidermotropism, and Pautrier microabscess formation. Immunostaining showed CD3 positivity within the distal nail matrix, nail bed, and hyponychium. One-third of the cells stained positive for CD4, while the majority stained positive for CD8. Most notably, the skin, nails, and blood showed identical clonal rearrangement of TCRγ.⁴ Nail matrix biopsies in MF patients rarely have been reported in the literature, but those that are available show similar features to those seen in SS patients. Harland et al¹⁷ summarized the findings of 4 case reports of CTCL patients that included nail biopsies by stating, “[a]ll histopathologic findings from nail biopsies showed a dense subepithelial infiltrate of lymphocytes with marked epitheliotropism.” These histopathologic abnormalities are akin to skin biopsies in MF patients, thus providing an essential link to the disease state of MF and the nail abnormalities found within SS patients.

Treatment of the nail problems found within SS is challenging due to limited research. Parmentier et al⁴ noted an SS patient who was treated with topical mechlorethamine applied directly to the nail. In this case, topical mechlorethamine was effective at treating onychomadesis, subungual distal hyperkeratosis, and onycholysis within 6 months.⁴ Another SS patient, who presented with thickening and yellowing of the nail, had reported a proximal nail plate that resolved after chemotherapy. The patient did not survive long enough to note complete improvement of the nail.³ In our study, patient 1 was treated with ciclopirox gel and terbinafine, which did not result in nail improvement. Nail treatments in SS patients have yet to show much improvement and thus need more research and focus in the literature.

Conclusion

Sézary syndrome is a rare CTCL that can present with clinical features that may be mistaken for other diseases. Nail abnormalities in SS patients may be related to fungal involvement, medical therapy, or the underlying disease process of SS. We report one of the largest populations of SS patients with specific reported nail abnormalities, thus expanding the possibilities of nail changes that accompany the disease. Continued research and studies involving SS can provide a better understanding of nail involvement and successful treatment of these clinical findings.

Sézary syndrome (SS) is an advanced leukemic form of cutaneous T-cell lymphoma (CTCL) that is characterized by generalized erythroderma and T-cell leukemia. Skin changes can include erythroderma, keratosis pilaris–like lesions, keratoderma, ectropion, alopecia, and nail changes.¹ Nail changes in SS patients frequently are overlooked and underreported; they vary greatly from patient to patient, and their incidence has not been widely evaluated in the literature.

In this retrospective study, we reviewed medical records from a previously collected CTCL clinic database at the University of Texas MD Anderson Cancer Center (Houston, Texas) and found nail abnormalities in 36 of 83 (43.4%) patients with a diagnosis of SS. Findings for 2 select cases are described in more detail; they were compared to prior case reports from the literature to establish a comprehensive list of nail irregularities that have been associated with SS.

Methods

We examined records from a previously collected CTCL clinic database at the University of Texas MD Anderson Cancer Center. This database was part of an institutional review board–approved protocol to prospectively collect data from patients with CTCL. Our search yielded 83 patients with SS who were seen between 2007 and 2014.

Results

Of the 83 cases reviewed from the CTCL database, 36 (43.4%) SS patients reported at least 1 nail abnormality on the fingernails or toenails. Patients ranged in age from 59 to 85 years and included 27 (75%) men and 9 (25%) women. Nail irregularities noted on physical examination are summarized in Table 1. More than half of the patients presented with nail thickening (58.3% [21/36]), dystrophy (55.6% [20/36]), or yellowing (55.6% [20/36]) of 1 or more nails. Other findings included 15 (41.7%) patients with subungual hyperkeratosis, 3 (8.3%) with Beau lines, and 1 (2.8%) with multiple oil spots consistent with salmon patches. Five (13.9%) patients had only 1 reported nail irregularity, and 1 (2.8%) patient had 6 irregularities. The average number of nail abnormalities per patient was 2.88 (range, 1–6). We selected 2 patients with extensive nail findings who represent the spectrum of nail findings in patients with SS.

Patient 1
A 71-year-old white man presented with a papular rash of 30 years’ duration. The eruption first occurred on the soles of the feet but progressed to generalized erythroderma. He was found to be colonized with methicillin-resistant Staphylococcus aureus. Over the next 9 months, the patient was diagnosed with SS at an outside institution and was treated with cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone, gemcitabine, etoposide, methylprednisolone, cytarabine, cisplatin, topical steroids, and intravenous methotrexate with no apparent improvement. At presentation to our institution, physical examination revealed pruritus; alopecia; generalized lymphadenopathy; erythroderma; and irregular nail findings, including yellowing, thickened fingernails and toenails with subungual debris, and splinter hemorrhage (Figure 1). A thick plaque with perioral distribution as well as erosions on the face and feet were noted. The total body surface area (BSA) affected was 100% (patches, 91%; plaques, 9%).

At diagnosis at our institution, the patient’s white blood cell (WBC) count was 17,800/µL (reference range, 4000–11,000/µL), with 11% Sézary cells noted. Biopsy of a lymph node from the inguinal area indicated T-cell lymphoma with clonal T-cell receptor (TCR) β gene rearrangement. Biopsy of lesional skin in the right groin area showed an atypical T-cell lymphocytic infiltrate with a CD4:CD8 ratio of 2.9:1 and partial loss of CD7 expression, consistent with mycosis fungoides (MF)/SS stage IVA. At presentation to our institution, the WBC count was 12,700/µL with a neutrophil count of 47% (reference range, 42%–66%), lymphocyte count of 36% (reference range, 24%–44%), monocyte count of 4% (reference range, 2%–7%), platelet count of 427,000/µL (reference range, 150,000–350,000/µL), hemoglobin of 9.9 g/dL (reference range, 14.0–17.5 g/dL), and lactate dehydrogenase of 733 U/L (reference range, 135–214 U/L). Lymphocytes were positive for CD2, CD3, CD4, CD5, CD25, CD52, TCRα, TCRβ, and TCR VB17; partial for CD26; and negative for CD7, CD8, and CD57. At follow-up 1 month later, the CD4⁺CD26⁻ T-cell population was 56%, which was consistent with SS T-cell lymphoma.

Skin scrapings from the generalized keratoderma on the patient’s feet were positive for fungal hyphae under potassium hydroxide examination. Nail clippings showed compact keratin with periodic acid–Schiff–positive small yeast forms admixed with bacterial organisms, consistent with onychomycosis. At our institution, the patient received extracorporeal photopheresis, whirlpool therapy (a type of hydrotherapy), steroid wet wraps, and intravenous vancomycin for methicillin-resistant S aureus. He also received bexarotene, levothyroxine sodium, and fenofibrate. After antibiotics and 2 sessions of photopheresis, the total BSA improved from 100% to 33%. The feet and nails were treated with ciclopirox gel and terbinafine, but neither the keratoderma nor the nails improved.

Patient 2
An 84-year-old white man with B-cell chronic lymphocytic leukemia also was diagnosed with SS at an outside institution. One year later, he presented to our institution with mild pruritus and swelling of the lower left leg, which was diagnosed as deep vein thrombosis. There was bilateral scaling of the palms, with fissures present on the left palm. The fingernails showed dystrophy with Beau lines, and the toenails were dystrophic with onycholysis on the bilateral great toes (Figure 2). Patches were noted on most of the body, including the feet, with plaques limited to the hands; the total BSA affected was 80%. Flow cytometry showed an elevated Sézary cell count (CD4⁺CD26⁻) of 4700 cells/µL. Complete blood cell count with differential included a hemoglobin level of 11.4 g/dL, hematocrit level of 35.3% (reference range, 37%–47%), a platelet count of 217,000/µL, and a WBC count of 17,700/µL, of which 29% were neutrophils, 63% were lymphocytes, 6% were monocytes, and 2% were eosinophils. The lactate dehydrogenase level was elevated at 829 U/L. The patient had not been treated for chronic lymphocytic leukemia in the last 11 months due to adverse reactions to rituximab after 2 cycles of fludarabine, cyclophosphamide, and rituximab chemotherapy. First-line therapy for the patient was photopheresis for SS.

Comment

Nail changes are found in many cases of advanced-stage SS but rarely have been reported in the literature. A literature review of PubMed articles indexed for MEDLINE was conducted using the search terms Sézary, nail, onychodystrophy, cutaneous T-cell lymphoma, and CTCL. All results were reviewed for original reported cases of SS with at least 1 reported nail finding. A total of 7 reports^2-8 met these requirements with a total of 43 SS patients with reported nail findings, which are summarized in Tables 2 and 3.

Our findings are generally consistent with those previously described in the literature. Nail thickening, yellowing, subungual hyperkeratosis, dystrophy, and onycholysis are consistently some of the most common nail findings in patients with SS. In 2012, Martin and Duvic⁹ found that 52.9% (45/85) of SS patients with keratoderma on physical examination were positive for dermatophyte hyphae when skin scrapings were done under potassium hydroxide examination, a considerably greater incidence than in the general population (10%–20%). The nail changes seen in our SS patients were identical to those found in dermatophyte infections, including discoloration, subungual debris, nail thickening, onycholysis, and dystrophy.¹⁰ In patient 1, nail clippings were positive for onychomycosis, a common nail condition that is especially prevalent in older or immunocompromised patients.^9,10

Interestingly, findings not observed in the literature included salmon patches and Beau lines. Beau lines are horizontal depressions in the nail plate and often are indicative of temporary interruption of nail growth, such as due to an underlying disease process, severe illness, and/or chemotherapy.^11,12 In our review, patient 2 had clinical findings of Beau lines. Because the average time for fingernail regrowth is 3 to 6 months,¹³ it is reasonable to assume that physical findings associated with fludarabine, cyclophosphamide, and rituximab chemotherapy treatment would no longer be demonstrated 11 months after completion of therapy. On the other hand, paronychia was frequently observed by Damasco et al⁸ (63.2% [12/19] of their cases), yet it was not found in our database or the other literature reports we reviewed. Perhaps these differences are due to differences in patient populations and/or available therapies, lack of documentation, or small sample size and limited reports in the literature.

A common question is: Are the nail irregularities caused by the physical symptoms of advanced CTCL or by the underlying disease process in response to the atypical T cells? Erythroderma has been speculated to cause many of the clinical findings of nail abnormalities found in CTCL patients.^2,3 However, Fleming et al¹⁴ described an MF patient who experienced onychomadesis without erythroderma, which suggests that a different mechanism may cause these nail changes. The wide range of nail abnormalities in CTCL can cause problems with diagnosing the specific cause underlying the nail alteration.

To further complicate the issue, numerous therapies for CTCL also may cause nail changes, such as the previously described Beau lines. In 2010, Parmentier et al⁴ reported a patient with nail alterations that had been present for more than 1 year, with 9 of 10 fingernails demonstrating anonychia, onychomadesis, subungual distal hyperkeratosis, and onycholysis. In this case report, the authors were able to exclude phototherapy as the cause of onycholysis (visible separation of the nail plate from the nail bed) and other clinical nail findings in the SS patient based on the onset of nail changes prior to beginning psoralen plus UVA therapy and complete sparing of 1 finger.⁴ The findings in our patient 1, who had no history of psoralen plus UVA therapy at the time the irregular nail findings presented, supports this observation. Total skin electron beam therapy for MF also has been reported to cause temporary nail stasis and thus must be taken into account when considering nail changes in patients with MF/SS.¹⁵

A nail matrix biopsy may provide clues to the definitive cause of the clinically observed nail changes; however, this procedure typically is not performed due to patient concerns of postoperative complications including pain and nail dystrophy.¹⁶ Histopathology features were similar in reported nail biopsies of 2 SS patients.^3,4 Tosti et al³ reported that longitudinal biopsy showed a dense lymphocytic infiltrate of atypical lymphocytes with involuted nuclei and notable epidermotropism. Parmentier et al⁴ reported a longitudinal nail biopsy in an SS patient that presented with atypical lymphocytes, epidermotropism, and Pautrier microabscess formation. Immunostaining showed CD3 positivity within the distal nail matrix, nail bed, and hyponychium. One-third of the cells stained positive for CD4, while the majority stained positive for CD8. Most notably, the skin, nails, and blood showed identical clonal rearrangement of TCRγ.⁴ Nail matrix biopsies in MF patients rarely have been reported in the literature, but those that are available show similar features to those seen in SS patients. Harland et al¹⁷ summarized the findings of 4 case reports of CTCL patients that included nail biopsies by stating, “[a]ll histopathologic findings from nail biopsies showed a dense subepithelial infiltrate of lymphocytes with marked epitheliotropism.” These histopathologic abnormalities are akin to skin biopsies in MF patients, thus providing an essential link to the disease state of MF and the nail abnormalities found within SS patients.

Treatment of the nail problems found within SS is challenging due to limited research. Parmentier et al⁴ noted an SS patient who was treated with topical mechlorethamine applied directly to the nail. In this case, topical mechlorethamine was effective at treating onychomadesis, subungual distal hyperkeratosis, and onycholysis within 6 months.⁴ Another SS patient, who presented with thickening and yellowing of the nail, had reported a proximal nail plate that resolved after chemotherapy. The patient did not survive long enough to note complete improvement of the nail.³ In our study, patient 1 was treated with ciclopirox gel and terbinafine, which did not result in nail improvement. Nail treatments in SS patients have yet to show much improvement and thus need more research and focus in the literature.

Conclusion

Sézary syndrome is a rare CTCL that can present with clinical features that may be mistaken for other diseases. Nail abnormalities in SS patients may be related to fungal involvement, medical therapy, or the underlying disease process of SS. We report one of the largest populations of SS patients with specific reported nail abnormalities, thus expanding the possibilities of nail changes that accompany the disease. Continued research and studies involving SS can provide a better understanding of nail involvement and successful treatment of these clinical findings.

To the Editor:

A 25-year-old woman with no notable medical history was admitted to the hospital for suspected Stevens-Johnson syndrome (SJS). The patient was started on amoxicillin 7 days prior to the skin eruption for prophylaxis before removal of an intrauterine device. On the day of admission, she reported ocular discomfort, dysphagia, and dysuria. She developed erythema of the conjunctivae, face, chest, and proximal upper extremities, as well as erosions of the vermilion lips. She presented to the local emergency department and was transferred to our institution for urgent dermatologic consultation. On physical examination by the dermatology service, the patient had erythematous macules coalescing into patches with overlying flaccid bullae, some denuded, involving the face, chest, abdomen, back (Figure 1), bilateral upper extremities, bilateral thighs, and labia majora and minora. Additionally, she had conjunctivitis, superficial erosions of the vermilion lips, and tense bullae of the palms and soles. On palpation of the flaccid bullae, the Asboe-Hansen sign was elicited (Figure 2 and video). A shave biopsy of the newly elicited bullae was performed. Pathology showed a subepidermal bulla with confluent necrosis of the epidermis and minimal inflammatory infiltrate. An additional shave biopsy of perilesional skin was obtained for direct immunofluorescence, which was negative for IgG, C3, IgM, and IgA. Based on the clinical presentation involving more than 30% of the patient’s body surface area (BSA) and the pathology findings, a diagnosis of toxic epidermal necrolysis (TEN) was made. The patient remained in the intensive care unit with a multidisciplinary team consisting of dermatology, ophthalmology, gynecology, gastroenterology, and the general surgery burn group. Following treatment with intravenous immunoglobulin, systemic corticosteroids, and aggressive wound care, the patient made a full recovery.

Vidyard Video

Toxic epidermal necrolysis is a rare, acute, life-threatening mucocutaneous disease within a spectrum of adverse cutaneous drug reactions. The estimated worldwide incidence of TEN is 0.4 to 1.9 per million individuals annually.¹ Toxic epidermal necrolysis is clinically characterized by diffuse exfoliation of the skin and mucosae with flaccid bullae. These clinical features are a consequence of extensive keratinocyte death, leading to dermoepidermal junction dissociation. Commonly, there is a prodrome of fever, pharyngitis, and painful skin preceding the diffuse erythema and sloughing of skin and mucous membranes. Lesions typically first appear on the trunk and then follow a centrifugal spread, often sparing the distal aspects of the arms and legs.

Toxic epidermal necrolysis is part of a continuous spectrum with SJS. Less than 10% BSA involvement is considered SJS, 10% to 30% BSA involvement is SJS/TEN overlap, and more than 30% BSA detachment is TEN. Stevens-Johnson syndrome can progress to TEN. In TEN, the distribution of cutaneous lesions is more confluent, and mucosal involvement is more severe.² The differential diagnosis may include staphylococcal scalded skin syndrome, drug-induced linear IgA bullous dermatosis, severe acute graft-vs-host disease, drug reaction with eosinophilia and systemic symptoms, and invasive fungal dermatitis. An accurate diagnosis of TEN is imperative, as the management and morbidity of these diseases are vastly different. Toxic epidermal necrolysis has an estimated mortality rate of 25% to 30%, with sepsis leading to multiorgan failure being the most common cause of death.³

Although the pathophysiology of TEN has yet to be fully elucidated, it is thought to be a T cell–mediated process with CD8⁺ cells acting as the primary means of keratinocyte death. An estimated 80% to 95% of cases are due to drug reactions.³ The medications that are most commonly associated with TEN include allopurinol, antibiotics, nonsteroidal anti-inflammatory drugs, and anticonvulsants. Symptoms typically begin 7 to 21 days after starting the drug. Less commonly, Mycoplasma pneumoniae, dengue virus, cytomegalovirus, and contrast medium have been reported as inciting factors for TEN.²

The diagnosis of TEN is established by correlating clinical features with a histopathologic examination obtained from a lesional skin biopsy. The classic cutaneous features of TEN begin as erythematous, flesh-colored, dusky to violaceous macules and/or morbilliform or targetoid lesions. These early lesions have the tendency to coalesce. The cutaneous findings will eventually progress into flaccid bullae, diffuse epidermal sloughing, and full-thickness skin necrosis.^2,3 The evolution of skin lesions may be rapid or may take several days to develop. On palpation, the Nikolsky (lateral shearing of epidermis with minimal pressure) and Asboe-Hansen sign will be positive in patients with SJS/TEN, demonstrating that the associated blisters are flaccid and may be displaced peripherally.⁴ For an accurate diagnosis, the biopsy must contain full-thickness epidermis. It is imperative to choose a biopsy site from an acute blister, as old lesions of other diseases, such as erythema multiforme, will eventually become necrotic and mimic the histopathologic appearance of SJS/TEN, potentially leading to an incorrect diagnosis.⁴ Full-thickness epidermal necrosis has a high sensitivity but low specificity for TEN.³ The histologic features of TEN vary depending on the stage of the disease. Classic histologic findings include satellite necrosis of keratinocytes followed by full-thickness necrosis of keratinocytes and perivascular lymphoid infiltrates. The stratum corneum retains its original structure.⁴

The Asboe-Hansen sign, also known as the bulla spread sign, was originally described in 1960 as a diagnostic sign for pemphigus vulgaris.⁵ A positive Asboe-Hansen sign demonstrates the ability to enlarge a bulla in the lateral direction by applying perpendicular mechanical pressure to the roof of an intact bulla. The bulla is extended to adjacent nonblistered skin.⁶ A positive sign demonstrates decreased adhesion between keratinocytes or between the basal epidermal cells and the dermal connective tissue.⁵ In addition to pemphigus vulgaris, the Asboe-Hansen sign may be positive in TEN and SJS, as well as other diseases affecting the dermoepidermal junction including pemphigus foliaceus, pemphigus vegetans, and bullous pemphigoid. Asboe-Hansen⁵ made the argument that a fresh bulla should be biopsied if histopathologic diagnosis is necessary, as older bullae may exhibit epithelial cell regeneration and disturb an accurate diagnosis.

Accurate and early diagnosis of TEN is imperative, as prognosis is strongly correlated with the speed at which the offending drug is discontinued and appropriate medical treatment is initiated. Prompt withdrawal of the offending drug has been reported to reduce the risk for morbidity by 30% per day.⁷ Although classically associated with the pemphigus group of diseases, the Asboe-Hansen sign is of diagnostic value to the pathologist in diagnosing TEN by reproducing the same microscopic appearance of a fresh spontaneous blister. Due to the notable morbidity and mortality in SJS and TEN, the Asboe-Hansen sign should be attempted for the site of a lesional biopsy, as an accurate diagnosis relies on clinicopathologic correlation.

To the Editor:

A 25-year-old woman with no notable medical history was admitted to the hospital for suspected Stevens-Johnson syndrome (SJS). The patient was started on amoxicillin 7 days prior to the skin eruption for prophylaxis before removal of an intrauterine device. On the day of admission, she reported ocular discomfort, dysphagia, and dysuria. She developed erythema of the conjunctivae, face, chest, and proximal upper extremities, as well as erosions of the vermilion lips. She presented to the local emergency department and was transferred to our institution for urgent dermatologic consultation. On physical examination by the dermatology service, the patient had erythematous macules coalescing into patches with overlying flaccid bullae, some denuded, involving the face, chest, abdomen, back (Figure 1), bilateral upper extremities, bilateral thighs, and labia majora and minora. Additionally, she had conjunctivitis, superficial erosions of the vermilion lips, and tense bullae of the palms and soles. On palpation of the flaccid bullae, the Asboe-Hansen sign was elicited (Figure 2 and video). A shave biopsy of the newly elicited bullae was performed. Pathology showed a subepidermal bulla with confluent necrosis of the epidermis and minimal inflammatory infiltrate. An additional shave biopsy of perilesional skin was obtained for direct immunofluorescence, which was negative for IgG, C3, IgM, and IgA. Based on the clinical presentation involving more than 30% of the patient’s body surface area (BSA) and the pathology findings, a diagnosis of toxic epidermal necrolysis (TEN) was made. The patient remained in the intensive care unit with a multidisciplinary team consisting of dermatology, ophthalmology, gynecology, gastroenterology, and the general surgery burn group. Following treatment with intravenous immunoglobulin, systemic corticosteroids, and aggressive wound care, the patient made a full recovery.

Vidyard Video

Toxic epidermal necrolysis is a rare, acute, life-threatening mucocutaneous disease within a spectrum of adverse cutaneous drug reactions. The estimated worldwide incidence of TEN is 0.4 to 1.9 per million individuals annually.¹ Toxic epidermal necrolysis is clinically characterized by diffuse exfoliation of the skin and mucosae with flaccid bullae. These clinical features are a consequence of extensive keratinocyte death, leading to dermoepidermal junction dissociation. Commonly, there is a prodrome of fever, pharyngitis, and painful skin preceding the diffuse erythema and sloughing of skin and mucous membranes. Lesions typically first appear on the trunk and then follow a centrifugal spread, often sparing the distal aspects of the arms and legs.

Toxic epidermal necrolysis is part of a continuous spectrum with SJS. Less than 10% BSA involvement is considered SJS, 10% to 30% BSA involvement is SJS/TEN overlap, and more than 30% BSA detachment is TEN. Stevens-Johnson syndrome can progress to TEN. In TEN, the distribution of cutaneous lesions is more confluent, and mucosal involvement is more severe.² The differential diagnosis may include staphylococcal scalded skin syndrome, drug-induced linear IgA bullous dermatosis, severe acute graft-vs-host disease, drug reaction with eosinophilia and systemic symptoms, and invasive fungal dermatitis. An accurate diagnosis of TEN is imperative, as the management and morbidity of these diseases are vastly different. Toxic epidermal necrolysis has an estimated mortality rate of 25% to 30%, with sepsis leading to multiorgan failure being the most common cause of death.³

Although the pathophysiology of TEN has yet to be fully elucidated, it is thought to be a T cell–mediated process with CD8⁺ cells acting as the primary means of keratinocyte death. An estimated 80% to 95% of cases are due to drug reactions.³ The medications that are most commonly associated with TEN include allopurinol, antibiotics, nonsteroidal anti-inflammatory drugs, and anticonvulsants. Symptoms typically begin 7 to 21 days after starting the drug. Less commonly, Mycoplasma pneumoniae, dengue virus, cytomegalovirus, and contrast medium have been reported as inciting factors for TEN.²

The diagnosis of TEN is established by correlating clinical features with a histopathologic examination obtained from a lesional skin biopsy. The classic cutaneous features of TEN begin as erythematous, flesh-colored, dusky to violaceous macules and/or morbilliform or targetoid lesions. These early lesions have the tendency to coalesce. The cutaneous findings will eventually progress into flaccid bullae, diffuse epidermal sloughing, and full-thickness skin necrosis.^2,3 The evolution of skin lesions may be rapid or may take several days to develop. On palpation, the Nikolsky (lateral shearing of epidermis with minimal pressure) and Asboe-Hansen sign will be positive in patients with SJS/TEN, demonstrating that the associated blisters are flaccid and may be displaced peripherally.⁴ For an accurate diagnosis, the biopsy must contain full-thickness epidermis. It is imperative to choose a biopsy site from an acute blister, as old lesions of other diseases, such as erythema multiforme, will eventually become necrotic and mimic the histopathologic appearance of SJS/TEN, potentially leading to an incorrect diagnosis.⁴ Full-thickness epidermal necrosis has a high sensitivity but low specificity for TEN.³ The histologic features of TEN vary depending on the stage of the disease. Classic histologic findings include satellite necrosis of keratinocytes followed by full-thickness necrosis of keratinocytes and perivascular lymphoid infiltrates. The stratum corneum retains its original structure.⁴

The Asboe-Hansen sign, also known as the bulla spread sign, was originally described in 1960 as a diagnostic sign for pemphigus vulgaris.⁵ A positive Asboe-Hansen sign demonstrates the ability to enlarge a bulla in the lateral direction by applying perpendicular mechanical pressure to the roof of an intact bulla. The bulla is extended to adjacent nonblistered skin.⁶ A positive sign demonstrates decreased adhesion between keratinocytes or between the basal epidermal cells and the dermal connective tissue.⁵ In addition to pemphigus vulgaris, the Asboe-Hansen sign may be positive in TEN and SJS, as well as other diseases affecting the dermoepidermal junction including pemphigus foliaceus, pemphigus vegetans, and bullous pemphigoid. Asboe-Hansen⁵ made the argument that a fresh bulla should be biopsied if histopathologic diagnosis is necessary, as older bullae may exhibit epithelial cell regeneration and disturb an accurate diagnosis.

Accurate and early diagnosis of TEN is imperative, as prognosis is strongly correlated with the speed at which the offending drug is discontinued and appropriate medical treatment is initiated. Prompt withdrawal of the offending drug has been reported to reduce the risk for morbidity by 30% per day.⁷ Although classically associated with the pemphigus group of diseases, the Asboe-Hansen sign is of diagnostic value to the pathologist in diagnosing TEN by reproducing the same microscopic appearance of a fresh spontaneous blister. Due to the notable morbidity and mortality in SJS and TEN, the Asboe-Hansen sign should be attempted for the site of a lesional biopsy, as an accurate diagnosis relies on clinicopathologic correlation.

To the Editor:

A 25-year-old woman with no notable medical history was admitted to the hospital for suspected Stevens-Johnson syndrome (SJS). The patient was started on amoxicillin 7 days prior to the skin eruption for prophylaxis before removal of an intrauterine device. On the day of admission, she reported ocular discomfort, dysphagia, and dysuria. She developed erythema of the conjunctivae, face, chest, and proximal upper extremities, as well as erosions of the vermilion lips. She presented to the local emergency department and was transferred to our institution for urgent dermatologic consultation. On physical examination by the dermatology service, the patient had erythematous macules coalescing into patches with overlying flaccid bullae, some denuded, involving the face, chest, abdomen, back (Figure 1), bilateral upper extremities, bilateral thighs, and labia majora and minora. Additionally, she had conjunctivitis, superficial erosions of the vermilion lips, and tense bullae of the palms and soles. On palpation of the flaccid bullae, the Asboe-Hansen sign was elicited (Figure 2 and video). A shave biopsy of the newly elicited bullae was performed. Pathology showed a subepidermal bulla with confluent necrosis of the epidermis and minimal inflammatory infiltrate. An additional shave biopsy of perilesional skin was obtained for direct immunofluorescence, which was negative for IgG, C3, IgM, and IgA. Based on the clinical presentation involving more than 30% of the patient’s body surface area (BSA) and the pathology findings, a diagnosis of toxic epidermal necrolysis (TEN) was made. The patient remained in the intensive care unit with a multidisciplinary team consisting of dermatology, ophthalmology, gynecology, gastroenterology, and the general surgery burn group. Following treatment with intravenous immunoglobulin, systemic corticosteroids, and aggressive wound care, the patient made a full recovery.

Vidyard Video

Toxic epidermal necrolysis is a rare, acute, life-threatening mucocutaneous disease within a spectrum of adverse cutaneous drug reactions. The estimated worldwide incidence of TEN is 0.4 to 1.9 per million individuals annually.¹ Toxic epidermal necrolysis is clinically characterized by diffuse exfoliation of the skin and mucosae with flaccid bullae. These clinical features are a consequence of extensive keratinocyte death, leading to dermoepidermal junction dissociation. Commonly, there is a prodrome of fever, pharyngitis, and painful skin preceding the diffuse erythema and sloughing of skin and mucous membranes. Lesions typically first appear on the trunk and then follow a centrifugal spread, often sparing the distal aspects of the arms and legs.

Toxic epidermal necrolysis is part of a continuous spectrum with SJS. Less than 10% BSA involvement is considered SJS, 10% to 30% BSA involvement is SJS/TEN overlap, and more than 30% BSA detachment is TEN. Stevens-Johnson syndrome can progress to TEN. In TEN, the distribution of cutaneous lesions is more confluent, and mucosal involvement is more severe.² The differential diagnosis may include staphylococcal scalded skin syndrome, drug-induced linear IgA bullous dermatosis, severe acute graft-vs-host disease, drug reaction with eosinophilia and systemic symptoms, and invasive fungal dermatitis. An accurate diagnosis of TEN is imperative, as the management and morbidity of these diseases are vastly different. Toxic epidermal necrolysis has an estimated mortality rate of 25% to 30%, with sepsis leading to multiorgan failure being the most common cause of death.³

Although the pathophysiology of TEN has yet to be fully elucidated, it is thought to be a T cell–mediated process with CD8⁺ cells acting as the primary means of keratinocyte death. An estimated 80% to 95% of cases are due to drug reactions.³ The medications that are most commonly associated with TEN include allopurinol, antibiotics, nonsteroidal anti-inflammatory drugs, and anticonvulsants. Symptoms typically begin 7 to 21 days after starting the drug. Less commonly, Mycoplasma pneumoniae, dengue virus, cytomegalovirus, and contrast medium have been reported as inciting factors for TEN.²

The diagnosis of TEN is established by correlating clinical features with a histopathologic examination obtained from a lesional skin biopsy. The classic cutaneous features of TEN begin as erythematous, flesh-colored, dusky to violaceous macules and/or morbilliform or targetoid lesions. These early lesions have the tendency to coalesce. The cutaneous findings will eventually progress into flaccid bullae, diffuse epidermal sloughing, and full-thickness skin necrosis.^2,3 The evolution of skin lesions may be rapid or may take several days to develop. On palpation, the Nikolsky (lateral shearing of epidermis with minimal pressure) and Asboe-Hansen sign will be positive in patients with SJS/TEN, demonstrating that the associated blisters are flaccid and may be displaced peripherally.⁴ For an accurate diagnosis, the biopsy must contain full-thickness epidermis. It is imperative to choose a biopsy site from an acute blister, as old lesions of other diseases, such as erythema multiforme, will eventually become necrotic and mimic the histopathologic appearance of SJS/TEN, potentially leading to an incorrect diagnosis.⁴ Full-thickness epidermal necrosis has a high sensitivity but low specificity for TEN.³ The histologic features of TEN vary depending on the stage of the disease. Classic histologic findings include satellite necrosis of keratinocytes followed by full-thickness necrosis of keratinocytes and perivascular lymphoid infiltrates. The stratum corneum retains its original structure.⁴

The Asboe-Hansen sign, also known as the bulla spread sign, was originally described in 1960 as a diagnostic sign for pemphigus vulgaris.⁵ A positive Asboe-Hansen sign demonstrates the ability to enlarge a bulla in the lateral direction by applying perpendicular mechanical pressure to the roof of an intact bulla. The bulla is extended to adjacent nonblistered skin.⁶ A positive sign demonstrates decreased adhesion between keratinocytes or between the basal epidermal cells and the dermal connective tissue.⁵ In addition to pemphigus vulgaris, the Asboe-Hansen sign may be positive in TEN and SJS, as well as other diseases affecting the dermoepidermal junction including pemphigus foliaceus, pemphigus vegetans, and bullous pemphigoid. Asboe-Hansen⁵ made the argument that a fresh bulla should be biopsied if histopathologic diagnosis is necessary, as older bullae may exhibit epithelial cell regeneration and disturb an accurate diagnosis.

Accurate and early diagnosis of TEN is imperative, as prognosis is strongly correlated with the speed at which the offending drug is discontinued and appropriate medical treatment is initiated. Prompt withdrawal of the offending drug has been reported to reduce the risk for morbidity by 30% per day.⁷ Although classically associated with the pemphigus group of diseases, the Asboe-Hansen sign is of diagnostic value to the pathologist in diagnosing TEN by reproducing the same microscopic appearance of a fresh spontaneous blister. Due to the notable morbidity and mortality in SJS and TEN, the Asboe-Hansen sign should be attempted for the site of a lesional biopsy, as an accurate diagnosis relies on clinicopathologic correlation.

To the Editor:

Lichen amyloidosis (LA) classically presents as a pruritic, hyperkeratotic, papular eruption localized to the pretibial surface of the legs.¹ Nonpruritic and generalized variants have been reported but are rare.² Although it is the most common subtype of primary localized cutaneous amyloidosis, LA is a benign condition but is difficult to eradicate.¹ The precise pathophysiology is poorly understood, but chronic frictional irritation is closely associated with the eruption. We present a nongeneralized case of LA in an atypical location.

A healthy 30-year-old woman presented with an intermittent itchy rash on the elbows and knees of 2 years’ duration. The patient was first diagnosed with lichen simplex chronicus (LSC) and initially responded well to treatment with fluocinonide ointment 0.05%. Nearly 2 years after the initial presentation, she developed recurrent symptoms and sought further treatment. She reported frequent scratching in association with episodes of anxiety. Examination revealed numerous 1- to 3-mm, flesh-colored to light brown, monomorphic, dome-shaped papules over the extensor surfaces of the bilateral arms and left pretibial surface (Figure 1).

^4-6

The possibility remains that this patient first presented with LSC 2 years prior and secondarily developed LA due to chronic trauma. Indeed, LA has been proposed as a variant of LSC. In both conditions, scratching seems to be the most important factor in the development of lesions. It has been proposed that treatment should primarily focus on the amelioration of pruritus.⁵

Five percent to 10% of cases of LA have been found to have some form of upper extremity involvement.⁷ However, these cases typically are associated with a generalized presentation involving the trunk and arms.^2,7 Our patient had no evidence of disease elsewhere. When evaluating a localized, pruritic, monomorphic, papular eruption on the extensor surfaces of the arms, LA may be an important consideration.

To the Editor:

Lichen amyloidosis (LA) classically presents as a pruritic, hyperkeratotic, papular eruption localized to the pretibial surface of the legs.¹ Nonpruritic and generalized variants have been reported but are rare.² Although it is the most common subtype of primary localized cutaneous amyloidosis, LA is a benign condition but is difficult to eradicate.¹ The precise pathophysiology is poorly understood, but chronic frictional irritation is closely associated with the eruption. We present a nongeneralized case of LA in an atypical location.

A healthy 30-year-old woman presented with an intermittent itchy rash on the elbows and knees of 2 years’ duration. The patient was first diagnosed with lichen simplex chronicus (LSC) and initially responded well to treatment with fluocinonide ointment 0.05%. Nearly 2 years after the initial presentation, she developed recurrent symptoms and sought further treatment. She reported frequent scratching in association with episodes of anxiety. Examination revealed numerous 1- to 3-mm, flesh-colored to light brown, monomorphic, dome-shaped papules over the extensor surfaces of the bilateral arms and left pretibial surface (Figure 1).

^4-6

The possibility remains that this patient first presented with LSC 2 years prior and secondarily developed LA due to chronic trauma. Indeed, LA has been proposed as a variant of LSC. In both conditions, scratching seems to be the most important factor in the development of lesions. It has been proposed that treatment should primarily focus on the amelioration of pruritus.⁵

Five percent to 10% of cases of LA have been found to have some form of upper extremity involvement.⁷ However, these cases typically are associated with a generalized presentation involving the trunk and arms.^2,7 Our patient had no evidence of disease elsewhere. When evaluating a localized, pruritic, monomorphic, papular eruption on the extensor surfaces of the arms, LA may be an important consideration.

To the Editor:

Lichen amyloidosis (LA) classically presents as a pruritic, hyperkeratotic, papular eruption localized to the pretibial surface of the legs.¹ Nonpruritic and generalized variants have been reported but are rare.² Although it is the most common subtype of primary localized cutaneous amyloidosis, LA is a benign condition but is difficult to eradicate.¹ The precise pathophysiology is poorly understood, but chronic frictional irritation is closely associated with the eruption. We present a nongeneralized case of LA in an atypical location.

A healthy 30-year-old woman presented with an intermittent itchy rash on the elbows and knees of 2 years’ duration. The patient was first diagnosed with lichen simplex chronicus (LSC) and initially responded well to treatment with fluocinonide ointment 0.05%. Nearly 2 years after the initial presentation, she developed recurrent symptoms and sought further treatment. She reported frequent scratching in association with episodes of anxiety. Examination revealed numerous 1- to 3-mm, flesh-colored to light brown, monomorphic, dome-shaped papules over the extensor surfaces of the bilateral arms and left pretibial surface (Figure 1).

^4-6

The possibility remains that this patient first presented with LSC 2 years prior and secondarily developed LA due to chronic trauma. Indeed, LA has been proposed as a variant of LSC. In both conditions, scratching seems to be the most important factor in the development of lesions. It has been proposed that treatment should primarily focus on the amelioration of pruritus.⁵

Five percent to 10% of cases of LA have been found to have some form of upper extremity involvement.⁷ However, these cases typically are associated with a generalized presentation involving the trunk and arms.^2,7 Our patient had no evidence of disease elsewhere. When evaluating a localized, pruritic, monomorphic, papular eruption on the extensor surfaces of the arms, LA may be an important consideration.

The Diagnosis: Lichen Nitidus 

Our patient represents a case of lichen nitidus (LN) that was diagnosed through clinicopathologic correlation, with the pathology results showing a lymphohistiocytic infiltrate in the papillary dermis enclosed by acanthotic rete ridges on either side. Lichen nitidus was first described by Pinkus in 1901 as a variant of lichen planus.¹ It is a rare chronic inflammatory disease that is most prevalent in children and adolescents.² Clinically, the lesions appear as 1- to 2-mm, shiny, flesh-colored papules with central umbilication.³ Typically, lesions are localized and discrete; however, vesicular, hemorrhagic, perforating, spinous follicular, linear, generalized, and actinic variants all have been reported in the literature. Lichen nitidus has a predilection for the lower abdomen, medial thighs, penis, forearms, ventral wrists, and hands.⁴ Cases of LN have been reported on the palms, soles, nails, and mucosa, presenting a diagnostic challenge.⁵ The pathogenesis of LN is unknown, and all races and sexes are affected equally.⁶  

Histopathologically, LN has distinct findings including a well-circumscribed lymphohistiocytic infiltrate in the papillary dermis embraced by elongated and acanthotic rete ridges.² These histopathologic characteristics were seen in our patient's biopsy specimen (Figure) and have been described as the ball-and-claw configuration. Lichen nitidus may be pruritic but typically is asymptomatic.⁷ It often spontaneously regresses within months to years without any treatment⁷; however, successful outcomes have been seen with topical steroids, UVA/UVB phototherapy, and retinoids.² Our patient was treated with topical steroids. 

The differential diagnosis for LN includes verruca plana, dyshidrotic eczema, acral persistent papular mucinosis (APPM), and molluscum contagiosum. Verruca plana can occur as 1- to 5-mm, grouped, flesh-colored papules on the face, neck, dorsal hands, wrists, or knees.⁸ Most commonly, verruca plana occurs due to human papillomavirus type 3 and less commonly human papillomavirus types 10, 27, and 41. Verruca plana is easily differentiated from LN on pathology with findings of epidermal hyperkeratosis, irregular acanthosis, and koilocytic changes.⁸  

Dyshidrotic eczema is a pruritic vesicular rash that is classically distributed symmetrically on the palmar aspects of the hands and lateral fingers.⁹ Histopathology of the lesions reveals spongiosis with an epidermal lymphocytic infiltrate. Exacerbating factors include exposure to allergens, stress, fungal infections, and genetic predisposition.⁹ 

Acral persistent papular mucinosis can present as multiple, 2- to 5-mm, flesh-colored papules on the dorsal aspects of the hands.¹⁰ However, the demographic is different from LN, as APPM most commonly affects middle-aged females versus adolescents. Lesions of APPM may multiply or spontaneously remit over time. Acral persistent papular mucinosis generally is asymptomatic but can be treated with cryotherapy, topical corticosteroids, electrodesiccation, or CO₂ lasers for cosmetic purposes. Acral persistent papular mucinosis can be easily distinguished from LN on histology, as it will show areas of focal, well-circumscribed mucin in the papillary dermis and a spared Grenz zone.¹⁰ 

Molluscum contagiosum is a common viral skin infection caused by the poxvirus that affects children and adults.¹¹ The skin lesions appear as 2- to 4-mm, dome-shaped, flesh-colored papules with central umbilication on the limbs, trunk, or face. Clinicians may choose to monitor lesions of molluscum contagiosum, as it is a self-limited condition, or it may be treated with cryotherapy, salicylic acid, imiquimod, curettage, laser, or cimetidine.¹¹ On histology, epidermal budlike proliferations can be appreciated in the dermis, and characteristic large, eosinophilic, intracytoplasmic inclusion or molluscum bodies are found in the epidermis.¹² 

The Diagnosis: Lichen Nitidus 

Our patient represents a case of lichen nitidus (LN) that was diagnosed through clinicopathologic correlation, with the pathology results showing a lymphohistiocytic infiltrate in the papillary dermis enclosed by acanthotic rete ridges on either side. Lichen nitidus was first described by Pinkus in 1901 as a variant of lichen planus.¹ It is a rare chronic inflammatory disease that is most prevalent in children and adolescents.² Clinically, the lesions appear as 1- to 2-mm, shiny, flesh-colored papules with central umbilication.³ Typically, lesions are localized and discrete; however, vesicular, hemorrhagic, perforating, spinous follicular, linear, generalized, and actinic variants all have been reported in the literature. Lichen nitidus has a predilection for the lower abdomen, medial thighs, penis, forearms, ventral wrists, and hands.⁴ Cases of LN have been reported on the palms, soles, nails, and mucosa, presenting a diagnostic challenge.⁵ The pathogenesis of LN is unknown, and all races and sexes are affected equally.⁶  

Histopathologically, LN has distinct findings including a well-circumscribed lymphohistiocytic infiltrate in the papillary dermis embraced by elongated and acanthotic rete ridges.² These histopathologic characteristics were seen in our patient's biopsy specimen (Figure) and have been described as the ball-and-claw configuration. Lichen nitidus may be pruritic but typically is asymptomatic.⁷ It often spontaneously regresses within months to years without any treatment⁷; however, successful outcomes have been seen with topical steroids, UVA/UVB phototherapy, and retinoids.² Our patient was treated with topical steroids. 

The differential diagnosis for LN includes verruca plana, dyshidrotic eczema, acral persistent papular mucinosis (APPM), and molluscum contagiosum. Verruca plana can occur as 1- to 5-mm, grouped, flesh-colored papules on the face, neck, dorsal hands, wrists, or knees.⁸ Most commonly, verruca plana occurs due to human papillomavirus type 3 and less commonly human papillomavirus types 10, 27, and 41. Verruca plana is easily differentiated from LN on pathology with findings of epidermal hyperkeratosis, irregular acanthosis, and koilocytic changes.⁸  

Dyshidrotic eczema is a pruritic vesicular rash that is classically distributed symmetrically on the palmar aspects of the hands and lateral fingers.⁹ Histopathology of the lesions reveals spongiosis with an epidermal lymphocytic infiltrate. Exacerbating factors include exposure to allergens, stress, fungal infections, and genetic predisposition.⁹ 

Acral persistent papular mucinosis can present as multiple, 2- to 5-mm, flesh-colored papules on the dorsal aspects of the hands.¹⁰ However, the demographic is different from LN, as APPM most commonly affects middle-aged females versus adolescents. Lesions of APPM may multiply or spontaneously remit over time. Acral persistent papular mucinosis generally is asymptomatic but can be treated with cryotherapy, topical corticosteroids, electrodesiccation, or CO₂ lasers for cosmetic purposes. Acral persistent papular mucinosis can be easily distinguished from LN on histology, as it will show areas of focal, well-circumscribed mucin in the papillary dermis and a spared Grenz zone.¹⁰ 

Molluscum contagiosum is a common viral skin infection caused by the poxvirus that affects children and adults.¹¹ The skin lesions appear as 2- to 4-mm, dome-shaped, flesh-colored papules with central umbilication on the limbs, trunk, or face. Clinicians may choose to monitor lesions of molluscum contagiosum, as it is a self-limited condition, or it may be treated with cryotherapy, salicylic acid, imiquimod, curettage, laser, or cimetidine.¹¹ On histology, epidermal budlike proliferations can be appreciated in the dermis, and characteristic large, eosinophilic, intracytoplasmic inclusion or molluscum bodies are found in the epidermis.¹² 

The Diagnosis: Lichen Nitidus 

Our patient represents a case of lichen nitidus (LN) that was diagnosed through clinicopathologic correlation, with the pathology results showing a lymphohistiocytic infiltrate in the papillary dermis enclosed by acanthotic rete ridges on either side. Lichen nitidus was first described by Pinkus in 1901 as a variant of lichen planus.¹ It is a rare chronic inflammatory disease that is most prevalent in children and adolescents.² Clinically, the lesions appear as 1- to 2-mm, shiny, flesh-colored papules with central umbilication.³ Typically, lesions are localized and discrete; however, vesicular, hemorrhagic, perforating, spinous follicular, linear, generalized, and actinic variants all have been reported in the literature. Lichen nitidus has a predilection for the lower abdomen, medial thighs, penis, forearms, ventral wrists, and hands.⁴ Cases of LN have been reported on the palms, soles, nails, and mucosa, presenting a diagnostic challenge.⁵ The pathogenesis of LN is unknown, and all races and sexes are affected equally.⁶  

Histopathologically, LN has distinct findings including a well-circumscribed lymphohistiocytic infiltrate in the papillary dermis embraced by elongated and acanthotic rete ridges.² These histopathologic characteristics were seen in our patient's biopsy specimen (Figure) and have been described as the ball-and-claw configuration. Lichen nitidus may be pruritic but typically is asymptomatic.⁷ It often spontaneously regresses within months to years without any treatment⁷; however, successful outcomes have been seen with topical steroids, UVA/UVB phototherapy, and retinoids.² Our patient was treated with topical steroids. 

The differential diagnosis for LN includes verruca plana, dyshidrotic eczema, acral persistent papular mucinosis (APPM), and molluscum contagiosum. Verruca plana can occur as 1- to 5-mm, grouped, flesh-colored papules on the face, neck, dorsal hands, wrists, or knees.⁸ Most commonly, verruca plana occurs due to human papillomavirus type 3 and less commonly human papillomavirus types 10, 27, and 41. Verruca plana is easily differentiated from LN on pathology with findings of epidermal hyperkeratosis, irregular acanthosis, and koilocytic changes.⁸  

Dyshidrotic eczema is a pruritic vesicular rash that is classically distributed symmetrically on the palmar aspects of the hands and lateral fingers.⁹ Histopathology of the lesions reveals spongiosis with an epidermal lymphocytic infiltrate. Exacerbating factors include exposure to allergens, stress, fungal infections, and genetic predisposition.⁹ 

Acral persistent papular mucinosis can present as multiple, 2- to 5-mm, flesh-colored papules on the dorsal aspects of the hands.¹⁰ However, the demographic is different from LN, as APPM most commonly affects middle-aged females versus adolescents. Lesions of APPM may multiply or spontaneously remit over time. Acral persistent papular mucinosis generally is asymptomatic but can be treated with cryotherapy, topical corticosteroids, electrodesiccation, or CO₂ lasers for cosmetic purposes. Acral persistent papular mucinosis can be easily distinguished from LN on histology, as it will show areas of focal, well-circumscribed mucin in the papillary dermis and a spared Grenz zone.¹⁰ 

Molluscum contagiosum is a common viral skin infection caused by the poxvirus that affects children and adults.¹¹ The skin lesions appear as 2- to 4-mm, dome-shaped, flesh-colored papules with central umbilication on the limbs, trunk, or face. Clinicians may choose to monitor lesions of molluscum contagiosum, as it is a self-limited condition, or it may be treated with cryotherapy, salicylic acid, imiquimod, curettage, laser, or cimetidine.¹¹ On histology, epidermal budlike proliferations can be appreciated in the dermis, and characteristic large, eosinophilic, intracytoplasmic inclusion or molluscum bodies are found in the epidermis.¹² 

The Diagnosis: Unilateral Dermatomal Trichoepithelioma  

Adnexal lesions presenting with a linear and/or dermatomal pattern rarely have been reported. Bolognia et al¹ performed a comprehensive review of Blaschko lines and skin conditions that follow such a pattern. The authors found that adnexal-related lesions included linear nevus comedonicus, linear basal cell nevus with comedones (linear basaloid follicular hamartoma), unilateral nevoid basal cell carcinoma (BCC), linear trichoepithelioma, linear trichodiscoma, linear hamartoma of the follicular infundibulum, nevus sebaceous, syringocystadenoma papilliferum, porokeratotic eccrine ostial and dermal duct nevus, linear eccrine poroma, linear spiradenoma, linear syringoma, and linear eccrine syringofibroadenoma.¹  

Trichoepithelioma is a hair follicle-related neoplastic lesion presenting most commonly as the autosomal-dominant multiple familial type with lesions mainly centered on the face. Initial genetic studies associated the disease with loss of heterozygosity in the 9p21 region and further studies identified mutations in the CYLD (cylindromatosis [turban tumor syndrome]) gene on chromosome 16q12-q13.^2,3 Unilateral, linear, and dermatomal forms of trichoepithelioma rarely are reported. In 1986, Geffner et al⁴ reported a case of linear and dermatomal trichoepithelioma in a 10-year-old girl. In addition to discrete solitary lesions affecting the face, she developed lesions on the left shoulder, left side of the trunk, and left lower leg following dermatomal distribution. In 2006, 2 cases of dermatomal trichoepitheliomas affecting the face in children, as in our case, were reported.^5,6 Another case involving the neck was reported in 2016.⁷ Although classic multiple familial trichoepithelioma can be part of conditions such as Brooke-Spiegler⁸ and Rombo syndromes,⁹ no syndromal association has been reported thus far with the unilateral, linear, or dermatomal variants.  

Our case showed typical histopathologic features of trichoepithelioma, including discrete islands of basaloid cells in the dermis set in a conspicuous fibroblastic stroma. Focal connection with the epidermis was present. Most of the islands showed peripheral palisading and horn cysts lined by eosinophilic cells. The fibroblastic component was tightly adherent to the epithelial component, and only stromal clefts were detected. Papillary mesenchymal bodies also were detected as oval aggregates of fibroblastic cells invaginating into epithelial islands to form hair papillae. 

Histopathologically, the 2 most important differential diagnoses of trichoepithelioma include BCC and basaloid follicular hamartoma. In differentiating BCC from trichoepithelioma, the presence of dense fibroblastic stroma and papillary mesenchymal bodies characterize trichoepithelioma, while a fibromucinous stroma with mucinous retraction artifacts and clefting between the basaloid islands and the stroma characterize BCC (Figure 1).¹⁰ Immunohistochemical studies using antibodies against Bcl-2, CD34, CD10, androgen receptor, Ki-67, cytokeratin 19, and PHLDA1 (pleckstrin homologylike domain family A member 1) have reportedly been utilized to differentiate trichoepithelioma from BCC.^11,12 Basaloid follicular hamartoma is characterized by thin anastomosing strands and branching cords of undifferentiated basaloid cells that replace or associate hair follicles in a latticelike pattern (Figure 2). The strands usually are vertically oriented perpendicular to the epidermis. Peripheral palisading is possible, and the basaloid strands are surrounded with cellular connective tissue stroma.¹³ Tumor islands in eccrine poroma show broad connections with the epidermis and are composed of poroid cells that show evident ductal differentiation with eosinophilic cuticles (Figure 3).¹⁴ Spiradenoma is characterized by capsulated deep-seated tumorous nodules not connected with the epidermis and composed of light and dark cells with ductal differentiation and vascular stroma (Figure 4). Scattered lymphocytes within the tumor lobules and in the stroma also are seen. Eosinophilic hyaline globules rarely can be present.¹⁵ 

Many pathologists consider trichoepithelioma as the superficial variant of trichoblastoma. According to the recent World Health Organization classification of benign tumors with follicular differentiation, trichoepithelioma is considered synonymous with trichoblastoma.¹⁶ 

Trichoepitheliomas are benign tumors, and therapy is mainly directed at removal for cosmetic purposes. Several methods of removal are available including electrocautery, laser therapy, and surgery. Awareness of the possible dermatomal distribution of hair follicle and other adnexal-related conditions is important, and such lesions should be thought of in the differential diagnosis of unilateral and/or dermatomal lesions.

The Diagnosis: Unilateral Dermatomal Trichoepithelioma  

Adnexal lesions presenting with a linear and/or dermatomal pattern rarely have been reported. Bolognia et al¹ performed a comprehensive review of Blaschko lines and skin conditions that follow such a pattern. The authors found that adnexal-related lesions included linear nevus comedonicus, linear basal cell nevus with comedones (linear basaloid follicular hamartoma), unilateral nevoid basal cell carcinoma (BCC), linear trichoepithelioma, linear trichodiscoma, linear hamartoma of the follicular infundibulum, nevus sebaceous, syringocystadenoma papilliferum, porokeratotic eccrine ostial and dermal duct nevus, linear eccrine poroma, linear spiradenoma, linear syringoma, and linear eccrine syringofibroadenoma.¹  

Trichoepithelioma is a hair follicle-related neoplastic lesion presenting most commonly as the autosomal-dominant multiple familial type with lesions mainly centered on the face. Initial genetic studies associated the disease with loss of heterozygosity in the 9p21 region and further studies identified mutations in the CYLD (cylindromatosis [turban tumor syndrome]) gene on chromosome 16q12-q13.^2,3 Unilateral, linear, and dermatomal forms of trichoepithelioma rarely are reported. In 1986, Geffner et al⁴ reported a case of linear and dermatomal trichoepithelioma in a 10-year-old girl. In addition to discrete solitary lesions affecting the face, she developed lesions on the left shoulder, left side of the trunk, and left lower leg following dermatomal distribution. In 2006, 2 cases of dermatomal trichoepitheliomas affecting the face in children, as in our case, were reported.^5,6 Another case involving the neck was reported in 2016.⁷ Although classic multiple familial trichoepithelioma can be part of conditions such as Brooke-Spiegler⁸ and Rombo syndromes,⁹ no syndromal association has been reported thus far with the unilateral, linear, or dermatomal variants.  

Our case showed typical histopathologic features of trichoepithelioma, including discrete islands of basaloid cells in the dermis set in a conspicuous fibroblastic stroma. Focal connection with the epidermis was present. Most of the islands showed peripheral palisading and horn cysts lined by eosinophilic cells. The fibroblastic component was tightly adherent to the epithelial component, and only stromal clefts were detected. Papillary mesenchymal bodies also were detected as oval aggregates of fibroblastic cells invaginating into epithelial islands to form hair papillae. 

Histopathologically, the 2 most important differential diagnoses of trichoepithelioma include BCC and basaloid follicular hamartoma. In differentiating BCC from trichoepithelioma, the presence of dense fibroblastic stroma and papillary mesenchymal bodies characterize trichoepithelioma, while a fibromucinous stroma with mucinous retraction artifacts and clefting between the basaloid islands and the stroma characterize BCC (Figure 1).¹⁰ Immunohistochemical studies using antibodies against Bcl-2, CD34, CD10, androgen receptor, Ki-67, cytokeratin 19, and PHLDA1 (pleckstrin homologylike domain family A member 1) have reportedly been utilized to differentiate trichoepithelioma from BCC.^11,12 Basaloid follicular hamartoma is characterized by thin anastomosing strands and branching cords of undifferentiated basaloid cells that replace or associate hair follicles in a latticelike pattern (Figure 2). The strands usually are vertically oriented perpendicular to the epidermis. Peripheral palisading is possible, and the basaloid strands are surrounded with cellular connective tissue stroma.¹³ Tumor islands in eccrine poroma show broad connections with the epidermis and are composed of poroid cells that show evident ductal differentiation with eosinophilic cuticles (Figure 3).¹⁴ Spiradenoma is characterized by capsulated deep-seated tumorous nodules not connected with the epidermis and composed of light and dark cells with ductal differentiation and vascular stroma (Figure 4). Scattered lymphocytes within the tumor lobules and in the stroma also are seen. Eosinophilic hyaline globules rarely can be present.¹⁵ 

Many pathologists consider trichoepithelioma as the superficial variant of trichoblastoma. According to the recent World Health Organization classification of benign tumors with follicular differentiation, trichoepithelioma is considered synonymous with trichoblastoma.¹⁶ 

Trichoepitheliomas are benign tumors, and therapy is mainly directed at removal for cosmetic purposes. Several methods of removal are available including electrocautery, laser therapy, and surgery. Awareness of the possible dermatomal distribution of hair follicle and other adnexal-related conditions is important, and such lesions should be thought of in the differential diagnosis of unilateral and/or dermatomal lesions.

The Diagnosis: Unilateral Dermatomal Trichoepithelioma  

Adnexal lesions presenting with a linear and/or dermatomal pattern rarely have been reported. Bolognia et al¹ performed a comprehensive review of Blaschko lines and skin conditions that follow such a pattern. The authors found that adnexal-related lesions included linear nevus comedonicus, linear basal cell nevus with comedones (linear basaloid follicular hamartoma), unilateral nevoid basal cell carcinoma (BCC), linear trichoepithelioma, linear trichodiscoma, linear hamartoma of the follicular infundibulum, nevus sebaceous, syringocystadenoma papilliferum, porokeratotic eccrine ostial and dermal duct nevus, linear eccrine poroma, linear spiradenoma, linear syringoma, and linear eccrine syringofibroadenoma.¹  

Trichoepithelioma is a hair follicle-related neoplastic lesion presenting most commonly as the autosomal-dominant multiple familial type with lesions mainly centered on the face. Initial genetic studies associated the disease with loss of heterozygosity in the 9p21 region and further studies identified mutations in the CYLD (cylindromatosis [turban tumor syndrome]) gene on chromosome 16q12-q13.^2,3 Unilateral, linear, and dermatomal forms of trichoepithelioma rarely are reported. In 1986, Geffner et al⁴ reported a case of linear and dermatomal trichoepithelioma in a 10-year-old girl. In addition to discrete solitary lesions affecting the face, she developed lesions on the left shoulder, left side of the trunk, and left lower leg following dermatomal distribution. In 2006, 2 cases of dermatomal trichoepitheliomas affecting the face in children, as in our case, were reported.^5,6 Another case involving the neck was reported in 2016.⁷ Although classic multiple familial trichoepithelioma can be part of conditions such as Brooke-Spiegler⁸ and Rombo syndromes,⁹ no syndromal association has been reported thus far with the unilateral, linear, or dermatomal variants.  

Our case showed typical histopathologic features of trichoepithelioma, including discrete islands of basaloid cells in the dermis set in a conspicuous fibroblastic stroma. Focal connection with the epidermis was present. Most of the islands showed peripheral palisading and horn cysts lined by eosinophilic cells. The fibroblastic component was tightly adherent to the epithelial component, and only stromal clefts were detected. Papillary mesenchymal bodies also were detected as oval aggregates of fibroblastic cells invaginating into epithelial islands to form hair papillae. 

Histopathologically, the 2 most important differential diagnoses of trichoepithelioma include BCC and basaloid follicular hamartoma. In differentiating BCC from trichoepithelioma, the presence of dense fibroblastic stroma and papillary mesenchymal bodies characterize trichoepithelioma, while a fibromucinous stroma with mucinous retraction artifacts and clefting between the basaloid islands and the stroma characterize BCC (Figure 1).¹⁰ Immunohistochemical studies using antibodies against Bcl-2, CD34, CD10, androgen receptor, Ki-67, cytokeratin 19, and PHLDA1 (pleckstrin homologylike domain family A member 1) have reportedly been utilized to differentiate trichoepithelioma from BCC.^11,12 Basaloid follicular hamartoma is characterized by thin anastomosing strands and branching cords of undifferentiated basaloid cells that replace or associate hair follicles in a latticelike pattern (Figure 2). The strands usually are vertically oriented perpendicular to the epidermis. Peripheral palisading is possible, and the basaloid strands are surrounded with cellular connective tissue stroma.¹³ Tumor islands in eccrine poroma show broad connections with the epidermis and are composed of poroid cells that show evident ductal differentiation with eosinophilic cuticles (Figure 3).¹⁴ Spiradenoma is characterized by capsulated deep-seated tumorous nodules not connected with the epidermis and composed of light and dark cells with ductal differentiation and vascular stroma (Figure 4). Scattered lymphocytes within the tumor lobules and in the stroma also are seen. Eosinophilic hyaline globules rarely can be present.¹⁵ 

Many pathologists consider trichoepithelioma as the superficial variant of trichoblastoma. According to the recent World Health Organization classification of benign tumors with follicular differentiation, trichoepithelioma is considered synonymous with trichoblastoma.¹⁶ 

Trichoepitheliomas are benign tumors, and therapy is mainly directed at removal for cosmetic purposes. Several methods of removal are available including electrocautery, laser therapy, and surgery. Awareness of the possible dermatomal distribution of hair follicle and other adnexal-related conditions is important, and such lesions should be thought of in the differential diagnosis of unilateral and/or dermatomal lesions.

The Diagnosis: Juvenile Dermatomyositis 

Juvenile dermatomyositis (JDM) is a rare idiopathic inflammatory myopathy of childhood that is autoimmune in nature with an annual incidence ranging from 2.5 to 4.1 cases per million children. Its peak incidence is between 5 and 10 years of age, and it affects girls more than boys at a 2-fold to 5-fold greater rate.¹ Juvenile dermatomyositis is characterized by skeletal muscle weakness in the presence of distinctive rashes, including Gottron papules and heliotrope erythema. Muscle weakness typically is proximal and symmetrical, and eventually patients may have trouble rising from a seated position or lifting objects overhead. Other skin manifestations include nail fold capillary changes, calcinosis cutis, and less commonly ulcerations signifying vasculopathy of the skin.² A subset of patients will present with juvenile amyopathic dermatomyositis. These children have the characteristic skin changes without the muscle weakness or elevated muscle enzymes for more than 6 months; however, one-quarter may go on to develop mysositis.³ 

Diagnosis of JDM traditionally was based on the following 5 diagnostic criteria: characteristic skin rash, proximal muscle weakness, elevated muscle enzymes, myopathic changes on electromyogram, and typical muscle biopsy.¹ Current practice shows a broadening of diagnostic criteria using new techniques in the diagnosis of JDM. To make the diagnosis, the patient must have the characteristic skin manifestations with a minimum of 3 other criteria.⁴ A 2006 international consensus survey expanded the list of criteria to include typical findings on magnetic resonance imaging (MRI), nail fold capillaroscopy abnormalities, calcinosis, and
dysphonia.⁵  

To assess muscle disease, MRI is utilized because it is a reliable noninvasive tool to assess muscle inflammation. Muscle biopsy is only recommended if the diagnosis is unclear.⁵ The results of the MRI in our patient displayed symmetric mild fatty atrophy of the gluteus maximus muscle, as well as edema in the right rectus femoris and left vastus lateralis muscles, suggesting early findings of myositis. Muscle enzymes may not be diagnostic because  they are not always elevated at diagnosis. Our patient had a normal creatinine kinase level (92 U/L [reference range, <190 U/L]), and both aldolase and lactate dehydrogenase also were within reference range. Conversely, antinuclear antibodies frequently are positive in patients with JDM, such as in our patient at a 1:320 dilution, but are nonspecific and nondiagnostic. It is recommended to include nail fold capillaroscopy to evaluate periungual capillary changes because nailfold capillary density is a sensitive measure of both skin and muscle disease.⁵ Using dermoscopy, nail fold capillary dilation was observed in our patient. 

Other differential diagnoses can have somewhat similar clinical features to JDM. Infantile papular acrodermatitis, commonly referred to as Gianotti-Crosti syndrome, is a viral exanthem that affects children (median age, 2 years).⁶ The rash appears as monomorphous, flat-topped, pink to brown papules affecting the face, buttocks, and arms; it typically spontaneously resolves in 10 days.⁶ 

Juvenile-onset lupus is a chronic autoimmune disorder that can involve any organ system and typically affects children aged 11 to 12 years with a female preponderance. Skin manifestations are similar to adult-onset lupus and include malar rash, discoid rash, oral ulcerations, petechiae, palpable purpura, and digital telangiectasia and ulcers. ⁷ 

Juvenile scleroderma is rare connective-tissue disorder that also has multiple organ involvement. Cutaneous involvement can range from isolated morphealike plaques to diffuse sclerotic lesions with growth disturbances, contractures, and facial atrophy.⁸ 

Verrucae planae, commonly referred to as flat warts, are papules caused primarily by human papillomavirus types 3, 10, 28, and 41. Children and young adults commonly are affected, and warts can appear on the hands, as in our patient.⁶ 

Treatment of JDM depends on disease severity at initial presentation and requires a multidisciplinary approach. The mainstay of treatment is high-dose oral prednisone in combination with disease-modifying drugs such as methotrexate and cyclosporin A. Patients with more severe presentations (eg, ulcerative skin disease) or life-threatening organ involvement are treated with cyclophosphamide, usually in combination with high-dose glucocorticoids.⁹ 

Early detection with aggressive treatment is vital to reduce morbidity and mortality from organ damage and disease complications. Mortality rates have dropped to 3%¹⁰ in recent decades with the use of systemic glucocorticoids. Delayed treatment is associated with a prolonged disease course and poorer outcomes. Disease complications in children with JDM include osteoporosis, calcinosis, and intestinal perforation; however, with early treatment, children with JDM can expect full recovery and to live a normal life as compared to adults with dermatomyositis.¹⁰ 

Prior to our patient's diagnosis, the family was assigned to move to an overseas location through the US Military with no direct access to advanced medical care. Early detection and diagnosis of JDM through an astute clinical examination allowed the patient and her family to remain in the continental United States to continue receiving specialty care.   
 

The Diagnosis: Juvenile Dermatomyositis 

Juvenile dermatomyositis (JDM) is a rare idiopathic inflammatory myopathy of childhood that is autoimmune in nature with an annual incidence ranging from 2.5 to 4.1 cases per million children. Its peak incidence is between 5 and 10 years of age, and it affects girls more than boys at a 2-fold to 5-fold greater rate.¹ Juvenile dermatomyositis is characterized by skeletal muscle weakness in the presence of distinctive rashes, including Gottron papules and heliotrope erythema. Muscle weakness typically is proximal and symmetrical, and eventually patients may have trouble rising from a seated position or lifting objects overhead. Other skin manifestations include nail fold capillary changes, calcinosis cutis, and less commonly ulcerations signifying vasculopathy of the skin.² A subset of patients will present with juvenile amyopathic dermatomyositis. These children have the characteristic skin changes without the muscle weakness or elevated muscle enzymes for more than 6 months; however, one-quarter may go on to develop mysositis.³ 

Diagnosis of JDM traditionally was based on the following 5 diagnostic criteria: characteristic skin rash, proximal muscle weakness, elevated muscle enzymes, myopathic changes on electromyogram, and typical muscle biopsy.¹ Current practice shows a broadening of diagnostic criteria using new techniques in the diagnosis of JDM. To make the diagnosis, the patient must have the characteristic skin manifestations with a minimum of 3 other criteria.⁴ A 2006 international consensus survey expanded the list of criteria to include typical findings on magnetic resonance imaging (MRI), nail fold capillaroscopy abnormalities, calcinosis, and
dysphonia.⁵  

To assess muscle disease, MRI is utilized because it is a reliable noninvasive tool to assess muscle inflammation. Muscle biopsy is only recommended if the diagnosis is unclear.⁵ The results of the MRI in our patient displayed symmetric mild fatty atrophy of the gluteus maximus muscle, as well as edema in the right rectus femoris and left vastus lateralis muscles, suggesting early findings of myositis. Muscle enzymes may not be diagnostic because  they are not always elevated at diagnosis. Our patient had a normal creatinine kinase level (92 U/L [reference range, <190 U/L]), and both aldolase and lactate dehydrogenase also were within reference range. Conversely, antinuclear antibodies frequently are positive in patients with JDM, such as in our patient at a 1:320 dilution, but are nonspecific and nondiagnostic. It is recommended to include nail fold capillaroscopy to evaluate periungual capillary changes because nailfold capillary density is a sensitive measure of both skin and muscle disease.⁵ Using dermoscopy, nail fold capillary dilation was observed in our patient. 

Other differential diagnoses can have somewhat similar clinical features to JDM. Infantile papular acrodermatitis, commonly referred to as Gianotti-Crosti syndrome, is a viral exanthem that affects children (median age, 2 years).⁶ The rash appears as monomorphous, flat-topped, pink to brown papules affecting the face, buttocks, and arms; it typically spontaneously resolves in 10 days.⁶ 

Juvenile-onset lupus is a chronic autoimmune disorder that can involve any organ system and typically affects children aged 11 to 12 years with a female preponderance. Skin manifestations are similar to adult-onset lupus and include malar rash, discoid rash, oral ulcerations, petechiae, palpable purpura, and digital telangiectasia and ulcers. ⁷ 

Juvenile scleroderma is rare connective-tissue disorder that also has multiple organ involvement. Cutaneous involvement can range from isolated morphealike plaques to diffuse sclerotic lesions with growth disturbances, contractures, and facial atrophy.⁸ 

Verrucae planae, commonly referred to as flat warts, are papules caused primarily by human papillomavirus types 3, 10, 28, and 41. Children and young adults commonly are affected, and warts can appear on the hands, as in our patient.⁶ 

Treatment of JDM depends on disease severity at initial presentation and requires a multidisciplinary approach. The mainstay of treatment is high-dose oral prednisone in combination with disease-modifying drugs such as methotrexate and cyclosporin A. Patients with more severe presentations (eg, ulcerative skin disease) or life-threatening organ involvement are treated with cyclophosphamide, usually in combination with high-dose glucocorticoids.⁹ 

Early detection with aggressive treatment is vital to reduce morbidity and mortality from organ damage and disease complications. Mortality rates have dropped to 3%¹⁰ in recent decades with the use of systemic glucocorticoids. Delayed treatment is associated with a prolonged disease course and poorer outcomes. Disease complications in children with JDM include osteoporosis, calcinosis, and intestinal perforation; however, with early treatment, children with JDM can expect full recovery and to live a normal life as compared to adults with dermatomyositis.¹⁰ 

Prior to our patient's diagnosis, the family was assigned to move to an overseas location through the US Military with no direct access to advanced medical care. Early detection and diagnosis of JDM through an astute clinical examination allowed the patient and her family to remain in the continental United States to continue receiving specialty care.   
 

The Diagnosis: Juvenile Dermatomyositis 

Juvenile dermatomyositis (JDM) is a rare idiopathic inflammatory myopathy of childhood that is autoimmune in nature with an annual incidence ranging from 2.5 to 4.1 cases per million children. Its peak incidence is between 5 and 10 years of age, and it affects girls more than boys at a 2-fold to 5-fold greater rate.¹ Juvenile dermatomyositis is characterized by skeletal muscle weakness in the presence of distinctive rashes, including Gottron papules and heliotrope erythema. Muscle weakness typically is proximal and symmetrical, and eventually patients may have trouble rising from a seated position or lifting objects overhead. Other skin manifestations include nail fold capillary changes, calcinosis cutis, and less commonly ulcerations signifying vasculopathy of the skin.² A subset of patients will present with juvenile amyopathic dermatomyositis. These children have the characteristic skin changes without the muscle weakness or elevated muscle enzymes for more than 6 months; however, one-quarter may go on to develop mysositis.³ 

Diagnosis of JDM traditionally was based on the following 5 diagnostic criteria: characteristic skin rash, proximal muscle weakness, elevated muscle enzymes, myopathic changes on electromyogram, and typical muscle biopsy.¹ Current practice shows a broadening of diagnostic criteria using new techniques in the diagnosis of JDM. To make the diagnosis, the patient must have the characteristic skin manifestations with a minimum of 3 other criteria.⁴ A 2006 international consensus survey expanded the list of criteria to include typical findings on magnetic resonance imaging (MRI), nail fold capillaroscopy abnormalities, calcinosis, and
dysphonia.⁵  

To assess muscle disease, MRI is utilized because it is a reliable noninvasive tool to assess muscle inflammation. Muscle biopsy is only recommended if the diagnosis is unclear.⁵ The results of the MRI in our patient displayed symmetric mild fatty atrophy of the gluteus maximus muscle, as well as edema in the right rectus femoris and left vastus lateralis muscles, suggesting early findings of myositis. Muscle enzymes may not be diagnostic because  they are not always elevated at diagnosis. Our patient had a normal creatinine kinase level (92 U/L [reference range, <190 U/L]), and both aldolase and lactate dehydrogenase also were within reference range. Conversely, antinuclear antibodies frequently are positive in patients with JDM, such as in our patient at a 1:320 dilution, but are nonspecific and nondiagnostic. It is recommended to include nail fold capillaroscopy to evaluate periungual capillary changes because nailfold capillary density is a sensitive measure of both skin and muscle disease.⁵ Using dermoscopy, nail fold capillary dilation was observed in our patient. 

Other differential diagnoses can have somewhat similar clinical features to JDM. Infantile papular acrodermatitis, commonly referred to as Gianotti-Crosti syndrome, is a viral exanthem that affects children (median age, 2 years).⁶ The rash appears as monomorphous, flat-topped, pink to brown papules affecting the face, buttocks, and arms; it typically spontaneously resolves in 10 days.⁶ 

Juvenile-onset lupus is a chronic autoimmune disorder that can involve any organ system and typically affects children aged 11 to 12 years with a female preponderance. Skin manifestations are similar to adult-onset lupus and include malar rash, discoid rash, oral ulcerations, petechiae, palpable purpura, and digital telangiectasia and ulcers. ⁷ 

Juvenile scleroderma is rare connective-tissue disorder that also has multiple organ involvement. Cutaneous involvement can range from isolated morphealike plaques to diffuse sclerotic lesions with growth disturbances, contractures, and facial atrophy.⁸ 

Verrucae planae, commonly referred to as flat warts, are papules caused primarily by human papillomavirus types 3, 10, 28, and 41. Children and young adults commonly are affected, and warts can appear on the hands, as in our patient.⁶ 

Treatment of JDM depends on disease severity at initial presentation and requires a multidisciplinary approach. The mainstay of treatment is high-dose oral prednisone in combination with disease-modifying drugs such as methotrexate and cyclosporin A. Patients with more severe presentations (eg, ulcerative skin disease) or life-threatening organ involvement are treated with cyclophosphamide, usually in combination with high-dose glucocorticoids.⁹ 

Early detection with aggressive treatment is vital to reduce morbidity and mortality from organ damage and disease complications. Mortality rates have dropped to 3%¹⁰ in recent decades with the use of systemic glucocorticoids. Delayed treatment is associated with a prolonged disease course and poorer outcomes. Disease complications in children with JDM include osteoporosis, calcinosis, and intestinal perforation; however, with early treatment, children with JDM can expect full recovery and to live a normal life as compared to adults with dermatomyositis.¹⁰ 

Prior to our patient's diagnosis, the family was assigned to move to an overseas location through the US Military with no direct access to advanced medical care. Early detection and diagnosis of JDM through an astute clinical examination allowed the patient and her family to remain in the continental United States to continue receiving specialty care.   
 

As the US population continues to grow and patients become more aware of their health needs, payers are beginning to recognize the benefits of more efficient and cost-effective health care. With the implementation of the new Medicare Physician Fee Schedule on January 1, 2019, some old billing codes were revalued while others were replaced entirely with new codes.¹ The restructuring of the standard biopsy codes now takes the complexity of different sampling techniques into consideration. Furthermore, Current Procedural Terminology (CPT) Category III tracking codes for some imaging devices (eg, optical coherence tomography) added in 2017 require more data before obtaining a Category I reimbursable code, while codes for other imaging devices such as reflectance confocal microscopy (RCM) remain relatively the same.^2-4 Notably, the majority of the new 2019 telemedicine codes are applicable to dermatology.^2,3 In this article, we discuss the new CPT codes for reporting diagnostic procedures, including biopsy, noninvasive imaging, and telemedicine services. We also provide a summary of the national average reimbursement rates for these procedures. 

Background on Reimbursement 

To better understand how reimbursement works, it is important to know that all billing codes are provided a relative value unit (RVU), a number representing the value of the work involved and cost of providing a service relative to other services.⁵ The total RVU consists of the work RVU (wRVU), practice expense RVU (peRVU), and malpractice expense RVU (mRVU). The wRVU represents the time, effort, and complexity involved in performing the service. The peRVU reflects the direct cost of supplies, personnel, and durable equipment involved in providing the service, excluding typical office overhead costs such as rent, utilities, and administrative staff. The mRVU is to cover the cost of malpractice insurance.⁵ The peRVU can be further specified as facility versus nonfacility services depending on where the service is performed.⁶ A facility peRVU is for services completed in a facility such as a hospital, outpatient hospital setting, or nursing home. The facility provides some of the involved supplies, personnel, and equipment for which they can recapture costs by separate reporting, resulting in a lower total RVU for the provider charges compared with nonfacility locations where the physician must provide these items.⁶ Many physicians may not be aware of how critical their role is in determining their own reimbursement rates by understanding RVUs and properly filling out Relative Value Scale Update Committee (RUC) surveys. If surveys sent to practitioners are accurately completed, RVUs have the potential to be fairly valued; however, if respondents are unaware of all of the components that are inherent to a procedure, they may end up minimizing the effort or time involved, which would skew the results and hurt those who perform the procedure. Rather than inputting appropriate preoperative and postoperative service times, many respondents often put 0s and 1s throughout the survey, which misrepresents the amount of time involved for a procedure. For example, inputting a preoperative time as 0 or 1 minute may severely underestimate the work involved for a procedure if the true preoperative time is 5 minutes. Such survey responses affect whether or not RVUs are valued appropriately. 

The billing codes and their RVUs as well as Medicare payment values in your area can be found on the Centers for Medicare & Medicaid Services website.^2,3 Table 1 provides a comparison of the old and new biopsy codes, and Table 2 shows the new RCM codes. 

Biopsy Codes 

Prior to 2019, biopsies were reimbursed using CPT code 11100 for the initial biopsy and 11101 for each additional biopsy.² Called up for refinement in the RUC process, initial data from the Physician Practice Expense Information Survey pointed to the likelihood of different sampling techniques having different amounts of work being supplied by different techniques.¹ Imaging modalities such as dermoscopy or RCM could help minimize the need for surgical biopsies. Dermoscopy, which has been proven to allow for more efficient and accurate diagnoses in dermatology, is reimbursed in Europe but not in the United States.^7-9 In 2016, CPT codes 96931 through 96936 were created for RCM and are covered by most insurances.¹⁰ Optical coherence tomography, another noninvasive imaging technology, currently is not reimbursed but did receive Category III codes (0470T-0471T), also known as a tracking codes, in 2017.⁴ Category III codes are used for emerging technologies that have future potential but do not have enough US-based evidence to support receiving Category I CPT codes. The use of Category III codes allows for data collection on emerging technologies and services, with the potential to convert the Category III codes to Category I codes once certain criteria are met.¹¹ 

Beginning in 2019, the standard biopsy codes 11100 and 11101 were replaced with 6 new codes to represent primary (11102, 11104, 11106) and add-on biopsies (11103, 11105, 11107) based on the sampling technique utilized and the thickness of the sample (Table 1). Previously, the biopsy codes did not reflect the complexity of the different biopsy techniques, whereas the new codes provide differentiation of the method of removal (ie, tangential, punch, incisional).^2,3 The base code is dependent on whichever biopsy performed has the highest complexity, with incisional biopsy--a partial excision--being considered the most complex.³ Punch biopsy is considered the next level of complexity, followed by tangential biopsy. Each of the 6 new biopsy codes also received a new wRVU, which determines reimbursement under Medicare and most other insurers when combined with direct peRVU and mRVU. Additional biopsies, reported using the add-on codes, are reimbursed at a lower level than the base codes because of removal of duplicate inputs for preservice and postservice care.³  

Telehealth Codes 

Telemedicine services offer another form of imaging that providers can use to communicate remotely with patients through a live interactive video stream (with audio), a store-and-forward system with photographs or videos shared asynchronously, or remote patient monitoring.¹² Although live video streaming uses a webcam, store-and-forward services involve sending photographs or videos electronically for later evaluation.^12,13 Remote patient monitoring allows the collection of health-related data and transmission to a physician without the need for an office visit.¹³ Most states require physicians to have a license in the state in which the patient is located at the time of the encounter. Given the difficulty of applying for licensure in multiple states, several states started creating their own special licenses to allow out-of-state providers to offer services through telemedicine.¹⁴ The Federation of State Medical Boards then created the Interstate Medical Licensure Compact (IMLC) for an expedited process to apply for medical licensure in other states. The IMLC was formed to increase access to health care in underserved or rural areas including but not limited to the use of telemedicine.¹⁵ To qualify for IMLC, a physician must have a medical license in a state registered with the IMLC (ie, state of principal license) and have at least one of the following in their state of principal license: primary residence, 25% of their medical practice, a current employer, or US federal income taxes filed.¹⁵ The remaining states that do not have a licensing process for telemedicine allow practice in contiguous states or may provide temporary licenses dependent on the situation.¹⁴ 

Since 2017, billing codes for telemedicine have been the same as those used for in-person evaluation and management services with modifiers -95 or GQ added to the end of the code. Modifier -95 has been used for real-time telemedicine services, while modifier GQ has been used for store-and-forward services.¹⁶ For example, the code 99201, which is used to bill for new patients at outpatient visits, would become 99201-95 if performed using a live audio and video feed or 99201-GQ if information was sent electronically for later analysis. To receive reimbursement from Medicare, modifier -95 requires real-time communication using both audio and video; however, modifier GQ is only reimbursable in federal telemedicine demonstration programs in Alaska or Hawaii.¹² Note that reimbursement is up to the discretion of private providers, and even Medicare reimbursement can vary from state to state. 

In 2019, new Healthcare Common Procedure Coding System telemedicine codes were introduced to include virtual check-ins (G2012) and evaluation of patient-transmitted images and videos (G2010). G2010 is the first store-and-forward code that has the potential to be reimbursed outside of Alaska or Hawaii.^3,12 G2012 allows providers to monitor the patients' well-being outside of the office setting, a cost-effective alternative if patients do not require a full visit. More detailed descriptions of the new codes can be found in Table 3.¹ 

Final Thoughts 

As insurance providers continue to better monitor health care costs, it is of utmost importance that physicians become more involved in accurately assessing their services and procedures, given that the changes in RVUs mirror the Centers for Medicare & Medicaid Services' utilization of the RUC's interpretation of our survey responses.¹ The current billing codes attempt to better represent the work involved for each service, one example being the modification to more specific biopsy codes in 2019.  

With the growth of technology, CPT and Healthcare Common Procedure Coding System codes also reflect a push toward more efficient health care delivery and broader coverage for provider services, as demonstrated by the introduction of new telemedicine codes as well as recent additions of noninvasive imaging codes. Although technology makes health care more cost-effective for patients, clinicians can still maintain their overall reimbursements by efficiently seeing an increasing number of patients; for example, a patient diagnosed noninvasively using RCM can then receive same-day care, which impacts patients' quality of life by minimizing travel time, number of office visits, and time taken off from work, while allowing providers to manage a higher patient volume more productively. The new CPT codes discussed here reflect the growth of medical technology potential, which increases our diagnostic capability, making it even more critical for physicians to engage with these developments. 
 

As the US population continues to grow and patients become more aware of their health needs, payers are beginning to recognize the benefits of more efficient and cost-effective health care. With the implementation of the new Medicare Physician Fee Schedule on January 1, 2019, some old billing codes were revalued while others were replaced entirely with new codes.¹ The restructuring of the standard biopsy codes now takes the complexity of different sampling techniques into consideration. Furthermore, Current Procedural Terminology (CPT) Category III tracking codes for some imaging devices (eg, optical coherence tomography) added in 2017 require more data before obtaining a Category I reimbursable code, while codes for other imaging devices such as reflectance confocal microscopy (RCM) remain relatively the same.^2-4 Notably, the majority of the new 2019 telemedicine codes are applicable to dermatology.^2,3 In this article, we discuss the new CPT codes for reporting diagnostic procedures, including biopsy, noninvasive imaging, and telemedicine services. We also provide a summary of the national average reimbursement rates for these procedures. 

Background on Reimbursement 

To better understand how reimbursement works, it is important to know that all billing codes are provided a relative value unit (RVU), a number representing the value of the work involved and cost of providing a service relative to other services.⁵ The total RVU consists of the work RVU (wRVU), practice expense RVU (peRVU), and malpractice expense RVU (mRVU). The wRVU represents the time, effort, and complexity involved in performing the service. The peRVU reflects the direct cost of supplies, personnel, and durable equipment involved in providing the service, excluding typical office overhead costs such as rent, utilities, and administrative staff. The mRVU is to cover the cost of malpractice insurance.⁵ The peRVU can be further specified as facility versus nonfacility services depending on where the service is performed.⁶ A facility peRVU is for services completed in a facility such as a hospital, outpatient hospital setting, or nursing home. The facility provides some of the involved supplies, personnel, and equipment for which they can recapture costs by separate reporting, resulting in a lower total RVU for the provider charges compared with nonfacility locations where the physician must provide these items.⁶ Many physicians may not be aware of how critical their role is in determining their own reimbursement rates by understanding RVUs and properly filling out Relative Value Scale Update Committee (RUC) surveys. If surveys sent to practitioners are accurately completed, RVUs have the potential to be fairly valued; however, if respondents are unaware of all of the components that are inherent to a procedure, they may end up minimizing the effort or time involved, which would skew the results and hurt those who perform the procedure. Rather than inputting appropriate preoperative and postoperative service times, many respondents often put 0s and 1s throughout the survey, which misrepresents the amount of time involved for a procedure. For example, inputting a preoperative time as 0 or 1 minute may severely underestimate the work involved for a procedure if the true preoperative time is 5 minutes. Such survey responses affect whether or not RVUs are valued appropriately. 

The billing codes and their RVUs as well as Medicare payment values in your area can be found on the Centers for Medicare & Medicaid Services website.^2,3 Table 1 provides a comparison of the old and new biopsy codes, and Table 2 shows the new RCM codes. 

Biopsy Codes 

Prior to 2019, biopsies were reimbursed using CPT code 11100 for the initial biopsy and 11101 for each additional biopsy.² Called up for refinement in the RUC process, initial data from the Physician Practice Expense Information Survey pointed to the likelihood of different sampling techniques having different amounts of work being supplied by different techniques.¹ Imaging modalities such as dermoscopy or RCM could help minimize the need for surgical biopsies. Dermoscopy, which has been proven to allow for more efficient and accurate diagnoses in dermatology, is reimbursed in Europe but not in the United States.^7-9 In 2016, CPT codes 96931 through 96936 were created for RCM and are covered by most insurances.¹⁰ Optical coherence tomography, another noninvasive imaging technology, currently is not reimbursed but did receive Category III codes (0470T-0471T), also known as a tracking codes, in 2017.⁴ Category III codes are used for emerging technologies that have future potential but do not have enough US-based evidence to support receiving Category I CPT codes. The use of Category III codes allows for data collection on emerging technologies and services, with the potential to convert the Category III codes to Category I codes once certain criteria are met.¹¹ 

Beginning in 2019, the standard biopsy codes 11100 and 11101 were replaced with 6 new codes to represent primary (11102, 11104, 11106) and add-on biopsies (11103, 11105, 11107) based on the sampling technique utilized and the thickness of the sample (Table 1). Previously, the biopsy codes did not reflect the complexity of the different biopsy techniques, whereas the new codes provide differentiation of the method of removal (ie, tangential, punch, incisional).^2,3 The base code is dependent on whichever biopsy performed has the highest complexity, with incisional biopsy--a partial excision--being considered the most complex.³ Punch biopsy is considered the next level of complexity, followed by tangential biopsy. Each of the 6 new biopsy codes also received a new wRVU, which determines reimbursement under Medicare and most other insurers when combined with direct peRVU and mRVU. Additional biopsies, reported using the add-on codes, are reimbursed at a lower level than the base codes because of removal of duplicate inputs for preservice and postservice care.³  

Telehealth Codes 

Telemedicine services offer another form of imaging that providers can use to communicate remotely with patients through a live interactive video stream (with audio), a store-and-forward system with photographs or videos shared asynchronously, or remote patient monitoring.¹² Although live video streaming uses a webcam, store-and-forward services involve sending photographs or videos electronically for later evaluation.^12,13 Remote patient monitoring allows the collection of health-related data and transmission to a physician without the need for an office visit.¹³ Most states require physicians to have a license in the state in which the patient is located at the time of the encounter. Given the difficulty of applying for licensure in multiple states, several states started creating their own special licenses to allow out-of-state providers to offer services through telemedicine.¹⁴ The Federation of State Medical Boards then created the Interstate Medical Licensure Compact (IMLC) for an expedited process to apply for medical licensure in other states. The IMLC was formed to increase access to health care in underserved or rural areas including but not limited to the use of telemedicine.¹⁵ To qualify for IMLC, a physician must have a medical license in a state registered with the IMLC (ie, state of principal license) and have at least one of the following in their state of principal license: primary residence, 25% of their medical practice, a current employer, or US federal income taxes filed.¹⁵ The remaining states that do not have a licensing process for telemedicine allow practice in contiguous states or may provide temporary licenses dependent on the situation.¹⁴ 

Since 2017, billing codes for telemedicine have been the same as those used for in-person evaluation and management services with modifiers -95 or GQ added to the end of the code. Modifier -95 has been used for real-time telemedicine services, while modifier GQ has been used for store-and-forward services.¹⁶ For example, the code 99201, which is used to bill for new patients at outpatient visits, would become 99201-95 if performed using a live audio and video feed or 99201-GQ if information was sent electronically for later analysis. To receive reimbursement from Medicare, modifier -95 requires real-time communication using both audio and video; however, modifier GQ is only reimbursable in federal telemedicine demonstration programs in Alaska or Hawaii.¹² Note that reimbursement is up to the discretion of private providers, and even Medicare reimbursement can vary from state to state. 

In 2019, new Healthcare Common Procedure Coding System telemedicine codes were introduced to include virtual check-ins (G2012) and evaluation of patient-transmitted images and videos (G2010). G2010 is the first store-and-forward code that has the potential to be reimbursed outside of Alaska or Hawaii.^3,12 G2012 allows providers to monitor the patients' well-being outside of the office setting, a cost-effective alternative if patients do not require a full visit. More detailed descriptions of the new codes can be found in Table 3.¹ 

Final Thoughts 

As insurance providers continue to better monitor health care costs, it is of utmost importance that physicians become more involved in accurately assessing their services and procedures, given that the changes in RVUs mirror the Centers for Medicare & Medicaid Services' utilization of the RUC's interpretation of our survey responses.¹ The current billing codes attempt to better represent the work involved for each service, one example being the modification to more specific biopsy codes in 2019.  

With the growth of technology, CPT and Healthcare Common Procedure Coding System codes also reflect a push toward more efficient health care delivery and broader coverage for provider services, as demonstrated by the introduction of new telemedicine codes as well as recent additions of noninvasive imaging codes. Although technology makes health care more cost-effective for patients, clinicians can still maintain their overall reimbursements by efficiently seeing an increasing number of patients; for example, a patient diagnosed noninvasively using RCM can then receive same-day care, which impacts patients' quality of life by minimizing travel time, number of office visits, and time taken off from work, while allowing providers to manage a higher patient volume more productively. The new CPT codes discussed here reflect the growth of medical technology potential, which increases our diagnostic capability, making it even more critical for physicians to engage with these developments. 
 

As the US population continues to grow and patients become more aware of their health needs, payers are beginning to recognize the benefits of more efficient and cost-effective health care. With the implementation of the new Medicare Physician Fee Schedule on January 1, 2019, some old billing codes were revalued while others were replaced entirely with new codes.¹ The restructuring of the standard biopsy codes now takes the complexity of different sampling techniques into consideration. Furthermore, Current Procedural Terminology (CPT) Category III tracking codes for some imaging devices (eg, optical coherence tomography) added in 2017 require more data before obtaining a Category I reimbursable code, while codes for other imaging devices such as reflectance confocal microscopy (RCM) remain relatively the same.^2-4 Notably, the majority of the new 2019 telemedicine codes are applicable to dermatology.^2,3 In this article, we discuss the new CPT codes for reporting diagnostic procedures, including biopsy, noninvasive imaging, and telemedicine services. We also provide a summary of the national average reimbursement rates for these procedures. 

Background on Reimbursement 

To better understand how reimbursement works, it is important to know that all billing codes are provided a relative value unit (RVU), a number representing the value of the work involved and cost of providing a service relative to other services.⁵ The total RVU consists of the work RVU (wRVU), practice expense RVU (peRVU), and malpractice expense RVU (mRVU). The wRVU represents the time, effort, and complexity involved in performing the service. The peRVU reflects the direct cost of supplies, personnel, and durable equipment involved in providing the service, excluding typical office overhead costs such as rent, utilities, and administrative staff. The mRVU is to cover the cost of malpractice insurance.⁵ The peRVU can be further specified as facility versus nonfacility services depending on where the service is performed.⁶ A facility peRVU is for services completed in a facility such as a hospital, outpatient hospital setting, or nursing home. The facility provides some of the involved supplies, personnel, and equipment for which they can recapture costs by separate reporting, resulting in a lower total RVU for the provider charges compared with nonfacility locations where the physician must provide these items.⁶ Many physicians may not be aware of how critical their role is in determining their own reimbursement rates by understanding RVUs and properly filling out Relative Value Scale Update Committee (RUC) surveys. If surveys sent to practitioners are accurately completed, RVUs have the potential to be fairly valued; however, if respondents are unaware of all of the components that are inherent to a procedure, they may end up minimizing the effort or time involved, which would skew the results and hurt those who perform the procedure. Rather than inputting appropriate preoperative and postoperative service times, many respondents often put 0s and 1s throughout the survey, which misrepresents the amount of time involved for a procedure. For example, inputting a preoperative time as 0 or 1 minute may severely underestimate the work involved for a procedure if the true preoperative time is 5 minutes. Such survey responses affect whether or not RVUs are valued appropriately. 

The billing codes and their RVUs as well as Medicare payment values in your area can be found on the Centers for Medicare & Medicaid Services website.^2,3 Table 1 provides a comparison of the old and new biopsy codes, and Table 2 shows the new RCM codes. 

Biopsy Codes 

Prior to 2019, biopsies were reimbursed using CPT code 11100 for the initial biopsy and 11101 for each additional biopsy.² Called up for refinement in the RUC process, initial data from the Physician Practice Expense Information Survey pointed to the likelihood of different sampling techniques having different amounts of work being supplied by different techniques.¹ Imaging modalities such as dermoscopy or RCM could help minimize the need for surgical biopsies. Dermoscopy, which has been proven to allow for more efficient and accurate diagnoses in dermatology, is reimbursed in Europe but not in the United States.^7-9 In 2016, CPT codes 96931 through 96936 were created for RCM and are covered by most insurances.¹⁰ Optical coherence tomography, another noninvasive imaging technology, currently is not reimbursed but did receive Category III codes (0470T-0471T), also known as a tracking codes, in 2017.⁴ Category III codes are used for emerging technologies that have future potential but do not have enough US-based evidence to support receiving Category I CPT codes. The use of Category III codes allows for data collection on emerging technologies and services, with the potential to convert the Category III codes to Category I codes once certain criteria are met.¹¹ 

Beginning in 2019, the standard biopsy codes 11100 and 11101 were replaced with 6 new codes to represent primary (11102, 11104, 11106) and add-on biopsies (11103, 11105, 11107) based on the sampling technique utilized and the thickness of the sample (Table 1). Previously, the biopsy codes did not reflect the complexity of the different biopsy techniques, whereas the new codes provide differentiation of the method of removal (ie, tangential, punch, incisional).^2,3 The base code is dependent on whichever biopsy performed has the highest complexity, with incisional biopsy--a partial excision--being considered the most complex.³ Punch biopsy is considered the next level of complexity, followed by tangential biopsy. Each of the 6 new biopsy codes also received a new wRVU, which determines reimbursement under Medicare and most other insurers when combined with direct peRVU and mRVU. Additional biopsies, reported using the add-on codes, are reimbursed at a lower level than the base codes because of removal of duplicate inputs for preservice and postservice care.³  

Telehealth Codes 

Telemedicine services offer another form of imaging that providers can use to communicate remotely with patients through a live interactive video stream (with audio), a store-and-forward system with photographs or videos shared asynchronously, or remote patient monitoring.¹² Although live video streaming uses a webcam, store-and-forward services involve sending photographs or videos electronically for later evaluation.^12,13 Remote patient monitoring allows the collection of health-related data and transmission to a physician without the need for an office visit.¹³ Most states require physicians to have a license in the state in which the patient is located at the time of the encounter. Given the difficulty of applying for licensure in multiple states, several states started creating their own special licenses to allow out-of-state providers to offer services through telemedicine.¹⁴ The Federation of State Medical Boards then created the Interstate Medical Licensure Compact (IMLC) for an expedited process to apply for medical licensure in other states. The IMLC was formed to increase access to health care in underserved or rural areas including but not limited to the use of telemedicine.¹⁵ To qualify for IMLC, a physician must have a medical license in a state registered with the IMLC (ie, state of principal license) and have at least one of the following in their state of principal license: primary residence, 25% of their medical practice, a current employer, or US federal income taxes filed.¹⁵ The remaining states that do not have a licensing process for telemedicine allow practice in contiguous states or may provide temporary licenses dependent on the situation.¹⁴ 

Since 2017, billing codes for telemedicine have been the same as those used for in-person evaluation and management services with modifiers -95 or GQ added to the end of the code. Modifier -95 has been used for real-time telemedicine services, while modifier GQ has been used for store-and-forward services.¹⁶ For example, the code 99201, which is used to bill for new patients at outpatient visits, would become 99201-95 if performed using a live audio and video feed or 99201-GQ if information was sent electronically for later analysis. To receive reimbursement from Medicare, modifier -95 requires real-time communication using both audio and video; however, modifier GQ is only reimbursable in federal telemedicine demonstration programs in Alaska or Hawaii.¹² Note that reimbursement is up to the discretion of private providers, and even Medicare reimbursement can vary from state to state. 

In 2019, new Healthcare Common Procedure Coding System telemedicine codes were introduced to include virtual check-ins (G2012) and evaluation of patient-transmitted images and videos (G2010). G2010 is the first store-and-forward code that has the potential to be reimbursed outside of Alaska or Hawaii.^3,12 G2012 allows providers to monitor the patients' well-being outside of the office setting, a cost-effective alternative if patients do not require a full visit. More detailed descriptions of the new codes can be found in Table 3.¹ 

Final Thoughts 

As insurance providers continue to better monitor health care costs, it is of utmost importance that physicians become more involved in accurately assessing their services and procedures, given that the changes in RVUs mirror the Centers for Medicare & Medicaid Services' utilization of the RUC's interpretation of our survey responses.¹ The current billing codes attempt to better represent the work involved for each service, one example being the modification to more specific biopsy codes in 2019.  

With the growth of technology, CPT and Healthcare Common Procedure Coding System codes also reflect a push toward more efficient health care delivery and broader coverage for provider services, as demonstrated by the introduction of new telemedicine codes as well as recent additions of noninvasive imaging codes. Although technology makes health care more cost-effective for patients, clinicians can still maintain their overall reimbursements by efficiently seeing an increasing number of patients; for example, a patient diagnosed noninvasively using RCM can then receive same-day care, which impacts patients' quality of life by minimizing travel time, number of office visits, and time taken off from work, while allowing providers to manage a higher patient volume more productively. The new CPT codes discussed here reflect the growth of medical technology potential, which increases our diagnostic capability, making it even more critical for physicians to engage with these developments.