MDedge Dermatology

New research could change how experts think about graying hair and what can be done about it. Traditionally, experts thought that undifferentiated stem cells in the hair follicle get called to duty, transform to melanocytes, and then die off.

New evidence points more to a cycle wherein undifferentiated stem cells mature to perform their hair-coloring duties and then transform back to their primitive form. To accomplish this, they need to stay on the move.

When these special stem cells get “stuck” in the follicle, gray hair is the result, according to a new study reported online in Nature.

Curtoicurto/Thinkstock

The regeneration cycle of melanocyte stem cells (McSCs) to melanocytes and back again can last for years. However, McSCs die sooner than do other cells nearby, such as hair follicle stem cells. This difference can explain why people go gray but still grow hair.

“It was thought that melanocyte stem cells are maintained in an undifferentiated state, instead of repeating differentiation and de-differentiation,” said the study’s senior investigator Mayumi Ito, PhD, professor in the departments of dermatology and cell biology at NYU Langone Health, New York.

The process involves different compartments in the hair follicle – the germ area is where the stem cells regenerate; the follicle bulge is where they get stuck. A different microenvironment in each location dictates how they change. This “chameleon-like” property surprised researchers.

Now that investigators figured out how gray hair might get started, a next step will be to search for a way to stop it.

The research has been performed in mice to date but could translate to humans. “Because the structure of the hair follicle is similar between mice and humans, we speculate that human melanocytes may also demonstrate the plasticity during hair regeneration,” Dr. Ito told this news organization.

Future findings could also lead to new therapies. “Our study suggests that moving melanocytes to a proper location within the hair follicle may help prevent gray hair,” Dr. Ito said.

Given the known effects of ultraviolet B (UVB) radiation on melanocytes, Dr. Ito and colleagues wanted to see what effect it might have on this cycle. So in the study, they exposed hair follicles of mice to UVB radiation and report it speeds up the process for McSCs to transform to color-producing melanocytes. They found that these McSCs can regenerate or change back to undifferentiated stem cells, so UVB radiation does not interrupt the process.
 

A melanoma clue?

The study also could have implications for melanoma. Unlike other tumors, melanocytes that cause cancer can self-renew even from a fully differentiated, pigmented form, the researchers note.

This makes melanomas more difficult to eliminate.

“Our study suggests normal melanocytes are very plastic and can reverse a differentiation state. Melanoma cells are known to be very plastic,” Dr. Ito said. “We consider this feature of melanoma may be related to the high plasticity of original melanocytes.”

The finding that melanocyte stem cells “are more plastic than maybe previously given credit for … certainly has implications in melanoma,” agreed Melissa Harris, PhD, associate professor, department of biology at the University of Alabama, Birmingham, when asked to comment on the study.
 

Small technology, big insights?

The advanced technology used by Dr. Ito and colleagues in the study included 3D-intravital imaging and single-cell RNA sequencing to track the stem cells in almost real time as they aged and moved within each hair follicle.

“This paper uses a nice mix of classic and modern techniques to help answer a question that many in the field of pigmentation biology have suspected for a long time. Not all dormant melanocyte stem cells are created equal,” Dr. Harris said.

“The one question not answered in this paper is how to reverse the dysfunction of the melanocyte stem cell ‘stuck’ in the hair bulge,” Dr. Harris added. “There are numerous clinical case studies in humans showing medicine-induced hair repigmentation, and perhaps these cases are examples of dysfunctional melanocyte stem cells becoming ‘unstuck.’ ”
 

‘Very interesting’ findings

The study and its results “are very interesting from a mechanistic perspective and basic science view,” said Anthony M. Rossi, MD, a private practice dermatologist and assistant attending dermatologist at Memorial Sloan Kettering Cancer Center in New York, when asked to comment on the results.

The research provides another view of how melanocyte stem cells can pigment the hair shaft, Dr. Rossi added. “It gives insight into the behavior of stem cells and how they can travel and change state, something not well-known before.”

Dr. Rossi cautioned that other mechanisms are likely taking place. He pointed out that graying of hair can actually occur after a sudden stress event, as well as with vitamin B12 deficiency, thyroid disease, vitiligo-related autoimmune destruction, neurofibromatosis, tuberous sclerosis, and alopecia areata.

The “standout concept” in this paper is that the melanocyte stem cells are stranded and are not getting the right signal from the microenvironment to amplify and appropriately migrate to provide pigment to the hair shaft, said Paradi Mirmirani, MD, a private practice dermatologist in Vallejo, Calif.

It could be challenging to find the right signaling to reverse the graying process, Dr. Mirmirani added. “But the first step is always to understand the underlying basic mechanism. It would be interesting to see if other factors such as smoking, stress … influence the melanocyte stem cells in the same way.”

Grants from the National Institutes of Health and the Department of Defense supported the study. Dr. Ito, Dr. Harris, Dr. Mirmirani, and Dr. Rossi had no relevant disclosures.

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

New research could change how experts think about graying hair and what can be done about it. Traditionally, experts thought that undifferentiated stem cells in the hair follicle get called to duty, transform to melanocytes, and then die off.

New evidence points more to a cycle wherein undifferentiated stem cells mature to perform their hair-coloring duties and then transform back to their primitive form. To accomplish this, they need to stay on the move.

When these special stem cells get “stuck” in the follicle, gray hair is the result, according to a new study reported online in Nature.

Curtoicurto/Thinkstock

The regeneration cycle of melanocyte stem cells (McSCs) to melanocytes and back again can last for years. However, McSCs die sooner than do other cells nearby, such as hair follicle stem cells. This difference can explain why people go gray but still grow hair.

“It was thought that melanocyte stem cells are maintained in an undifferentiated state, instead of repeating differentiation and de-differentiation,” said the study’s senior investigator Mayumi Ito, PhD, professor in the departments of dermatology and cell biology at NYU Langone Health, New York.

The process involves different compartments in the hair follicle – the germ area is where the stem cells regenerate; the follicle bulge is where they get stuck. A different microenvironment in each location dictates how they change. This “chameleon-like” property surprised researchers.

Now that investigators figured out how gray hair might get started, a next step will be to search for a way to stop it.

The research has been performed in mice to date but could translate to humans. “Because the structure of the hair follicle is similar between mice and humans, we speculate that human melanocytes may also demonstrate the plasticity during hair regeneration,” Dr. Ito told this news organization.

Future findings could also lead to new therapies. “Our study suggests that moving melanocytes to a proper location within the hair follicle may help prevent gray hair,” Dr. Ito said.

Given the known effects of ultraviolet B (UVB) radiation on melanocytes, Dr. Ito and colleagues wanted to see what effect it might have on this cycle. So in the study, they exposed hair follicles of mice to UVB radiation and report it speeds up the process for McSCs to transform to color-producing melanocytes. They found that these McSCs can regenerate or change back to undifferentiated stem cells, so UVB radiation does not interrupt the process.
 

A melanoma clue?

The study also could have implications for melanoma. Unlike other tumors, melanocytes that cause cancer can self-renew even from a fully differentiated, pigmented form, the researchers note.

This makes melanomas more difficult to eliminate.

“Our study suggests normal melanocytes are very plastic and can reverse a differentiation state. Melanoma cells are known to be very plastic,” Dr. Ito said. “We consider this feature of melanoma may be related to the high plasticity of original melanocytes.”

The finding that melanocyte stem cells “are more plastic than maybe previously given credit for … certainly has implications in melanoma,” agreed Melissa Harris, PhD, associate professor, department of biology at the University of Alabama, Birmingham, when asked to comment on the study.
 

Small technology, big insights?

The advanced technology used by Dr. Ito and colleagues in the study included 3D-intravital imaging and single-cell RNA sequencing to track the stem cells in almost real time as they aged and moved within each hair follicle.

“This paper uses a nice mix of classic and modern techniques to help answer a question that many in the field of pigmentation biology have suspected for a long time. Not all dormant melanocyte stem cells are created equal,” Dr. Harris said.

“The one question not answered in this paper is how to reverse the dysfunction of the melanocyte stem cell ‘stuck’ in the hair bulge,” Dr. Harris added. “There are numerous clinical case studies in humans showing medicine-induced hair repigmentation, and perhaps these cases are examples of dysfunctional melanocyte stem cells becoming ‘unstuck.’ ”
 

‘Very interesting’ findings

The study and its results “are very interesting from a mechanistic perspective and basic science view,” said Anthony M. Rossi, MD, a private practice dermatologist and assistant attending dermatologist at Memorial Sloan Kettering Cancer Center in New York, when asked to comment on the results.

The research provides another view of how melanocyte stem cells can pigment the hair shaft, Dr. Rossi added. “It gives insight into the behavior of stem cells and how they can travel and change state, something not well-known before.”

Dr. Rossi cautioned that other mechanisms are likely taking place. He pointed out that graying of hair can actually occur after a sudden stress event, as well as with vitamin B12 deficiency, thyroid disease, vitiligo-related autoimmune destruction, neurofibromatosis, tuberous sclerosis, and alopecia areata.

The “standout concept” in this paper is that the melanocyte stem cells are stranded and are not getting the right signal from the microenvironment to amplify and appropriately migrate to provide pigment to the hair shaft, said Paradi Mirmirani, MD, a private practice dermatologist in Vallejo, Calif.

It could be challenging to find the right signaling to reverse the graying process, Dr. Mirmirani added. “But the first step is always to understand the underlying basic mechanism. It would be interesting to see if other factors such as smoking, stress … influence the melanocyte stem cells in the same way.”

Grants from the National Institutes of Health and the Department of Defense supported the study. Dr. Ito, Dr. Harris, Dr. Mirmirani, and Dr. Rossi had no relevant disclosures.

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

New research could change how experts think about graying hair and what can be done about it. Traditionally, experts thought that undifferentiated stem cells in the hair follicle get called to duty, transform to melanocytes, and then die off.

New evidence points more to a cycle wherein undifferentiated stem cells mature to perform their hair-coloring duties and then transform back to their primitive form. To accomplish this, they need to stay on the move.

When these special stem cells get “stuck” in the follicle, gray hair is the result, according to a new study reported online in Nature.

Curtoicurto/Thinkstock

The regeneration cycle of melanocyte stem cells (McSCs) to melanocytes and back again can last for years. However, McSCs die sooner than do other cells nearby, such as hair follicle stem cells. This difference can explain why people go gray but still grow hair.

“It was thought that melanocyte stem cells are maintained in an undifferentiated state, instead of repeating differentiation and de-differentiation,” said the study’s senior investigator Mayumi Ito, PhD, professor in the departments of dermatology and cell biology at NYU Langone Health, New York.

The process involves different compartments in the hair follicle – the germ area is where the stem cells regenerate; the follicle bulge is where they get stuck. A different microenvironment in each location dictates how they change. This “chameleon-like” property surprised researchers.

Now that investigators figured out how gray hair might get started, a next step will be to search for a way to stop it.

The research has been performed in mice to date but could translate to humans. “Because the structure of the hair follicle is similar between mice and humans, we speculate that human melanocytes may also demonstrate the plasticity during hair regeneration,” Dr. Ito told this news organization.

Future findings could also lead to new therapies. “Our study suggests that moving melanocytes to a proper location within the hair follicle may help prevent gray hair,” Dr. Ito said.

Given the known effects of ultraviolet B (UVB) radiation on melanocytes, Dr. Ito and colleagues wanted to see what effect it might have on this cycle. So in the study, they exposed hair follicles of mice to UVB radiation and report it speeds up the process for McSCs to transform to color-producing melanocytes. They found that these McSCs can regenerate or change back to undifferentiated stem cells, so UVB radiation does not interrupt the process.
 

A melanoma clue?

The study also could have implications for melanoma. Unlike other tumors, melanocytes that cause cancer can self-renew even from a fully differentiated, pigmented form, the researchers note.

This makes melanomas more difficult to eliminate.

“Our study suggests normal melanocytes are very plastic and can reverse a differentiation state. Melanoma cells are known to be very plastic,” Dr. Ito said. “We consider this feature of melanoma may be related to the high plasticity of original melanocytes.”

The finding that melanocyte stem cells “are more plastic than maybe previously given credit for … certainly has implications in melanoma,” agreed Melissa Harris, PhD, associate professor, department of biology at the University of Alabama, Birmingham, when asked to comment on the study.
 

Small technology, big insights?

The advanced technology used by Dr. Ito and colleagues in the study included 3D-intravital imaging and single-cell RNA sequencing to track the stem cells in almost real time as they aged and moved within each hair follicle.

“This paper uses a nice mix of classic and modern techniques to help answer a question that many in the field of pigmentation biology have suspected for a long time. Not all dormant melanocyte stem cells are created equal,” Dr. Harris said.

“The one question not answered in this paper is how to reverse the dysfunction of the melanocyte stem cell ‘stuck’ in the hair bulge,” Dr. Harris added. “There are numerous clinical case studies in humans showing medicine-induced hair repigmentation, and perhaps these cases are examples of dysfunctional melanocyte stem cells becoming ‘unstuck.’ ”
 

‘Very interesting’ findings

The study and its results “are very interesting from a mechanistic perspective and basic science view,” said Anthony M. Rossi, MD, a private practice dermatologist and assistant attending dermatologist at Memorial Sloan Kettering Cancer Center in New York, when asked to comment on the results.

The research provides another view of how melanocyte stem cells can pigment the hair shaft, Dr. Rossi added. “It gives insight into the behavior of stem cells and how they can travel and change state, something not well-known before.”

Dr. Rossi cautioned that other mechanisms are likely taking place. He pointed out that graying of hair can actually occur after a sudden stress event, as well as with vitamin B12 deficiency, thyroid disease, vitiligo-related autoimmune destruction, neurofibromatosis, tuberous sclerosis, and alopecia areata.

The “standout concept” in this paper is that the melanocyte stem cells are stranded and are not getting the right signal from the microenvironment to amplify and appropriately migrate to provide pigment to the hair shaft, said Paradi Mirmirani, MD, a private practice dermatologist in Vallejo, Calif.

It could be challenging to find the right signaling to reverse the graying process, Dr. Mirmirani added. “But the first step is always to understand the underlying basic mechanism. It would be interesting to see if other factors such as smoking, stress … influence the melanocyte stem cells in the same way.”

Grants from the National Institutes of Health and the Department of Defense supported the study. Dr. Ito, Dr. Harris, Dr. Mirmirani, and Dr. Rossi had no relevant disclosures.

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

The U.S. Food and Drug Administration has granted Fast Track designation for Cabaletta Bio’s cell therapy CABA-201 for the treatment of systemic lupus erythematosus (SLE) and lupus nephritis (LN), the company announced May 1.
 

The FDA cleared Cabaletta to begin a phase 1/2 clinical trial of CABA-201, the statement says, which will be the first trial accessing Cabaletta’s Chimeric Antigen Receptor T cells for Autoimmunity (CARTA) approach. CABA-201, a 4-1BB–containing fully human CD19-CAR T-cell investigational therapy, is designed to target and deplete CD19-positive B cells, “enabling an ‘immune system reset’ with durable remission in patients with SLE,” according to the press release. This news organization previously reported on a small study in Germany, published in Nature Medicine, that also used anti-CD19 CAR T cells to treat five patients with SLE.

Wikimedia Commons/FitzColinGerald/Creative Commons License

This upcoming open-label study will enroll two cohorts containing six patients each. One cohort will be patients with SLE and active LN, and the other will be patients with SLE without renal involvement. The therapy is designed as a one-time infusion and will be administered at a dose of 1.0 x 106 cells/kg.

“We believe the FDA’s decision to grant Fast Track Designation for CABA-201 underscores the unmet need for a treatment that has the potential to provide deep and durable responses for people living with lupus and potentially other autoimmune diseases where B cells contribute to disease,” David J. Chang, MD, chief medical officer of Cabaletta, said in the press release.

FDA Fast Track is a process designed to expedite the development and review of drugs and other therapeutics that treat serious conditions and address unmet medical needs. Companies that receive Fast Track designation for a drug have the opportunity for more frequent meetings and written communication with the FDA about the drug’s development plan and design of clinical trials. The fast-tracked drug can also be eligible for accelerated approval and priority review if relevant criteria are met.

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

The U.S. Food and Drug Administration has granted Fast Track designation for Cabaletta Bio’s cell therapy CABA-201 for the treatment of systemic lupus erythematosus (SLE) and lupus nephritis (LN), the company announced May 1.
 

The FDA cleared Cabaletta to begin a phase 1/2 clinical trial of CABA-201, the statement says, which will be the first trial accessing Cabaletta’s Chimeric Antigen Receptor T cells for Autoimmunity (CARTA) approach. CABA-201, a 4-1BB–containing fully human CD19-CAR T-cell investigational therapy, is designed to target and deplete CD19-positive B cells, “enabling an ‘immune system reset’ with durable remission in patients with SLE,” according to the press release. This news organization previously reported on a small study in Germany, published in Nature Medicine, that also used anti-CD19 CAR T cells to treat five patients with SLE.

Wikimedia Commons/FitzColinGerald/Creative Commons License

This upcoming open-label study will enroll two cohorts containing six patients each. One cohort will be patients with SLE and active LN, and the other will be patients with SLE without renal involvement. The therapy is designed as a one-time infusion and will be administered at a dose of 1.0 x 106 cells/kg.

“We believe the FDA’s decision to grant Fast Track Designation for CABA-201 underscores the unmet need for a treatment that has the potential to provide deep and durable responses for people living with lupus and potentially other autoimmune diseases where B cells contribute to disease,” David J. Chang, MD, chief medical officer of Cabaletta, said in the press release.

FDA Fast Track is a process designed to expedite the development and review of drugs and other therapeutics that treat serious conditions and address unmet medical needs. Companies that receive Fast Track designation for a drug have the opportunity for more frequent meetings and written communication with the FDA about the drug’s development plan and design of clinical trials. The fast-tracked drug can also be eligible for accelerated approval and priority review if relevant criteria are met.

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

The U.S. Food and Drug Administration has granted Fast Track designation for Cabaletta Bio’s cell therapy CABA-201 for the treatment of systemic lupus erythematosus (SLE) and lupus nephritis (LN), the company announced May 1.
 

The FDA cleared Cabaletta to begin a phase 1/2 clinical trial of CABA-201, the statement says, which will be the first trial accessing Cabaletta’s Chimeric Antigen Receptor T cells for Autoimmunity (CARTA) approach. CABA-201, a 4-1BB–containing fully human CD19-CAR T-cell investigational therapy, is designed to target and deplete CD19-positive B cells, “enabling an ‘immune system reset’ with durable remission in patients with SLE,” according to the press release. This news organization previously reported on a small study in Germany, published in Nature Medicine, that also used anti-CD19 CAR T cells to treat five patients with SLE.

Wikimedia Commons/FitzColinGerald/Creative Commons License

This upcoming open-label study will enroll two cohorts containing six patients each. One cohort will be patients with SLE and active LN, and the other will be patients with SLE without renal involvement. The therapy is designed as a one-time infusion and will be administered at a dose of 1.0 x 106 cells/kg.

“We believe the FDA’s decision to grant Fast Track Designation for CABA-201 underscores the unmet need for a treatment that has the potential to provide deep and durable responses for people living with lupus and potentially other autoimmune diseases where B cells contribute to disease,” David J. Chang, MD, chief medical officer of Cabaletta, said in the press release.

FDA Fast Track is a process designed to expedite the development and review of drugs and other therapeutics that treat serious conditions and address unmet medical needs. Companies that receive Fast Track designation for a drug have the opportunity for more frequent meetings and written communication with the FDA about the drug’s development plan and design of clinical trials. The fast-tracked drug can also be eligible for accelerated approval and priority review if relevant criteria are met.

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

PHOENIX – While the use of lasers and energy-based devices for genitourinary indications dates back more than 50 years, a large body of scientific evidence has since accumulated for conditions ranging from genitourinary syndrome of menopause (GSM), lichen sclerosus, urinary incontinence, and vulvovaginal laxity.

“Even a cursory review of PubMed today yields over 100,000 results” on this topic, Macrene R. Alexiades, MD, PhD, associate clinical professor of dermatology at Yale University, New Haven, Conn., said at the annual conference of the American Society for Laser Medicine and Surgery. “Add to that radiofrequency and various diagnoses, the number of publications has skyrocketed, particularly over the last 10 years.”

What has been missing from this hot research topic all these years, she continued, is that no one has distilled this pile of data into a practical guide for office-based clinicians who use lasers and energy-based devices for genitourinary conditions – until now. Working with experts in gynecology and urogynecology, Dr. Alexiades spearheaded a 2-year-long effort to assemble a document on optimal protocols and best practices for genitourinary application of lasers and energy-based devices. The document, published soon after the ASLMS meeting in Lasers in Medicine and Surgery, includes a table that lists the current Food and Drug Administration approval status of devices in genitourinary applications, as well as individual sections dedicated to fractional lasers, radiofrequency (RF) devices, and high-intensity focused electromagnetic technology. It concludes with a section on the current status of clearances and future pathways.

“The work we did was exhaustive,” said Dr. Alexiades, who is also founder and director of Dermatology & Laser Surgery Center of New York. “We went through all the clinical trial data and compiled the parameters that, as a consensus, we agree are best practices for each technology for which we had rigorous published data.”

The document contains a brief background on the history of the devices used for genitourinary issues and it addresses core topics for each technology, such as conditions treated, contraindications, preoperative physical assessment and preparation, perioperative protocols, and postoperative care.

Contraindications to the genitourinary use of lasers and energy-based devices are numerous and include use of an intrauterine device, active urinary tract or genital infection, vaginal bleeding, current pregnancy, active or recent malignancy, having an electrical implant anywhere in the body, significant concurrent illness, and an anticoagulative or thromboembolic condition or taking anticoagulant medications 1 week prior to the procedure. Another condition to screen for is advanced prolapse, which was considered a contraindication in all clinical trials, she added. “It’s important that you’re able to do the speculum exam and stage the prolapse” so that a patient with this contraindication is not treated.

Dr. Alexiades shared the following highlights from the document’s section related to the use of fractional CO₂ lasers:

Preoperative management. Schedule the treatment one week after the patient’s menstrual period. Patients should avoid blood thinners for 7 days and avoid intercourse the night before the procedure. Reschedule in the case of fever, chills, or vaginal bleeding or discharge.

Preoperative physical exam and testing. A normal speculum exam and a recent negative PAP smear are required. For those of child-bearing potential, a pregnancy test is warranted. Obtain written and verbal consent, including discussion of all treatment options, risks, and benefits. No topical or local anesthesia is necessary internally. “Externally, we sometimes apply topical lidocaine gel, but I have found that’s not necessary in most cases,” Dr. Alexiades said. “The treatment is so quick.”

Peri-operative management. In general, device settings are provided by the manufacturer. “For most of the studies that had successful outcomes and no adverse events, researchers adhered to the mild or moderate settings on the technology,” she said. Energy settings were between 15 and 30 watts, delivered at a laser fluence of about 250-300 mJ/cm² with a spacing of microbeams 1 mm apart. Typically, three treatments are done at 1-month intervals and maintenance treatments are recommended at 6 and 12 months based on duration of the outcomes.

Vulvovaginal postoperative management. A 3-day recovery time is recommended with avoidance of intercourse during this period, because “re-epithelialization is usually complete in 3 days, so we want to give the opportunity for the lining to heal prior to introducing any friction, Dr. Alexiades said.” Rarely, spotting or discharge may occur and there should be no discomfort. “Any severe discomfort or burning may potentially signify infection and should prompt evaluation and possibly vaginal cultures. The patient can shower, but we recommend avoiding seated baths to decrease any introduction of infectious agents.”

Patients should be followed up monthly until three treatments are completed, and a maintenance treatment is considered appropriate between 6 and 12 months. “I do recommend doing a 1-month follow-up following the final treatment, unless it’s a patient who has already had a series of three treatments and is coming in for maintenance,” she said.

In a study from her own practice, Dr. Alexiades evaluated a series of three fractional CO₂ laser treatments to the vulva and vagina with a 1-year follow-up in postmenopausal patients. She used the Vaginal Health Index (VHI) to assess changes in vaginal elasticity, fluid volume, vaginal pH, epithelial integrity, and moisture. She and her colleagues discovered that there was improvement in every VHI category after treatment and during the follow-up interval up to 6 months.

“Between 6 and 12 months, we started to see a return a bit toward baseline on all of these parameters,” she said. “The serendipitous discovery that I made during the course of that study was that early intervention improves outcomes. I observed that the younger, most recently postmenopausal cohort seemed to attain normal or near normal VHI quicker than the more extended postmenopausal cohorts.”

In an editorial published in 2020, Dr. Alexiades reviewed the effects of fractional CO₂ laser treatment of vulvar skin on vaginal pH and referred to a study she conducted that found that the mean baseline pH pretreatment was 6.32 in the cohort of postmenopausal patients, and was reduced after 3 treatments. “Postmenopausally, the normal acidic pH becomes alkaline,” she said. But she did not expect to see an additional reduction in pH following the treatment out to 6 months. “This indicates that, whatever the wound healing and other restorative effects of these devices are, they seem to continue out to 6 months, at which point it turns around and moves toward baseline [levels].”

Dr. Alexiades highlighted two published meta-analyses of studies related to the genitourinary use of lasers and energy-based devices. One included 59 studies of 3,609 women treated for vaginal rejuvenation using either radiofrequency or fractional ablative laser therapy. The studies reported improvements in symptoms of GSM/VVA and sexual function, high patient satisfaction, with minor adverse events, including treatment-associated vaginal swelling or vaginal discharge.

“Further research needs to be completed to determine which specific pathologies can be treated, if maintenance treatment is necessary, and long-term safety concerns,” the authors concluded.

In another review, researchers analyzed 64 studies related to vaginal laser therapy for GSM. Of these, 47 were before and after studies without a control group, 10 were controlled intervention studies, and 7 were observational cohort and cross-sectional studies.

Vaginal laser treatment “seems to improve scores on the visual analogue scale, Female Sexual Function Index, and the Vaginal Health Index over the short term,” the authors wrote. “Safety outcomes are underreported and short term. Further well-designed clinical trials with sham-laser control groups and evaluating objective variables are needed to provide the best evidence on efficacy.”

“Lasers and energy-based devices are now considered alternative therapeutic modalities for genitourinary conditions,” Dr. Alexiades concluded. “The shortcomings in the literature with respect to lasers and device treatments demonstrate the need for the consensus on best practices and protocols.”

During a separate presentation at the meeting, Michael Gold, MD, highlighted data from Grand View Research, a market research database, which estimated that the global women’s health and wellness market is valued at more than $31 billion globally and is expected to grow at a compound annual growth rate of 4.8% from 2022 to 2030.

“Sales of women’s health energy-based devices continue to grow as new technologies are developed,” said Dr. Gold, a Nashville, Tenn.–based dermatologist and cosmetic surgeon who is also editor-in-chief of the Journal of Cosmetic Dermatology. “Evolving societal norms have made discussions about feminine health issues acceptable. Suffering in silence is no longer necessary or advocated.”

Dr. Alexiades disclosed that she has conducted research for Candela Lasers, Lumenis, Allergan/AbbVie, InMode, and Endymed. She is also the founder and CEO of Macrene Actives. Dr. Gold disclosed that he is a consultant to and/or an investigator and a speaker for Joylux, InMode, and Alma Lasers.
 

PHOENIX – While the use of lasers and energy-based devices for genitourinary indications dates back more than 50 years, a large body of scientific evidence has since accumulated for conditions ranging from genitourinary syndrome of menopause (GSM), lichen sclerosus, urinary incontinence, and vulvovaginal laxity.

“Even a cursory review of PubMed today yields over 100,000 results” on this topic, Macrene R. Alexiades, MD, PhD, associate clinical professor of dermatology at Yale University, New Haven, Conn., said at the annual conference of the American Society for Laser Medicine and Surgery. “Add to that radiofrequency and various diagnoses, the number of publications has skyrocketed, particularly over the last 10 years.”

What has been missing from this hot research topic all these years, she continued, is that no one has distilled this pile of data into a practical guide for office-based clinicians who use lasers and energy-based devices for genitourinary conditions – until now. Working with experts in gynecology and urogynecology, Dr. Alexiades spearheaded a 2-year-long effort to assemble a document on optimal protocols and best practices for genitourinary application of lasers and energy-based devices. The document, published soon after the ASLMS meeting in Lasers in Medicine and Surgery, includes a table that lists the current Food and Drug Administration approval status of devices in genitourinary applications, as well as individual sections dedicated to fractional lasers, radiofrequency (RF) devices, and high-intensity focused electromagnetic technology. It concludes with a section on the current status of clearances and future pathways.

“The work we did was exhaustive,” said Dr. Alexiades, who is also founder and director of Dermatology & Laser Surgery Center of New York. “We went through all the clinical trial data and compiled the parameters that, as a consensus, we agree are best practices for each technology for which we had rigorous published data.”

The document contains a brief background on the history of the devices used for genitourinary issues and it addresses core topics for each technology, such as conditions treated, contraindications, preoperative physical assessment and preparation, perioperative protocols, and postoperative care.

Contraindications to the genitourinary use of lasers and energy-based devices are numerous and include use of an intrauterine device, active urinary tract or genital infection, vaginal bleeding, current pregnancy, active or recent malignancy, having an electrical implant anywhere in the body, significant concurrent illness, and an anticoagulative or thromboembolic condition or taking anticoagulant medications 1 week prior to the procedure. Another condition to screen for is advanced prolapse, which was considered a contraindication in all clinical trials, she added. “It’s important that you’re able to do the speculum exam and stage the prolapse” so that a patient with this contraindication is not treated.

Dr. Alexiades shared the following highlights from the document’s section related to the use of fractional CO₂ lasers:

Preoperative management. Schedule the treatment one week after the patient’s menstrual period. Patients should avoid blood thinners for 7 days and avoid intercourse the night before the procedure. Reschedule in the case of fever, chills, or vaginal bleeding or discharge.

Preoperative physical exam and testing. A normal speculum exam and a recent negative PAP smear are required. For those of child-bearing potential, a pregnancy test is warranted. Obtain written and verbal consent, including discussion of all treatment options, risks, and benefits. No topical or local anesthesia is necessary internally. “Externally, we sometimes apply topical lidocaine gel, but I have found that’s not necessary in most cases,” Dr. Alexiades said. “The treatment is so quick.”

Peri-operative management. In general, device settings are provided by the manufacturer. “For most of the studies that had successful outcomes and no adverse events, researchers adhered to the mild or moderate settings on the technology,” she said. Energy settings were between 15 and 30 watts, delivered at a laser fluence of about 250-300 mJ/cm² with a spacing of microbeams 1 mm apart. Typically, three treatments are done at 1-month intervals and maintenance treatments are recommended at 6 and 12 months based on duration of the outcomes.

Vulvovaginal postoperative management. A 3-day recovery time is recommended with avoidance of intercourse during this period, because “re-epithelialization is usually complete in 3 days, so we want to give the opportunity for the lining to heal prior to introducing any friction, Dr. Alexiades said.” Rarely, spotting or discharge may occur and there should be no discomfort. “Any severe discomfort or burning may potentially signify infection and should prompt evaluation and possibly vaginal cultures. The patient can shower, but we recommend avoiding seated baths to decrease any introduction of infectious agents.”

Patients should be followed up monthly until three treatments are completed, and a maintenance treatment is considered appropriate between 6 and 12 months. “I do recommend doing a 1-month follow-up following the final treatment, unless it’s a patient who has already had a series of three treatments and is coming in for maintenance,” she said.

In a study from her own practice, Dr. Alexiades evaluated a series of three fractional CO₂ laser treatments to the vulva and vagina with a 1-year follow-up in postmenopausal patients. She used the Vaginal Health Index (VHI) to assess changes in vaginal elasticity, fluid volume, vaginal pH, epithelial integrity, and moisture. She and her colleagues discovered that there was improvement in every VHI category after treatment and during the follow-up interval up to 6 months.

“Between 6 and 12 months, we started to see a return a bit toward baseline on all of these parameters,” she said. “The serendipitous discovery that I made during the course of that study was that early intervention improves outcomes. I observed that the younger, most recently postmenopausal cohort seemed to attain normal or near normal VHI quicker than the more extended postmenopausal cohorts.”

In an editorial published in 2020, Dr. Alexiades reviewed the effects of fractional CO₂ laser treatment of vulvar skin on vaginal pH and referred to a study she conducted that found that the mean baseline pH pretreatment was 6.32 in the cohort of postmenopausal patients, and was reduced after 3 treatments. “Postmenopausally, the normal acidic pH becomes alkaline,” she said. But she did not expect to see an additional reduction in pH following the treatment out to 6 months. “This indicates that, whatever the wound healing and other restorative effects of these devices are, they seem to continue out to 6 months, at which point it turns around and moves toward baseline [levels].”

Dr. Alexiades highlighted two published meta-analyses of studies related to the genitourinary use of lasers and energy-based devices. One included 59 studies of 3,609 women treated for vaginal rejuvenation using either radiofrequency or fractional ablative laser therapy. The studies reported improvements in symptoms of GSM/VVA and sexual function, high patient satisfaction, with minor adverse events, including treatment-associated vaginal swelling or vaginal discharge.

“Further research needs to be completed to determine which specific pathologies can be treated, if maintenance treatment is necessary, and long-term safety concerns,” the authors concluded.

In another review, researchers analyzed 64 studies related to vaginal laser therapy for GSM. Of these, 47 were before and after studies without a control group, 10 were controlled intervention studies, and 7 were observational cohort and cross-sectional studies.

Vaginal laser treatment “seems to improve scores on the visual analogue scale, Female Sexual Function Index, and the Vaginal Health Index over the short term,” the authors wrote. “Safety outcomes are underreported and short term. Further well-designed clinical trials with sham-laser control groups and evaluating objective variables are needed to provide the best evidence on efficacy.”

“Lasers and energy-based devices are now considered alternative therapeutic modalities for genitourinary conditions,” Dr. Alexiades concluded. “The shortcomings in the literature with respect to lasers and device treatments demonstrate the need for the consensus on best practices and protocols.”

During a separate presentation at the meeting, Michael Gold, MD, highlighted data from Grand View Research, a market research database, which estimated that the global women’s health and wellness market is valued at more than $31 billion globally and is expected to grow at a compound annual growth rate of 4.8% from 2022 to 2030.

“Sales of women’s health energy-based devices continue to grow as new technologies are developed,” said Dr. Gold, a Nashville, Tenn.–based dermatologist and cosmetic surgeon who is also editor-in-chief of the Journal of Cosmetic Dermatology. “Evolving societal norms have made discussions about feminine health issues acceptable. Suffering in silence is no longer necessary or advocated.”

Dr. Alexiades disclosed that she has conducted research for Candela Lasers, Lumenis, Allergan/AbbVie, InMode, and Endymed. She is also the founder and CEO of Macrene Actives. Dr. Gold disclosed that he is a consultant to and/or an investigator and a speaker for Joylux, InMode, and Alma Lasers.
 

PHOENIX – While the use of lasers and energy-based devices for genitourinary indications dates back more than 50 years, a large body of scientific evidence has since accumulated for conditions ranging from genitourinary syndrome of menopause (GSM), lichen sclerosus, urinary incontinence, and vulvovaginal laxity.

“Even a cursory review of PubMed today yields over 100,000 results” on this topic, Macrene R. Alexiades, MD, PhD, associate clinical professor of dermatology at Yale University, New Haven, Conn., said at the annual conference of the American Society for Laser Medicine and Surgery. “Add to that radiofrequency and various diagnoses, the number of publications has skyrocketed, particularly over the last 10 years.”

What has been missing from this hot research topic all these years, she continued, is that no one has distilled this pile of data into a practical guide for office-based clinicians who use lasers and energy-based devices for genitourinary conditions – until now. Working with experts in gynecology and urogynecology, Dr. Alexiades spearheaded a 2-year-long effort to assemble a document on optimal protocols and best practices for genitourinary application of lasers and energy-based devices. The document, published soon after the ASLMS meeting in Lasers in Medicine and Surgery, includes a table that lists the current Food and Drug Administration approval status of devices in genitourinary applications, as well as individual sections dedicated to fractional lasers, radiofrequency (RF) devices, and high-intensity focused electromagnetic technology. It concludes with a section on the current status of clearances and future pathways.

“The work we did was exhaustive,” said Dr. Alexiades, who is also founder and director of Dermatology & Laser Surgery Center of New York. “We went through all the clinical trial data and compiled the parameters that, as a consensus, we agree are best practices for each technology for which we had rigorous published data.”

The document contains a brief background on the history of the devices used for genitourinary issues and it addresses core topics for each technology, such as conditions treated, contraindications, preoperative physical assessment and preparation, perioperative protocols, and postoperative care.

Contraindications to the genitourinary use of lasers and energy-based devices are numerous and include use of an intrauterine device, active urinary tract or genital infection, vaginal bleeding, current pregnancy, active or recent malignancy, having an electrical implant anywhere in the body, significant concurrent illness, and an anticoagulative or thromboembolic condition or taking anticoagulant medications 1 week prior to the procedure. Another condition to screen for is advanced prolapse, which was considered a contraindication in all clinical trials, she added. “It’s important that you’re able to do the speculum exam and stage the prolapse” so that a patient with this contraindication is not treated.

Dr. Alexiades shared the following highlights from the document’s section related to the use of fractional CO₂ lasers:

Preoperative management. Schedule the treatment one week after the patient’s menstrual period. Patients should avoid blood thinners for 7 days and avoid intercourse the night before the procedure. Reschedule in the case of fever, chills, or vaginal bleeding or discharge.

Preoperative physical exam and testing. A normal speculum exam and a recent negative PAP smear are required. For those of child-bearing potential, a pregnancy test is warranted. Obtain written and verbal consent, including discussion of all treatment options, risks, and benefits. No topical or local anesthesia is necessary internally. “Externally, we sometimes apply topical lidocaine gel, but I have found that’s not necessary in most cases,” Dr. Alexiades said. “The treatment is so quick.”

Peri-operative management. In general, device settings are provided by the manufacturer. “For most of the studies that had successful outcomes and no adverse events, researchers adhered to the mild or moderate settings on the technology,” she said. Energy settings were between 15 and 30 watts, delivered at a laser fluence of about 250-300 mJ/cm² with a spacing of microbeams 1 mm apart. Typically, three treatments are done at 1-month intervals and maintenance treatments are recommended at 6 and 12 months based on duration of the outcomes.

Vulvovaginal postoperative management. A 3-day recovery time is recommended with avoidance of intercourse during this period, because “re-epithelialization is usually complete in 3 days, so we want to give the opportunity for the lining to heal prior to introducing any friction, Dr. Alexiades said.” Rarely, spotting or discharge may occur and there should be no discomfort. “Any severe discomfort or burning may potentially signify infection and should prompt evaluation and possibly vaginal cultures. The patient can shower, but we recommend avoiding seated baths to decrease any introduction of infectious agents.”

Patients should be followed up monthly until three treatments are completed, and a maintenance treatment is considered appropriate between 6 and 12 months. “I do recommend doing a 1-month follow-up following the final treatment, unless it’s a patient who has already had a series of three treatments and is coming in for maintenance,” she said.

In a study from her own practice, Dr. Alexiades evaluated a series of three fractional CO₂ laser treatments to the vulva and vagina with a 1-year follow-up in postmenopausal patients. She used the Vaginal Health Index (VHI) to assess changes in vaginal elasticity, fluid volume, vaginal pH, epithelial integrity, and moisture. She and her colleagues discovered that there was improvement in every VHI category after treatment and during the follow-up interval up to 6 months.

“Between 6 and 12 months, we started to see a return a bit toward baseline on all of these parameters,” she said. “The serendipitous discovery that I made during the course of that study was that early intervention improves outcomes. I observed that the younger, most recently postmenopausal cohort seemed to attain normal or near normal VHI quicker than the more extended postmenopausal cohorts.”

In an editorial published in 2020, Dr. Alexiades reviewed the effects of fractional CO₂ laser treatment of vulvar skin on vaginal pH and referred to a study she conducted that found that the mean baseline pH pretreatment was 6.32 in the cohort of postmenopausal patients, and was reduced after 3 treatments. “Postmenopausally, the normal acidic pH becomes alkaline,” she said. But she did not expect to see an additional reduction in pH following the treatment out to 6 months. “This indicates that, whatever the wound healing and other restorative effects of these devices are, they seem to continue out to 6 months, at which point it turns around and moves toward baseline [levels].”

Dr. Alexiades highlighted two published meta-analyses of studies related to the genitourinary use of lasers and energy-based devices. One included 59 studies of 3,609 women treated for vaginal rejuvenation using either radiofrequency or fractional ablative laser therapy. The studies reported improvements in symptoms of GSM/VVA and sexual function, high patient satisfaction, with minor adverse events, including treatment-associated vaginal swelling or vaginal discharge.

“Further research needs to be completed to determine which specific pathologies can be treated, if maintenance treatment is necessary, and long-term safety concerns,” the authors concluded.

In another review, researchers analyzed 64 studies related to vaginal laser therapy for GSM. Of these, 47 were before and after studies without a control group, 10 were controlled intervention studies, and 7 were observational cohort and cross-sectional studies.

Vaginal laser treatment “seems to improve scores on the visual analogue scale, Female Sexual Function Index, and the Vaginal Health Index over the short term,” the authors wrote. “Safety outcomes are underreported and short term. Further well-designed clinical trials with sham-laser control groups and evaluating objective variables are needed to provide the best evidence on efficacy.”

“Lasers and energy-based devices are now considered alternative therapeutic modalities for genitourinary conditions,” Dr. Alexiades concluded. “The shortcomings in the literature with respect to lasers and device treatments demonstrate the need for the consensus on best practices and protocols.”

During a separate presentation at the meeting, Michael Gold, MD, highlighted data from Grand View Research, a market research database, which estimated that the global women’s health and wellness market is valued at more than $31 billion globally and is expected to grow at a compound annual growth rate of 4.8% from 2022 to 2030.

“Sales of women’s health energy-based devices continue to grow as new technologies are developed,” said Dr. Gold, a Nashville, Tenn.–based dermatologist and cosmetic surgeon who is also editor-in-chief of the Journal of Cosmetic Dermatology. “Evolving societal norms have made discussions about feminine health issues acceptable. Suffering in silence is no longer necessary or advocated.”

Dr. Alexiades disclosed that she has conducted research for Candela Lasers, Lumenis, Allergan/AbbVie, InMode, and Endymed. She is also the founder and CEO of Macrene Actives. Dr. Gold disclosed that he is a consultant to and/or an investigator and a speaker for Joylux, InMode, and Alma Lasers.
 

The Diagnosis: Pleomorphic Lipoma

Pleomorphic lipoma is a rare, benign, adipocytic neoplasm that presents in the subcutaneous tissues of the upper shoulder, back, or neck. It predominantly affects men aged 50 to 70 years. Most lesions are situated in the subcutaneous tissues; few cases of intramuscular and retroperitoneal tumors have been reported.¹ Clinically, pleomorphic lipomas present as painless, well-circumscribed lesions of the subcutaneous tissue that often resemble a lipoma or occasionally may be mistaken for liposarcoma. Histopathologic examination of ordinary lipomas reveals uniform mature adipocytes. However, pleomorphic lipomas consist of a mixture of multinucleated floretlike giant cells, variable-sized adipocytes, and fibrous tissue (ropy collagen bundles) with some myxoid and spindled areas.^1,2 The most characteristic histologic feature of pleomorphic lipoma is multinucleated floretlike giant cells. The nuclei of these giant cells appear hyperchromatic, enlarged, and disposed to the periphery of the cell in a circular pattern. Additionally, tumors frequently contain excess mature dense collagen bundles that are strongly refractile in polarized light. Numerous mast cells are present. Atypical lipoblasts and capillary networks commonly are not visible in pleomorphic lipoma.³ The spindle cells express CD34 on immunohistochemistry. Loss of Rb-1 expression is typical.⁴

Dermatofibrosarcoma protuberans is a slow-growing soft tissue sarcoma that commonly begins as a pink or violet plaque on the trunk or upper limbs. Involvement of the head or neck accounts for only 10% to 15% of cases.⁵ This tumor has low metastatic potential but is highly infiltrative of surrounding tissues. It is associated with a translocation between chromosomes 22 and 17, leading to the fusion of the platelet-derived growth factor subunit β, PDGFB, and collagen type 1α1, COL1A1, genes.⁵ Clinically, patients often report that the lesion was present for several years prior to presentation with general stability in size and shape. Eventually, untreated lesions progress to become nodules or tumors and may even bleed or ulcerate. Histology reveals a storiform spindle cell proliferation throughout the dermis with infiltration into subcutaneous fat, commonly appearing in a honeycomblike pattern (Figure 1). Numerous histologic variants exist, including myxoid, sclerosing, pigmented (Bednar tumor), myoid, atrophic, or fibrosarcomatous dermatofibrosarcoma protuberans, as well as a giant cell fibroblastoma variant.⁶ These tumor subtypes can exist independently or in association with one another, creating hybrid lesions that can closely mimic other entities such as pleomorphic lipoma. The spindle cells stain positively for CD34. Treatment of these tumors involves complete surgical excision or Mohs micrographic surgery; however, recurrence is common for tumors involving the head or neck.⁵

Superficial angiomyxoma is a slow-growing papule that most commonly appears on the trunk, head, or neck in middle-aged adults. Occasionally, patients with Carney complex also can develop lesions on the external ear or breast.⁷ Histologically, superficial angiomyxoma is a hypocellular tumor characterized by abundant myxoid stroma, thin blood vessels, and small spindled and stellate cells with minimal cytoplasm (Figure 2).⁸ Superficial angiomyxoma and pleomorphic lipoma present differently on histology; superficial angiomyxoma is not associated with nuclear atypia or pleomorphism, whereas pleomorphic lipoma characteristically contains multinucleated floretlike giant cells and pleomorphism. Frequently, there also is loss of normal PRKAR1A gene expression, which is responsible for protein kinase A regulatory subunit 1-alpha expression.⁸

Multinucleate cell angiohistiocytoma is a rare benign proliferation that presents with numerous red-violet asymptomatic papules that commonly appear on the upper and lower extremities of women aged 40 to 70 years. Lesions feature both a fibrohistiocytic and vascular component.9 Histologic examination commonly shows multinucleated cells with angular outlining in the superficial dermis accompanied by fibrosis and ectatic small-caliber vessels (Figure 3). Although both pleomorphic lipoma and multinucleate cell angiohistiocytoma have similar-appearing multinucleated giant cells, the latter has a proliferation of narrow vessels in thick collagen bundles and lacks an adipocytic component, which distinguishes it from the former.¹⁰ Multinucleate cell angiohistiocytoma also is characterized by a substantial number of factor XIIIa–positive fibrohistiocytic interstitial cells and vascular hyperplasia.⁹

Nodular fasciitis is a benign lesion involving the rapid proliferation of myofibroblasts and fibroblasts in the subcutaneous tissue and most commonly is encountered on the extremities or head and neck regions. Many cases appear at sites of prior trauma, especially in patients aged 20 to 40 years. However, in infants and children the lesions typically are found in the head and neck regions.¹¹ Clinically, lesions present as subcutaneous nodules. Histology reveals an infiltrative and poorly circumscribed proliferation of spindled myofibroblasts associated with myxoid stroma and dense collagen depositions. The spindled cells are loosely associated, rendering a tissue culture–like appearance (Figure 4). It also is common to see erythrocyte extravasation adjacent to myxoid stroma.¹¹ Positive stains include vimentin, smooth muscle actin, and CD68, though immunohistochemistry often is not necessary for diagnosis.¹² There often is abundant mitotic activity in nodular fasciitis, especially in early lesions, and the differential diagnosis includes sarcoma. Although nodular fasciitis is mitotically active, it does not show atypical mitotic figures. Nodular fasciitis commonly harbors a gene translocation of the MYH9 gene’s promoter region to the USP6 gene’s coding region.¹³

The Diagnosis: Pleomorphic Lipoma

Pleomorphic lipoma is a rare, benign, adipocytic neoplasm that presents in the subcutaneous tissues of the upper shoulder, back, or neck. It predominantly affects men aged 50 to 70 years. Most lesions are situated in the subcutaneous tissues; few cases of intramuscular and retroperitoneal tumors have been reported.¹ Clinically, pleomorphic lipomas present as painless, well-circumscribed lesions of the subcutaneous tissue that often resemble a lipoma or occasionally may be mistaken for liposarcoma. Histopathologic examination of ordinary lipomas reveals uniform mature adipocytes. However, pleomorphic lipomas consist of a mixture of multinucleated floretlike giant cells, variable-sized adipocytes, and fibrous tissue (ropy collagen bundles) with some myxoid and spindled areas.^1,2 The most characteristic histologic feature of pleomorphic lipoma is multinucleated floretlike giant cells. The nuclei of these giant cells appear hyperchromatic, enlarged, and disposed to the periphery of the cell in a circular pattern. Additionally, tumors frequently contain excess mature dense collagen bundles that are strongly refractile in polarized light. Numerous mast cells are present. Atypical lipoblasts and capillary networks commonly are not visible in pleomorphic lipoma.³ The spindle cells express CD34 on immunohistochemistry. Loss of Rb-1 expression is typical.⁴

Dermatofibrosarcoma protuberans is a slow-growing soft tissue sarcoma that commonly begins as a pink or violet plaque on the trunk or upper limbs. Involvement of the head or neck accounts for only 10% to 15% of cases.⁵ This tumor has low metastatic potential but is highly infiltrative of surrounding tissues. It is associated with a translocation between chromosomes 22 and 17, leading to the fusion of the platelet-derived growth factor subunit β, PDGFB, and collagen type 1α1, COL1A1, genes.⁵ Clinically, patients often report that the lesion was present for several years prior to presentation with general stability in size and shape. Eventually, untreated lesions progress to become nodules or tumors and may even bleed or ulcerate. Histology reveals a storiform spindle cell proliferation throughout the dermis with infiltration into subcutaneous fat, commonly appearing in a honeycomblike pattern (Figure 1). Numerous histologic variants exist, including myxoid, sclerosing, pigmented (Bednar tumor), myoid, atrophic, or fibrosarcomatous dermatofibrosarcoma protuberans, as well as a giant cell fibroblastoma variant.⁶ These tumor subtypes can exist independently or in association with one another, creating hybrid lesions that can closely mimic other entities such as pleomorphic lipoma. The spindle cells stain positively for CD34. Treatment of these tumors involves complete surgical excision or Mohs micrographic surgery; however, recurrence is common for tumors involving the head or neck.⁵

Superficial angiomyxoma is a slow-growing papule that most commonly appears on the trunk, head, or neck in middle-aged adults. Occasionally, patients with Carney complex also can develop lesions on the external ear or breast.⁷ Histologically, superficial angiomyxoma is a hypocellular tumor characterized by abundant myxoid stroma, thin blood vessels, and small spindled and stellate cells with minimal cytoplasm (Figure 2).⁸ Superficial angiomyxoma and pleomorphic lipoma present differently on histology; superficial angiomyxoma is not associated with nuclear atypia or pleomorphism, whereas pleomorphic lipoma characteristically contains multinucleated floretlike giant cells and pleomorphism. Frequently, there also is loss of normal PRKAR1A gene expression, which is responsible for protein kinase A regulatory subunit 1-alpha expression.⁸

Multinucleate cell angiohistiocytoma is a rare benign proliferation that presents with numerous red-violet asymptomatic papules that commonly appear on the upper and lower extremities of women aged 40 to 70 years. Lesions feature both a fibrohistiocytic and vascular component.9 Histologic examination commonly shows multinucleated cells with angular outlining in the superficial dermis accompanied by fibrosis and ectatic small-caliber vessels (Figure 3). Although both pleomorphic lipoma and multinucleate cell angiohistiocytoma have similar-appearing multinucleated giant cells, the latter has a proliferation of narrow vessels in thick collagen bundles and lacks an adipocytic component, which distinguishes it from the former.¹⁰ Multinucleate cell angiohistiocytoma also is characterized by a substantial number of factor XIIIa–positive fibrohistiocytic interstitial cells and vascular hyperplasia.⁹

Nodular fasciitis is a benign lesion involving the rapid proliferation of myofibroblasts and fibroblasts in the subcutaneous tissue and most commonly is encountered on the extremities or head and neck regions. Many cases appear at sites of prior trauma, especially in patients aged 20 to 40 years. However, in infants and children the lesions typically are found in the head and neck regions.¹¹ Clinically, lesions present as subcutaneous nodules. Histology reveals an infiltrative and poorly circumscribed proliferation of spindled myofibroblasts associated with myxoid stroma and dense collagen depositions. The spindled cells are loosely associated, rendering a tissue culture–like appearance (Figure 4). It also is common to see erythrocyte extravasation adjacent to myxoid stroma.¹¹ Positive stains include vimentin, smooth muscle actin, and CD68, though immunohistochemistry often is not necessary for diagnosis.¹² There often is abundant mitotic activity in nodular fasciitis, especially in early lesions, and the differential diagnosis includes sarcoma. Although nodular fasciitis is mitotically active, it does not show atypical mitotic figures. Nodular fasciitis commonly harbors a gene translocation of the MYH9 gene’s promoter region to the USP6 gene’s coding region.¹³

The Diagnosis: Pleomorphic Lipoma

Pleomorphic lipoma is a rare, benign, adipocytic neoplasm that presents in the subcutaneous tissues of the upper shoulder, back, or neck. It predominantly affects men aged 50 to 70 years. Most lesions are situated in the subcutaneous tissues; few cases of intramuscular and retroperitoneal tumors have been reported.¹ Clinically, pleomorphic lipomas present as painless, well-circumscribed lesions of the subcutaneous tissue that often resemble a lipoma or occasionally may be mistaken for liposarcoma. Histopathologic examination of ordinary lipomas reveals uniform mature adipocytes. However, pleomorphic lipomas consist of a mixture of multinucleated floretlike giant cells, variable-sized adipocytes, and fibrous tissue (ropy collagen bundles) with some myxoid and spindled areas.^1,2 The most characteristic histologic feature of pleomorphic lipoma is multinucleated floretlike giant cells. The nuclei of these giant cells appear hyperchromatic, enlarged, and disposed to the periphery of the cell in a circular pattern. Additionally, tumors frequently contain excess mature dense collagen bundles that are strongly refractile in polarized light. Numerous mast cells are present. Atypical lipoblasts and capillary networks commonly are not visible in pleomorphic lipoma.³ The spindle cells express CD34 on immunohistochemistry. Loss of Rb-1 expression is typical.⁴

Dermatofibrosarcoma protuberans is a slow-growing soft tissue sarcoma that commonly begins as a pink or violet plaque on the trunk or upper limbs. Involvement of the head or neck accounts for only 10% to 15% of cases.⁵ This tumor has low metastatic potential but is highly infiltrative of surrounding tissues. It is associated with a translocation between chromosomes 22 and 17, leading to the fusion of the platelet-derived growth factor subunit β, PDGFB, and collagen type 1α1, COL1A1, genes.⁵ Clinically, patients often report that the lesion was present for several years prior to presentation with general stability in size and shape. Eventually, untreated lesions progress to become nodules or tumors and may even bleed or ulcerate. Histology reveals a storiform spindle cell proliferation throughout the dermis with infiltration into subcutaneous fat, commonly appearing in a honeycomblike pattern (Figure 1). Numerous histologic variants exist, including myxoid, sclerosing, pigmented (Bednar tumor), myoid, atrophic, or fibrosarcomatous dermatofibrosarcoma protuberans, as well as a giant cell fibroblastoma variant.⁶ These tumor subtypes can exist independently or in association with one another, creating hybrid lesions that can closely mimic other entities such as pleomorphic lipoma. The spindle cells stain positively for CD34. Treatment of these tumors involves complete surgical excision or Mohs micrographic surgery; however, recurrence is common for tumors involving the head or neck.⁵

Superficial angiomyxoma is a slow-growing papule that most commonly appears on the trunk, head, or neck in middle-aged adults. Occasionally, patients with Carney complex also can develop lesions on the external ear or breast.⁷ Histologically, superficial angiomyxoma is a hypocellular tumor characterized by abundant myxoid stroma, thin blood vessels, and small spindled and stellate cells with minimal cytoplasm (Figure 2).⁸ Superficial angiomyxoma and pleomorphic lipoma present differently on histology; superficial angiomyxoma is not associated with nuclear atypia or pleomorphism, whereas pleomorphic lipoma characteristically contains multinucleated floretlike giant cells and pleomorphism. Frequently, there also is loss of normal PRKAR1A gene expression, which is responsible for protein kinase A regulatory subunit 1-alpha expression.⁸

Multinucleate cell angiohistiocytoma is a rare benign proliferation that presents with numerous red-violet asymptomatic papules that commonly appear on the upper and lower extremities of women aged 40 to 70 years. Lesions feature both a fibrohistiocytic and vascular component.9 Histologic examination commonly shows multinucleated cells with angular outlining in the superficial dermis accompanied by fibrosis and ectatic small-caliber vessels (Figure 3). Although both pleomorphic lipoma and multinucleate cell angiohistiocytoma have similar-appearing multinucleated giant cells, the latter has a proliferation of narrow vessels in thick collagen bundles and lacks an adipocytic component, which distinguishes it from the former.¹⁰ Multinucleate cell angiohistiocytoma also is characterized by a substantial number of factor XIIIa–positive fibrohistiocytic interstitial cells and vascular hyperplasia.⁹

Nodular fasciitis is a benign lesion involving the rapid proliferation of myofibroblasts and fibroblasts in the subcutaneous tissue and most commonly is encountered on the extremities or head and neck regions. Many cases appear at sites of prior trauma, especially in patients aged 20 to 40 years. However, in infants and children the lesions typically are found in the head and neck regions.¹¹ Clinically, lesions present as subcutaneous nodules. Histology reveals an infiltrative and poorly circumscribed proliferation of spindled myofibroblasts associated with myxoid stroma and dense collagen depositions. The spindled cells are loosely associated, rendering a tissue culture–like appearance (Figure 4). It also is common to see erythrocyte extravasation adjacent to myxoid stroma.¹¹ Positive stains include vimentin, smooth muscle actin, and CD68, though immunohistochemistry often is not necessary for diagnosis.¹² There often is abundant mitotic activity in nodular fasciitis, especially in early lesions, and the differential diagnosis includes sarcoma. Although nodular fasciitis is mitotically active, it does not show atypical mitotic figures. Nodular fasciitis commonly harbors a gene translocation of the MYH9 gene’s promoter region to the USP6 gene’s coding region.¹³

To the Editor:

Melanoma is an aggressive form of skin cancer with a high rate of metastasis and poor prognosis.¹ Historically, Hispanic and/or Latino patients have presented with more advanced-stage melanomas and have lower survival rates compared with non-Hispanic and/or non-Latino White patients.² In this study, we evaluated recent data from the last decade to investigate if disparities in melanoma tumor stage at diagnosis and risk for metastases continue to exist in the Hispanic and/or Latino population.

We conducted a retrospective review of melanoma patients at 2 major medical centers in Los Angeles, California—Keck Medicine of USC and Los Angeles County-USC Medical Center—from January 2010 to January 2020. The data collected from electronic medical records included age at melanoma diagnosis, sex, race and ethnicity, insurance type, Breslow depth of lesion, presence of ulceration, and presence of lymph node or distant metastases. Melanoma tumor stage was determined using the American Joint Committee on Cancer classification. Patients who self-reported their ethnicity as not Hispanic and/or Latino were designated to this group regardless of their reported race. Those patients who reported their ethnicity as not Hispanic and/or Latino and reported their race as White were designated as non-Hispanic and/or non-Latino White. This study was approved by the institutional review board of the University of Southern California (Los Angeles). Data analysis was performed using the Pearson χ² test, Fisher exact test, and Wilcoxon rank sum test. Statistical significance was determined at P<.05.

The final cohort of patients included 79 Hispanic and/or Latino patients and 402 non-Hispanic and/or non-Latino White patients. The median age for the Hispanic and/or Latino group was 54 years and 64 years for the non-Hispanic and/or non-Latino White group (P<.001). There was a greater percentage of females in the Hispanic and/or Latino group compared with the non-Hispanic and/or non-Latino White group (53.2% vs 34.6%)(P=.002). Hispanic and/or Latino patients presented with more advanced tumor stage melanomas (T3: 15.2%; T4: 21.5%) compared with non-Hispanic and/or non-Latino White patients (T3: 8.0%; T4: 10.7%)(P=.004). Furthermore, Hispanic and/or Latino patients had higher rates of lymph node metastases compared with non-Hispanic and/or non-Latino White patients (20.3% vs 7.7% [P<.001]) and higher rates of distant metastases (12.7% vs 5.2% [P=.014])(Table 1). The majority of Hispanic and/or Latino patients had Medicaid (39.2%), while most non-Hispanic and/or non-Latino White patients had a preferred provider organization insurance plan (37.3%) or Medicare (34.3%)(P<.001)(Table 2).

This retrospective study analyzing nearly 10 years of recent melanoma data found that disparities in melanoma diagnosis and treatment continue to exist among Hispanic and/or Latino patients. Compared to non-Hispanic and/or non-Latino White patients, Hispanic and/or Latino patients were diagnosed with melanoma at a younger age and the proportion of females with melanoma was higher. Cormier et al² also reported that Hispanic patients were younger at melanoma diagnosis, and females represented a larger majority of patients in the Hispanic population compared with the White population. Hispanic and/or Latino patients in our study had more advanced melanoma tumor stage at diagnosis and a higher risk of lymph node and distant metastases, similar to findings reported by Koblinksi et al.³

Our retrospective cohort study demonstrated that the demographics of Hispanic and/or Latino patients with melanoma differ from non-Hispanic and/or non-Latino White patients, specifically with a greater proportion of younger and female patients in the Hispanic and/or Latino population. We also found that Hispanic and/or Latino patients continue to experience worse melanoma outcomes compared with non-Hispanic and/or non-Latino White patients. Further studies are needed to investigate the etiologies behind these health care disparities and potential interventions to address them. In addition, there needs to be increased awareness of the risk for melanoma in Hispanic and/or Latino patients among both health care providers and patients.

Limitations of this study included a smaller sample size of patients from one geographic region. The retrospective design of this study also increased the risk for selection bias, as some of the patients may have had incomplete records or were lost to follow-up. Therefore, the study cohort may not be representative of the general population. Additionally, patients’ skin types could not be determined using standardized tools such as the Fitzpatrick scale, thus we could not assess how patient skin type may have affected melanoma outcomes.

To the Editor:

Melanoma is an aggressive form of skin cancer with a high rate of metastasis and poor prognosis.¹ Historically, Hispanic and/or Latino patients have presented with more advanced-stage melanomas and have lower survival rates compared with non-Hispanic and/or non-Latino White patients.² In this study, we evaluated recent data from the last decade to investigate if disparities in melanoma tumor stage at diagnosis and risk for metastases continue to exist in the Hispanic and/or Latino population.

We conducted a retrospective review of melanoma patients at 2 major medical centers in Los Angeles, California—Keck Medicine of USC and Los Angeles County-USC Medical Center—from January 2010 to January 2020. The data collected from electronic medical records included age at melanoma diagnosis, sex, race and ethnicity, insurance type, Breslow depth of lesion, presence of ulceration, and presence of lymph node or distant metastases. Melanoma tumor stage was determined using the American Joint Committee on Cancer classification. Patients who self-reported their ethnicity as not Hispanic and/or Latino were designated to this group regardless of their reported race. Those patients who reported their ethnicity as not Hispanic and/or Latino and reported their race as White were designated as non-Hispanic and/or non-Latino White. This study was approved by the institutional review board of the University of Southern California (Los Angeles). Data analysis was performed using the Pearson χ² test, Fisher exact test, and Wilcoxon rank sum test. Statistical significance was determined at P<.05.

The final cohort of patients included 79 Hispanic and/or Latino patients and 402 non-Hispanic and/or non-Latino White patients. The median age for the Hispanic and/or Latino group was 54 years and 64 years for the non-Hispanic and/or non-Latino White group (P<.001). There was a greater percentage of females in the Hispanic and/or Latino group compared with the non-Hispanic and/or non-Latino White group (53.2% vs 34.6%)(P=.002). Hispanic and/or Latino patients presented with more advanced tumor stage melanomas (T3: 15.2%; T4: 21.5%) compared with non-Hispanic and/or non-Latino White patients (T3: 8.0%; T4: 10.7%)(P=.004). Furthermore, Hispanic and/or Latino patients had higher rates of lymph node metastases compared with non-Hispanic and/or non-Latino White patients (20.3% vs 7.7% [P<.001]) and higher rates of distant metastases (12.7% vs 5.2% [P=.014])(Table 1). The majority of Hispanic and/or Latino patients had Medicaid (39.2%), while most non-Hispanic and/or non-Latino White patients had a preferred provider organization insurance plan (37.3%) or Medicare (34.3%)(P<.001)(Table 2).

This retrospective study analyzing nearly 10 years of recent melanoma data found that disparities in melanoma diagnosis and treatment continue to exist among Hispanic and/or Latino patients. Compared to non-Hispanic and/or non-Latino White patients, Hispanic and/or Latino patients were diagnosed with melanoma at a younger age and the proportion of females with melanoma was higher. Cormier et al² also reported that Hispanic patients were younger at melanoma diagnosis, and females represented a larger majority of patients in the Hispanic population compared with the White population. Hispanic and/or Latino patients in our study had more advanced melanoma tumor stage at diagnosis and a higher risk of lymph node and distant metastases, similar to findings reported by Koblinksi et al.³

Our retrospective cohort study demonstrated that the demographics of Hispanic and/or Latino patients with melanoma differ from non-Hispanic and/or non-Latino White patients, specifically with a greater proportion of younger and female patients in the Hispanic and/or Latino population. We also found that Hispanic and/or Latino patients continue to experience worse melanoma outcomes compared with non-Hispanic and/or non-Latino White patients. Further studies are needed to investigate the etiologies behind these health care disparities and potential interventions to address them. In addition, there needs to be increased awareness of the risk for melanoma in Hispanic and/or Latino patients among both health care providers and patients.

Limitations of this study included a smaller sample size of patients from one geographic region. The retrospective design of this study also increased the risk for selection bias, as some of the patients may have had incomplete records or were lost to follow-up. Therefore, the study cohort may not be representative of the general population. Additionally, patients’ skin types could not be determined using standardized tools such as the Fitzpatrick scale, thus we could not assess how patient skin type may have affected melanoma outcomes.

To the Editor:

Melanoma is an aggressive form of skin cancer with a high rate of metastasis and poor prognosis.¹ Historically, Hispanic and/or Latino patients have presented with more advanced-stage melanomas and have lower survival rates compared with non-Hispanic and/or non-Latino White patients.² In this study, we evaluated recent data from the last decade to investigate if disparities in melanoma tumor stage at diagnosis and risk for metastases continue to exist in the Hispanic and/or Latino population.

We conducted a retrospective review of melanoma patients at 2 major medical centers in Los Angeles, California—Keck Medicine of USC and Los Angeles County-USC Medical Center—from January 2010 to January 2020. The data collected from electronic medical records included age at melanoma diagnosis, sex, race and ethnicity, insurance type, Breslow depth of lesion, presence of ulceration, and presence of lymph node or distant metastases. Melanoma tumor stage was determined using the American Joint Committee on Cancer classification. Patients who self-reported their ethnicity as not Hispanic and/or Latino were designated to this group regardless of their reported race. Those patients who reported their ethnicity as not Hispanic and/or Latino and reported their race as White were designated as non-Hispanic and/or non-Latino White. This study was approved by the institutional review board of the University of Southern California (Los Angeles). Data analysis was performed using the Pearson χ² test, Fisher exact test, and Wilcoxon rank sum test. Statistical significance was determined at P<.05.

The final cohort of patients included 79 Hispanic and/or Latino patients and 402 non-Hispanic and/or non-Latino White patients. The median age for the Hispanic and/or Latino group was 54 years and 64 years for the non-Hispanic and/or non-Latino White group (P<.001). There was a greater percentage of females in the Hispanic and/or Latino group compared with the non-Hispanic and/or non-Latino White group (53.2% vs 34.6%)(P=.002). Hispanic and/or Latino patients presented with more advanced tumor stage melanomas (T3: 15.2%; T4: 21.5%) compared with non-Hispanic and/or non-Latino White patients (T3: 8.0%; T4: 10.7%)(P=.004). Furthermore, Hispanic and/or Latino patients had higher rates of lymph node metastases compared with non-Hispanic and/or non-Latino White patients (20.3% vs 7.7% [P<.001]) and higher rates of distant metastases (12.7% vs 5.2% [P=.014])(Table 1). The majority of Hispanic and/or Latino patients had Medicaid (39.2%), while most non-Hispanic and/or non-Latino White patients had a preferred provider organization insurance plan (37.3%) or Medicare (34.3%)(P<.001)(Table 2).

This retrospective study analyzing nearly 10 years of recent melanoma data found that disparities in melanoma diagnosis and treatment continue to exist among Hispanic and/or Latino patients. Compared to non-Hispanic and/or non-Latino White patients, Hispanic and/or Latino patients were diagnosed with melanoma at a younger age and the proportion of females with melanoma was higher. Cormier et al² also reported that Hispanic patients were younger at melanoma diagnosis, and females represented a larger majority of patients in the Hispanic population compared with the White population. Hispanic and/or Latino patients in our study had more advanced melanoma tumor stage at diagnosis and a higher risk of lymph node and distant metastases, similar to findings reported by Koblinksi et al.³

Our retrospective cohort study demonstrated that the demographics of Hispanic and/or Latino patients with melanoma differ from non-Hispanic and/or non-Latino White patients, specifically with a greater proportion of younger and female patients in the Hispanic and/or Latino population. We also found that Hispanic and/or Latino patients continue to experience worse melanoma outcomes compared with non-Hispanic and/or non-Latino White patients. Further studies are needed to investigate the etiologies behind these health care disparities and potential interventions to address them. In addition, there needs to be increased awareness of the risk for melanoma in Hispanic and/or Latino patients among both health care providers and patients.

Limitations of this study included a smaller sample size of patients from one geographic region. The retrospective design of this study also increased the risk for selection bias, as some of the patients may have had incomplete records or were lost to follow-up. Therefore, the study cohort may not be representative of the general population. Additionally, patients’ skin types could not be determined using standardized tools such as the Fitzpatrick scale, thus we could not assess how patient skin type may have affected melanoma outcomes.

Cutaneous Manifestations

Capsicum peppers are used worldwide in preparing spicy dishes. Their active ingredient—capsaicin—is used as a topical medicine to treat localized pain. Capsicum peppers can cause irritant contact dermatitis with symptoms of erythema, cutaneous burning, and itch.¹

Irritant contact dermatitis is a common occupational skin disorder. Many cooks have experienced the sting of a chili pepper after contact with the hands or eyes. Cases of chronic exposure to Capsicum peppers with persistent burning and pain have been called Hunan hand syndrome.²Capsicum peppers also have induced allergic contact dermatitis in a food production worker.³

Capsicum peppers also are used in pepper spray, tear gas, and animal repellents because of their stinging properties. These agents usually cause cutaneous tingling and burning that soon resolves; however, a review of 31 studies showed that crowd-control methods with Capsicum-containing tear gas and pepper spray can cause moderate to severe skin damage such as a persistent skin rash or erythema, or even first-, second-, or third-degree burns.⁴

Topical application of capsaicin isolate is meant to cause burning and deplete local neuropeptides, with a cutaneous reaction that ranges from mild to intolerable.^5,6 Capsaicin also is found in other products. In one published case report, a 3-year-old boy broke out in facial urticaria when his mother kissed him on the cheek after she applied lip plumper containing capsaicin to her lips.⁷ Dermatologists should consider capsaicin an active ingredient that can irritate the skin in the garden, in the kitchen, and in topical products.

Obtaining Relief

Capsaicin-induced dermatitis can be relieved by washing the area with soap, detergent, baking soda, or oily compounds that act as solvents for the nonpolar capsaicin.⁸ Application of ice water or a high-potency topical steroid also may help. If the reaction is severe and persistent, a continuous stellate ganglion block may alleviate the pain of capsaicin-induced contact dermatitis.⁹

Identifying Features and Plant Facts

The Capsicum genus includes chili peppers, paprika, and red peppers. Capsicum peppers are native to tropical regions of the Americas (Figure). The use of Capsicum peppers in food can be traced to Indigenous peoples of Mexico as early as 7000 bc.¹⁰ On the Scoville scale, which was developed to quantify the hotness of foods and spices, Capsicum peppers are rated at approximately 2 million units; by comparison, jalapeño peppers have a Scoville score of 4500¹¹ and capsaicin isolate has a score of 16 million units. Capsicum species rank among the hottest peppers in the world.

Capsicum belongs to the family Solanaceae, which includes tobacco, tomatoes, potatoes, and nightshade plants. There are many varieties of peppers in the Capsicum genus, with 5 domesticated species: Capsicum annuum, Capsicum baccatum, Capsicum chinense, Capsicum frutescens, and Capsicum pubescens. These include bell, poblano, cayenne, tabasco, habanero, and ají peppers, among others. Capsicum species grow as a shrub with flowers that rotate to stellate corollas and rounded berries of different sizes and colors.¹² Capsaicin and other alkaloids are concentrated in the fruit; therefore, Capsicum dermatitis is most commonly induced by contact with the flesh of peppers.

Capsaicin (8-methyl-6-nonanoyl vanillylamide) is a nonpolar phenol, which is why washing skin that has come in contact with capsaicin with water or vinegar alone is insufficient to solubilize it.¹³ Capsaicin binds to the transient receptor potential vanilloid 1 (TRPV1), a calcium channel on neurons that opens in response to heat. When bound, the channel opens at a lower temperature threshold and depolarizes nerve endings, leading to vasodilation and activation of sensory nerves.¹⁴ Substance P is released and the individual experiences a painful burning sensation. When purified capsaicin is frequently applied at an appropriate dose, synthesis of substance P is diminished, resulting in reduced local pain overall.¹⁵

Capsaicin does not affect neurons without TRPV1, and administration of capsaicin is not painful if given with anesthesia. An inappropriately high dose of capsaicin destroys cells in the epidermal barrier, resulting in water loss and inducing release of vasoactive peptides and inflammatory cytokines.¹ Careful handling of Capsicum peppers and capsaicin products can reduce the risk for irritation.

Medicinal Use

On-/Off-Label and Potential Uses—Capsaicin is US Food and Drug Administration approved for use in arthritis and musculoskeletal pain. It also is used to treat diabetic neuropathy,⁵ postherpetic neuralgia,⁶ psoriasis,¹⁶ and other conditions. Studies have shown that capsaicin might be useful in treating trigeminal neuralgia,¹⁷ fibromyalgia,¹⁸ migraines,¹⁴ cluster headaches,⁹ and HIV-associated distal sensory neuropathy.⁵

Delivery of Capsaicin—Capsaicin preferentially acts on C-fibers, which transmit dull, aching, chronic pain.¹⁹ The compound is available as a cream, lotion, and large bandage (for the lower back), as well as low- and high-dose patches. Capsaicin creams, lotions, and the low-dose patch are uncomfortable and must be applied for 4 to 6 weeks to take effect, which may impact patient adherence. The high-dose patch, which requires administration under local anesthesia by a health care worker, brings pain relief with a single use and improves adherence.¹¹ Synthetic TRPV1-agonist injectables based on capsaicin have undergone clinical trials for localized pain (eg, postoperative musculoskeletal pain); many patients experience pain relief, though benefit fades over weeks to months.^20,21

Use in Traditional Medicine—Capsicum peppers have been used to aid digestion and promote healing in gastrointestinal conditions, such as dyspepsia.²² The peppers are a source of important vitamins and minerals, including vitamins A, C, and E; many of the B complex vitamins; and magnesium, calcium, and iron.²³

Use as Cancer Therapy—Studies of the use of capsaicin in treating cancer have produced controversial results. In cell and animal models, capsaicin induces apoptosis through downregulation of the Bcl-2 protein; upregulation of oxidative stress, tribbles-related protein 3 (TRIB3), and caspase-3; and other pathways.^19,24-26 On the other hand, consumption of Capsicum peppers has been associated with cancer of the stomach and gallbladder.²⁷ Capsaicin might have anticarcinogenic properties, but its mechanism of action varies, depending on variables not fully understood.

Final Thoughts

Capsaicin is a neuropeptide-active compound found in Capsicum peppers that has many promising applications for use. However, dermatologists should be aware of the possibility of a skin reaction to this compound from handling peppers and using topical medicines. Exposure to capsaicin can cause irritant contact dermatitis that may require clinical care.

Cutaneous Manifestations

Capsicum peppers are used worldwide in preparing spicy dishes. Their active ingredient—capsaicin—is used as a topical medicine to treat localized pain. Capsicum peppers can cause irritant contact dermatitis with symptoms of erythema, cutaneous burning, and itch.¹

Irritant contact dermatitis is a common occupational skin disorder. Many cooks have experienced the sting of a chili pepper after contact with the hands or eyes. Cases of chronic exposure to Capsicum peppers with persistent burning and pain have been called Hunan hand syndrome.²Capsicum peppers also have induced allergic contact dermatitis in a food production worker.³

Capsicum peppers also are used in pepper spray, tear gas, and animal repellents because of their stinging properties. These agents usually cause cutaneous tingling and burning that soon resolves; however, a review of 31 studies showed that crowd-control methods with Capsicum-containing tear gas and pepper spray can cause moderate to severe skin damage such as a persistent skin rash or erythema, or even first-, second-, or third-degree burns.⁴

Topical application of capsaicin isolate is meant to cause burning and deplete local neuropeptides, with a cutaneous reaction that ranges from mild to intolerable.^5,6 Capsaicin also is found in other products. In one published case report, a 3-year-old boy broke out in facial urticaria when his mother kissed him on the cheek after she applied lip plumper containing capsaicin to her lips.⁷ Dermatologists should consider capsaicin an active ingredient that can irritate the skin in the garden, in the kitchen, and in topical products.

Obtaining Relief

Capsaicin-induced dermatitis can be relieved by washing the area with soap, detergent, baking soda, or oily compounds that act as solvents for the nonpolar capsaicin.⁸ Application of ice water or a high-potency topical steroid also may help. If the reaction is severe and persistent, a continuous stellate ganglion block may alleviate the pain of capsaicin-induced contact dermatitis.⁹

Identifying Features and Plant Facts

The Capsicum genus includes chili peppers, paprika, and red peppers. Capsicum peppers are native to tropical regions of the Americas (Figure). The use of Capsicum peppers in food can be traced to Indigenous peoples of Mexico as early as 7000 bc.¹⁰ On the Scoville scale, which was developed to quantify the hotness of foods and spices, Capsicum peppers are rated at approximately 2 million units; by comparison, jalapeño peppers have a Scoville score of 4500¹¹ and capsaicin isolate has a score of 16 million units. Capsicum species rank among the hottest peppers in the world.

Capsicum belongs to the family Solanaceae, which includes tobacco, tomatoes, potatoes, and nightshade plants. There are many varieties of peppers in the Capsicum genus, with 5 domesticated species: Capsicum annuum, Capsicum baccatum, Capsicum chinense, Capsicum frutescens, and Capsicum pubescens. These include bell, poblano, cayenne, tabasco, habanero, and ají peppers, among others. Capsicum species grow as a shrub with flowers that rotate to stellate corollas and rounded berries of different sizes and colors.¹² Capsaicin and other alkaloids are concentrated in the fruit; therefore, Capsicum dermatitis is most commonly induced by contact with the flesh of peppers.

Capsaicin (8-methyl-6-nonanoyl vanillylamide) is a nonpolar phenol, which is why washing skin that has come in contact with capsaicin with water or vinegar alone is insufficient to solubilize it.¹³ Capsaicin binds to the transient receptor potential vanilloid 1 (TRPV1), a calcium channel on neurons that opens in response to heat. When bound, the channel opens at a lower temperature threshold and depolarizes nerve endings, leading to vasodilation and activation of sensory nerves.¹⁴ Substance P is released and the individual experiences a painful burning sensation. When purified capsaicin is frequently applied at an appropriate dose, synthesis of substance P is diminished, resulting in reduced local pain overall.¹⁵

Capsaicin does not affect neurons without TRPV1, and administration of capsaicin is not painful if given with anesthesia. An inappropriately high dose of capsaicin destroys cells in the epidermal barrier, resulting in water loss and inducing release of vasoactive peptides and inflammatory cytokines.¹ Careful handling of Capsicum peppers and capsaicin products can reduce the risk for irritation.

Medicinal Use

On-/Off-Label and Potential Uses—Capsaicin is US Food and Drug Administration approved for use in arthritis and musculoskeletal pain. It also is used to treat diabetic neuropathy,⁵ postherpetic neuralgia,⁶ psoriasis,¹⁶ and other conditions. Studies have shown that capsaicin might be useful in treating trigeminal neuralgia,¹⁷ fibromyalgia,¹⁸ migraines,¹⁴ cluster headaches,⁹ and HIV-associated distal sensory neuropathy.⁵

Delivery of Capsaicin—Capsaicin preferentially acts on C-fibers, which transmit dull, aching, chronic pain.¹⁹ The compound is available as a cream, lotion, and large bandage (for the lower back), as well as low- and high-dose patches. Capsaicin creams, lotions, and the low-dose patch are uncomfortable and must be applied for 4 to 6 weeks to take effect, which may impact patient adherence. The high-dose patch, which requires administration under local anesthesia by a health care worker, brings pain relief with a single use and improves adherence.¹¹ Synthetic TRPV1-agonist injectables based on capsaicin have undergone clinical trials for localized pain (eg, postoperative musculoskeletal pain); many patients experience pain relief, though benefit fades over weeks to months.^20,21

Use in Traditional Medicine—Capsicum peppers have been used to aid digestion and promote healing in gastrointestinal conditions, such as dyspepsia.²² The peppers are a source of important vitamins and minerals, including vitamins A, C, and E; many of the B complex vitamins; and magnesium, calcium, and iron.²³

Use as Cancer Therapy—Studies of the use of capsaicin in treating cancer have produced controversial results. In cell and animal models, capsaicin induces apoptosis through downregulation of the Bcl-2 protein; upregulation of oxidative stress, tribbles-related protein 3 (TRIB3), and caspase-3; and other pathways.^19,24-26 On the other hand, consumption of Capsicum peppers has been associated with cancer of the stomach and gallbladder.²⁷ Capsaicin might have anticarcinogenic properties, but its mechanism of action varies, depending on variables not fully understood.

Final Thoughts

Capsaicin is a neuropeptide-active compound found in Capsicum peppers that has many promising applications for use. However, dermatologists should be aware of the possibility of a skin reaction to this compound from handling peppers and using topical medicines. Exposure to capsaicin can cause irritant contact dermatitis that may require clinical care.

Cutaneous Manifestations

Capsicum peppers are used worldwide in preparing spicy dishes. Their active ingredient—capsaicin—is used as a topical medicine to treat localized pain. Capsicum peppers can cause irritant contact dermatitis with symptoms of erythema, cutaneous burning, and itch.¹

Irritant contact dermatitis is a common occupational skin disorder. Many cooks have experienced the sting of a chili pepper after contact with the hands or eyes. Cases of chronic exposure to Capsicum peppers with persistent burning and pain have been called Hunan hand syndrome.²Capsicum peppers also have induced allergic contact dermatitis in a food production worker.³

Capsicum peppers also are used in pepper spray, tear gas, and animal repellents because of their stinging properties. These agents usually cause cutaneous tingling and burning that soon resolves; however, a review of 31 studies showed that crowd-control methods with Capsicum-containing tear gas and pepper spray can cause moderate to severe skin damage such as a persistent skin rash or erythema, or even first-, second-, or third-degree burns.⁴

Topical application of capsaicin isolate is meant to cause burning and deplete local neuropeptides, with a cutaneous reaction that ranges from mild to intolerable.^5,6 Capsaicin also is found in other products. In one published case report, a 3-year-old boy broke out in facial urticaria when his mother kissed him on the cheek after she applied lip plumper containing capsaicin to her lips.⁷ Dermatologists should consider capsaicin an active ingredient that can irritate the skin in the garden, in the kitchen, and in topical products.

Obtaining Relief

Capsaicin-induced dermatitis can be relieved by washing the area with soap, detergent, baking soda, or oily compounds that act as solvents for the nonpolar capsaicin.⁸ Application of ice water or a high-potency topical steroid also may help. If the reaction is severe and persistent, a continuous stellate ganglion block may alleviate the pain of capsaicin-induced contact dermatitis.⁹

Identifying Features and Plant Facts

The Capsicum genus includes chili peppers, paprika, and red peppers. Capsicum peppers are native to tropical regions of the Americas (Figure). The use of Capsicum peppers in food can be traced to Indigenous peoples of Mexico as early as 7000 bc.¹⁰ On the Scoville scale, which was developed to quantify the hotness of foods and spices, Capsicum peppers are rated at approximately 2 million units; by comparison, jalapeño peppers have a Scoville score of 4500¹¹ and capsaicin isolate has a score of 16 million units. Capsicum species rank among the hottest peppers in the world.

Capsicum belongs to the family Solanaceae, which includes tobacco, tomatoes, potatoes, and nightshade plants. There are many varieties of peppers in the Capsicum genus, with 5 domesticated species: Capsicum annuum, Capsicum baccatum, Capsicum chinense, Capsicum frutescens, and Capsicum pubescens. These include bell, poblano, cayenne, tabasco, habanero, and ají peppers, among others. Capsicum species grow as a shrub with flowers that rotate to stellate corollas and rounded berries of different sizes and colors.¹² Capsaicin and other alkaloids are concentrated in the fruit; therefore, Capsicum dermatitis is most commonly induced by contact with the flesh of peppers.

Capsaicin (8-methyl-6-nonanoyl vanillylamide) is a nonpolar phenol, which is why washing skin that has come in contact with capsaicin with water or vinegar alone is insufficient to solubilize it.¹³ Capsaicin binds to the transient receptor potential vanilloid 1 (TRPV1), a calcium channel on neurons that opens in response to heat. When bound, the channel opens at a lower temperature threshold and depolarizes nerve endings, leading to vasodilation and activation of sensory nerves.¹⁴ Substance P is released and the individual experiences a painful burning sensation. When purified capsaicin is frequently applied at an appropriate dose, synthesis of substance P is diminished, resulting in reduced local pain overall.¹⁵

Capsaicin does not affect neurons without TRPV1, and administration of capsaicin is not painful if given with anesthesia. An inappropriately high dose of capsaicin destroys cells in the epidermal barrier, resulting in water loss and inducing release of vasoactive peptides and inflammatory cytokines.¹ Careful handling of Capsicum peppers and capsaicin products can reduce the risk for irritation.

Medicinal Use

On-/Off-Label and Potential Uses—Capsaicin is US Food and Drug Administration approved for use in arthritis and musculoskeletal pain. It also is used to treat diabetic neuropathy,⁵ postherpetic neuralgia,⁶ psoriasis,¹⁶ and other conditions. Studies have shown that capsaicin might be useful in treating trigeminal neuralgia,¹⁷ fibromyalgia,¹⁸ migraines,¹⁴ cluster headaches,⁹ and HIV-associated distal sensory neuropathy.⁵

Delivery of Capsaicin—Capsaicin preferentially acts on C-fibers, which transmit dull, aching, chronic pain.¹⁹ The compound is available as a cream, lotion, and large bandage (for the lower back), as well as low- and high-dose patches. Capsaicin creams, lotions, and the low-dose patch are uncomfortable and must be applied for 4 to 6 weeks to take effect, which may impact patient adherence. The high-dose patch, which requires administration under local anesthesia by a health care worker, brings pain relief with a single use and improves adherence.¹¹ Synthetic TRPV1-agonist injectables based on capsaicin have undergone clinical trials for localized pain (eg, postoperative musculoskeletal pain); many patients experience pain relief, though benefit fades over weeks to months.^20,21

Use in Traditional Medicine—Capsicum peppers have been used to aid digestion and promote healing in gastrointestinal conditions, such as dyspepsia.²² The peppers are a source of important vitamins and minerals, including vitamins A, C, and E; many of the B complex vitamins; and magnesium, calcium, and iron.²³

Use as Cancer Therapy—Studies of the use of capsaicin in treating cancer have produced controversial results. In cell and animal models, capsaicin induces apoptosis through downregulation of the Bcl-2 protein; upregulation of oxidative stress, tribbles-related protein 3 (TRIB3), and caspase-3; and other pathways.^19,24-26 On the other hand, consumption of Capsicum peppers has been associated with cancer of the stomach and gallbladder.²⁷ Capsaicin might have anticarcinogenic properties, but its mechanism of action varies, depending on variables not fully understood.

Final Thoughts

Capsaicin is a neuropeptide-active compound found in Capsicum peppers that has many promising applications for use. However, dermatologists should be aware of the possibility of a skin reaction to this compound from handling peppers and using topical medicines. Exposure to capsaicin can cause irritant contact dermatitis that may require clinical care.

Eating disorders (EDs) and feeding disorders refer to a wide spectrum of complex biopsychosocial illnesses. The spectrum of EDs encompasses anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder, and other specified feeding or eating disorders. Feeding disorders, distinguished from EDs based on the absence of body image disturbance, include pica, rumination syndrome, and avoidant/restrictive food intake disorder (ARFID).¹

This spectrum of illnesses predominantly affect young females aged 15 to 45 years, with recent increases in the rates of EDs among males, patients with skin of color, and adolescent females.^2-5 Patients with EDs are at an elevated lifetime risk of suicidal ideation, suicide attempts, and other psychiatric comorbidities compared to the general population.⁶ Specifically, AN and BN are associated with high psychiatric morbidity and mortality. A meta-analysis by Arcelus et al⁷ demonstrated the weighted annual mortality for AN was 5.10 deaths per 1000 person-years (95% CI, 3.57-7.59) among patients with EDs and 4.55 deaths for studies that selected inpatients (95% CI, 3.09-6.28); for BN, the weighted mortality was 1.74 deaths per 1000 person-years (95% CI, 1.09-2.44). Unfortunately, ED diagnoses often are delayed or missed in clinical settings. Patients may lack insight into the severity of their illness, experience embarrassment about their eating behaviors, or actively avoid treatment for their ED.⁸

Pica—compulsive eating of nonnutritive substances outside the cultural norm—and rumination syndrome—regurgitation of undigested food—are feeding disorders more commonly recognized in childhood.^9-11 Pregnancy, intellectual disability, iron deficiency, and lead poisoning are other conditions associated with pica.^6,9,10 Avoidant/restrictive food intake disorder, a new diagnosis added to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)¹ in 2013, is an eating or feeding disturbance resulting in persistent failure to meet nutritional or energy needs. Etiologies of ARFID may include sensory sensitivities and/or a traumatic event related to eating, leading to avoidance of associated foods.¹²

Patients with an ED or a feeding disorder frequently experience malnutrition, including deficiencies, excesses, or imbalances in nutritional intake, which may lead to nutritional dermatoses.¹³ As a result, the skin may present the first visible clues to an ED diagnosis.^8,14-19 Gupta et al¹⁸ organized the skin signs of EDs into 4 categories: (1) those secondary to starvation or malnutrition; (2) cutaneous injury related to self-induced vomiting; (3) dermatoses due to laxative, diuretic, or emetic use; and (4) other concomitant psychiatric illnesses (eg, hand dermatitis from compulsive handwashing, dermatodaxia, onychophagia, trichotillomania). This review will focus on the effects of malnutrition and starvation on the skin.

Skin findings in patients with EDs offer the treating dermatologist a special opportunity for early diagnosis and appropriate consultation with specialists trained in ED treatment. It is important for dermatologists to be vigilant in looking for skin findings of nutritional dermatoses, especially in populations at an increased risk for developing an ED, such as young female patients. The approach to therapy and treatment must occur through a collaborative multidisciplinary effort in a thoughtful and nonjudgmental environment.

Xerosis

Xerosis, or dry skin, is the most common dermatologic finding in both adult and pediatric patients with AN and BN.^14,19 It presents as skin roughness, tightness, flaking, and scaling, which may be complicated by fissuring, itching, and bleeding.²⁰ In healthy skin, moisture is maintained by the stratum corneum and its lipids such as ceramides, cholesterol, and free fatty acids.²¹ Natural moisturizing factor (NMF) within the skin is composed of amino acids, ammonia, urea, uric acid, inorganic salts, lactic acid derivatives, and pyrrolidine-3-carboxylic acid.^20-22 Disruptions to this system result in increased transepidermal water loss and impaired barrier function.²³

In patients with ED, xerosis arises through several mechanisms. Chronic illness or starvation can lead to euthyroid sick syndrome with decreased peripheral conversion of thyroxine (T₄) to triiodothyronine (T₃).^24,25 In the context of functional hypothyroidism, xerosis can arise from decreased eccrine gland secretion.²⁶ Secretions of water, lactate, urea, sodium, and potassium from eccrine glands help to maintain NMF for skin hydration.²⁷ Persistent laxative or diuretic abuse and fluid intake restriction, which are common behaviors across the spectrum of EDs, lead to dehydration and electrolyte imbalances that can manifest as skin dryness.²⁰ Disrupted keratinocyte differentiation due to insufficient stores of vitamins and minerals involved in keratinocyte differentiation, such as vitamins A and C, selenium, and zinc, also may contribute to xerosis.^25,28,29

Severely restrictive eating patterns may lead to development of protein energy malnutrition (PEM). Cutaneous findings in PEM occur due to dysmaturation of epidermal keratinocytes and epidermal atrophy.³⁰ Patients with severe persistent depletion of macronutrients—carbohydrates, fat, and protein—may experience marasmus, resulting in loss of subcutaneous fat that causes the appearance of dry loose skin.^29,31

Xerosis is exceedingly common in the general population and has no predictive value in ED diagnosis; however, this finding should be noted in the context of other signs suggestive of an ED. Treatment of xerosis in the setting of an ED should focus on correction of the underlying malnutrition. Symptomatic alleviation requires improving skin hydration and repairing barrier function. Mild xerosis may not need treatment or can be ameliorated with over-the-counter moisturizers and emollients. Scaling secondary to dry skin can be improved by ingredients such as glycerol, urea, lactic acid, and dexpanthenol.^20,32 Glycerol and urea are small hydrophilic molecules that penetrate the stratum corneum and help to bind moisture within the skin to reduce transepidermal water loss. Urea and lactic acid are keratolytics of NMF commonly found in moisturizers and emollients.^33,34 Dexpanthenol may be used for soothing fissures and pruritus; in vitro and in vivo studies have demonstrated its ability to upregulate dermal fibroblast proliferation and epidermal re-epithelization to promote faster wound healing.³⁵

Lanugo

Lanugo is clinically apparent as a layer of fine, minimally pigmented hair. It is physiologically present on the skin surface of fetuses and newborns. In utero, lanugo plays an essential role in fetal skin protection from amniotic fluid, as well as promotion of proper hydration, thermoregulation, and innate immune development.^36-38 Although it may be found on approximately 30% of newborns as normal variation, its presence beyond the neonatal period signals underlying systemic disease and severe undernutrition.^16,36,39 Rarely, hypertrichosis lanuginosa acquisita has been reported in association with malignancy.^40,41 The finding of lanugo beyond the neonatal period should prompt exclusion of other medical disorders, including neoplasms, chronic infections, hyperthyroidism, malabsorption syndromes, and inflammatory bowel disease.^41-47

There is a limited understanding of the pathomechanism behind lanugo development in the context of malnutrition. Intentional starvation leads to loss of subcutaneous fat and a state of functional hypothyroidism.⁴⁸ Studies hypothesize that lanugo develops as a response to hypothermia, regulated by dermal papillae cell–derived exosomes that may stimulate hair growth via paracrine signaling to outer root sheath cells.^36,49 Molecular studies have found that T₃ impacts skin and hair differentiation and proliferation by modulating thyroid hormone receptor regulation of keratin expression in epithelial cells.^50,51 Lanugo may be a clinical indicator of severe malnutrition among ED patients, especially children and adolescents. A study of 30 patients aged 8 to 17 years with AN and BN who underwent a standard dermatologic examination found significant positive correlation between the presence of lanugo hair growth and concomitant amenorrhea (P<.01) as well as between lanugo hair and body mass index lower than 16 kg/m² (P<.05).¹⁹ Discovery of lanugo in the dermatology clinical setting should prompt a thorough history, including screening questions about eating patterns; attitudes on eating, exercise, and appearance; personal and family history of EDs or other psychiatric disorders; and screening for depression and anxiety. Given its association with other signs of severe malnutrition, a clinical finding of lanugo should prompt close physical examination for other potential signs of an ED and laboratory evaluation for electrolyte levels and blood counts.⁵² Resolution of lanugo secondary to an ED is achieved with restoration of normal total body fat.¹⁸ Treatment should be focused on appropriate weight gain with the guidance of an ED specialist.

Pruritus

The prevalence and pathomechanism of pruritus secondary to EDs remains unclear.^16,53,54 There have been limited reports of pruritus secondary to ED, with Gupta et al⁵³ providing a case series of 6 patients with generalized pruritus in association with starvation and/or rapid weight loss. The study reported remission of pruritus with nutritional rehabilitation and/or weight gain of 5 to 10 pounds. Laboratory evaluation ruled out other causes of pruritus such as cholestasis and uremia.⁵³ Other case reports have associated pruritus with iron deficiency, with anecdotal evidence of pruritus resolution following iron supplementation.^55-59 Although we found no studies specifically relating iron deficiency, EDs, and pruritus, iron deficiency routinely is seen in ED patients and has a known association with pica.^9,10,60 As such, iron deficiency may be a contributing factor in pruritus in ED patients. A UK study of 19 women with AN and a body mass index lower than 16 kg/m² found that more than half of the patients (11/19 [57.9%]) described pruritus on the St. Thomas’ Itch Questionnaire, postulating that pruritus may be a clinical feature of AN.⁶¹ Limited studies with small samples make it difficult to conclude whether pruritus arises as a direct consequence of malnutrition.

Treatment of pruritus should address the underlying ED, as the pathophysiology of itch as it relates to malnutrition is poorly understood. Correction of existing nutritional imbalances by iron supplementation and appropriate weight gain may lead to symptom resolution. Because xerosis may be a contributing factor to pruritus, correction of the xerosis also may be therapeutic. More studies are needed on the connection between pruritus and the nutritional imbalances encountered in patients with EDs.

Acrocyanosis

Acrocyanosis is clinically seen as bluish-dusky discoloration most commonly affecting the hands and feet but also may affect the nose, ears, and nipples. Acrocyanosis typically is a sign of cold intolerance, hypothesized to occur in the context of AN due to shunting of blood centrally in response to hypothermia.^39,62 The diminished oxyhemoglobin delivery to extremity sites leads to the characteristic blue color.⁶³ In a study of 211 adolescent females (age range, 13–17 years) with AN, physical examination revealed peripheral hypothermia and peripheral cyanosis in 80% and 43% of patients, respectively.⁴⁸ Cold intolerance seen in EDs may be secondary to a functional hypothyroid state similar to euthyroid sick syndrome seen in conditions of severe caloric deficit.²⁵

It is possible that anemia and dehydration can worsen acrocyanosis due to impaired delivery of oxyhemoglobin to the body’s periphery.⁶³ In a study of 14 ED patients requiring inpatient care, 6 were found to have underlying anemia following intravenous fluid supplementation.⁶⁴ On admission, the mean (SD) hemoglobin and hematocrit across 14 patients was 12.74 (2.19) and 37.42 (5.99), respectively. Following intravenous fluid supplementation, the mean (SD) hemoglobin and hematocrit decreased to 9.88 (1.79)(P<.001) and 29.56 (4.91)(P=.008), respectively. Most cases reported intentional restriction of dietary sodium and fluid intake, with 2 patients reporting a history of diuretic misuse.⁶⁴ These findings demonstrate that hemoglobin and hematocrit may be falsely normal in patients with AN due to hemoconcentration, suggesting that anemia may be underdiagnosed in inpatients with AN.

Beyond treatment of the underlying ED, acrocyanosis therapy is focused on improvement of circulation and avoidance of exacerbating factors. Pharmacologic intervention rarely is needed. Patients should be reassured that acrocyanosis is a benign condition and often can be improved by dressing warmly and avoiding exposure to cold. Severe cases may warrant trial treatment with nicotinic acid derivatives, α-adrenergic blockade, and topical minoxidil, which have demonstrated limited benefit in treating primary idiopathic acrocyanosis.⁶³

Carotenoderma

Carotenoderma—the presence of a yellow discoloration to skin secondary to hypercarotenemia—has been described in patients with EDs since the 1960s.^65,66 Beyond its clinical appearance, carotenoderma is asymptomatic. Carotenoids are lipid-soluble compounds present in the diet that are metabolized by the intestinal mucosa and liver to the primary conversion product, retinaldehyde, which is further converted to retinol, retinyl esters, and other retinoid metabolites.^67,68 Retinol is bound by lipoproteins and transported in the plasma, then deposited in peripheral tissues,⁶⁹ including in intercellular lipids in the stratum corneum, resulting in an orange hue that is most apparent in sites of increased skin thickness and sweating (eg, palms, soles, nasolabial folds).⁷⁰ In an observational study of ED patients, Glorio et al¹⁴ found that carotenoderma was present in 23.77% (29/122) and 25% (4/16) of patients with BN and other specified feeding or eating disorder, respectively; it was not noted among patients with AN. Prior case reports have provided anecdotal evidence of carotenoderma in AN patients.^66,71 In the setting of an ED, increased serum carotenoids likely are due to increased ingestion of carotene-rich foods, leading to increased levels of carotenoid-bound lipoproteins in the serum.⁷⁰ Resolution of xanthoderma requires restriction of carotenoid intake and may take 2 to 3 months to be clinically apparent. The lipophilic nature of carotenoids allows storage in body fat, prolonging resolution.⁷¹

Hair Changes

Telogen effluvium (TE) and hair pigmentary changes are clinical findings that have been reported in association with EDs.^14,16,19,72 Telogen effluvium occurs when physiologic stress causes a large portion of hairs in the anagen phase of growth to prematurely shift into the catagen then telogen phase. Approximately 2 to 3 months following the initial insult, there is clinically apparent excessive hair shedding compared to baseline.⁷³ Studies have demonstrated that patients with EDs commonly have psychiatric comorbidities such as mood and anxiety disorders, obsessive compulsive disorder, posttraumatic stress disorder, and panic disorder compared to the general population.^6,74-76 As such, stress experienced by ED patients may contribute to TE. Despite TE being commonly reported in ED patients,^16-18 there is a lack of controlled studies of TE in human subjects with ED. An animal model for TE demonstrated that stressed mice exhibited further progression in the hair cycle compared with nonstressed mice (P<.01); the majority of hair follicles in stressed mice were in the catagen phase, while the majority of hair follicles in nonstressed mice were in the anagen phase.⁷⁷ Stressed mice demonstrated an increased number of major histocompatibility complex class II⁺ cell clusters, composed mostly of activated macrophages, per 12.5-mm epidermal length compared to nonstressed mice (mean [SEM], 7.0 [1.1] vs 2.0 [0.3][P<.05]). This study illustrated that stress can lead to inflammatory cell recruitment and activation in the hair follicle microenvironment with growth-inhibitory effects.⁷⁷

The flag sign, or alternating bands of lesser and greater pigmentation in the hair, has been reported in cases of severe PEM.³¹ In addition, PEM may lead to scalp alopecia, dry and brittle hair, and/or hypopigmentation with periods of inadequate nutrition.^29,78 Scalp hair hypopigmentation, brittleness, and alopecia have been reported in pediatric patients with highly selective eating and/or ARFID.^79,80 Maruo et al⁸⁰ described a 3-year-old boy with ASD who consumed only potato chips for more than a year. Physical examination revealed reduced skin turgor overall and sparse red-brown hair on the scalp; laboratory testing showed deficiencies of protein, vitamin A, vitamin D, copper, and zinc. The patient was admitted for nutritional rehabilitation via nasogastric tube feeding, leading to resolution of laboratory abnormalities and growth of thicker black scalp hair over the course of several months.⁸⁰

Neuroendocrine control of keratin expression by thyroid-stimulating hormone (TSH) and thyroid hormones likely plays a role in the regulation of hair follicle activities, including hair growth, structure, and stem cell differentiation.^81,82 Altered thyroid hormone activity, which commonly is seen in patients with EDs,^24,25 may contribute to impaired hair growth and pigmentation.^26,51,83-85 Using tissue cultures of human anagen hair follicles, van Beek et al⁸⁵ provided in vitro evidence that T₃ and T₄ modulate scalp hair follicle growth and pigmentation. Both T₃- and T₄-treated tissue exhibited increased numbers of anagen and decreased numbers of catagen hair follicles in organ cultures compared with control (P<.01); on quantitative Fontana-Masson histochemistry, T₃ and T₄ significantly stimulated hair follicle melanin synthesis compared with control (P<.001 and P<.01, respectively).⁸⁵ Molecular studies by Bodó et al⁸³ have shown that the human scalp epidermis expresses TSH at the messenger RNA and protein levels. Both studies showed that intraepidermal TSH expression is downregulated by thyroid hormones.^83,85 Further studies are needed to examine the impact of malnutrition on local thyroid hormone signaling and action at the level of the dermis, epidermis, and hair follicle.

Discovery of TE, hair loss, and/or hair hypopigmentation should prompt close investigation for other signs of thyroid dysfunction, specifically secondary to malnutrition. Imbalances in TSH, T₃, and T₄ should be corrected. Nutritional deficiencies and dietary habits should be addressed through careful nutritional rehabilitation and targeted ED treatment.

Oral and Mucosal Symptoms

Symptoms of the oral cavity that may arise secondary to EDs and feeding disorders include glossitis, stomatitis, cheilitis, and dental erosions. Mucosal symptoms have been observed in patients with vitamin B deficiencies, inflammatory bowel disease, and other malabsorptive disorders, including patients with EDs.^86-88 Patients following restrictive diets, specifically strict vegan diets, without additional supplementation are at risk for developing vitamin B₁₂ deficiency. Because vitamin B₁₂ is stored in the liver, symptoms of deficiency appear when hepatic stores are depleted over the course of several years.⁸⁹ Insufficient vitamin B₁₂ prevents the proper functioning of methionine synthase, which is required for the conversion of homocysteine to methionine and for the conversion of methyl-tetrahydrofolate to tetrahydrofolate.⁸⁹ Impairment of this process impedes the synthesis of pyrimidine bases of DNA, disrupting the production of rapidly proliferating cells such as myeloid cells or mucosal lining cells. In cases of glossitis and/or stomatitis due to vitamin B₁₂ deficiency, resolution of lesions was achieved within 4 weeks of daily oral supplementation with vitamin B₁₂ at 2 μg daily.^90,91 Iron deficiency, a common finding in EDs, also may contribute to glossitis and angular cheilitis.²⁹ If uncovered, iron deficiency should be corrected by supplementation based on total deficit, age, and sex. Oral supplementation may be done with oral ferrous sulfate (325 mg provides 65 mg elemental iron) or with other iron salts such as ferrous gluconate (325 mg provides 38 mg elemental iron).²⁹ Mucosal symptoms of cheilitis and labial erythema may arise from irritation due to self-induced vomiting.⁸⁸

Dental erosion refers to loss of tooth structure via a chemical process that does not involve bacteria; in contrast, dental caries refer to tooth damage secondary to bacterial acid production. Patients with EDs who repeatedly self-induce vomiting have persistent introduction of gastric acids into the oral cavity, resulting in dissolution of the tooth enamel, which occurs when teeth are persistently exposed to a pH less than 5.5.⁹² Feeding disorders also may predispose patients to dental pathology. In a study of 60 pediatric patients, those with rumination syndrome were significantly more likely to have dental erosions than age- and sex-matched healthy controls (23/30 [77%] vs 4/30 [13%][P<.001]). The same study found no difference in the frequency of dental caries between children with and without rumination syndrome.⁹² These findings suggest that rumination syndrome increases the risk for dental erosions but not dental caries. The distribution of teeth affected by dental erosions may differ between EDs and feeding disorders. Patients with BN are more likely to experience involvement of the palatal surfaces of maxillary teeth, while patients with rumination syndrome had equal involvement of maxillary and mandibular teeth.⁹²

There is limited literature on the role of dentists in the care of patients with EDs and feeding disorders, though existing studies suggest inclusion of a dental care professional in multidisciplinary treatment along with emphasis on education around a home dental care regimen and frequent dental follow-up.^76,93,94 Prevention of further damage requires correction of the underlying behaviors and ED.

Other Dermatologic Findings

Russell sign refers to the development of calluses on the dorsal metacarpophalangeal joints of the dominant hand due to self-induced vomiting. Due to its specificity in purging-type EDs, the discovery of Russell sign should greatly increase suspicion for an ED.¹⁷ Patients with EDs also are at an increased risk for self-harming and body-focused repetitive behaviors, including skin cutting, superficial burning, onychophagia, and trichotillomania.¹⁹ It is important to recognize these signs in patients for whom an ED is suspected. The role of the dermatologist should include careful examination of the skin and documentation of findings that may aid in the diagnosis of an underlying ED.

Final Thoughts

A major limitation of this review is the reliance on small case reports and case series reporting cutaneous manifestations of ED. Controlled studies with larger cohorts are challenging in this population but are needed to substantiate the dermatologic signs commonly associated with EDs. Translational studies may help elucidate the pathomechanisms underlying dermatologic diseases such as lanugo, pruritus, and alopecia in the context of EDs and malnutrition. The known association between thyroid dysfunction and skin disease has been substantiated by clinical and basic science investigation, suggesting a notable role of thyroid hormone and TSH signaling in the skin local environment. Further investigation into nutritional and neuroendocrine regulation of skin health will aid in the diagnosis and treatment of patients impacted by EDs.

The treatment of the underlying ED is key in correcting associated skin disease, which requires interdisciplinary collaboration that addresses the psychological, behavioral, and social components of the condition. Following a diagnosis of ED, assessment should be made of the nutritional rehabilitation required to restore weight and nutritional status. Inpatient treatment may be indicated for patients requiring close monitoring to avoid refeeding syndrome, or those who meet the criteria for extreme AN in the DSM-5 (ie, body mass index <15 kg/m²),¹ or demonstrate signs of medical instability or organ failure secondary to malnutrition.⁶² Long-term recovery for ED patients should focus on behavioral therapy with a multidisciplinary team consisting of a psychiatrist, therapist, dietitian, and primary care provider. Comparative studies in large-scale trials of cognitive behavioral therapy, focal psychodynamic psychotherapy, and specialist supportive clinical management have shown little to no difference in efficacy in treating EDs.^75,95,96

Dermatologists may be the first providers to observe sequelae of nutritional and behavioral derangement in patients with EDs. Existing literature on the dermatologic findings of EDs report great heterogeneity of skin signs, with a very limited number of controlled studies available. Each cutaneous symptom described in this review should not be interpreted as an isolated pathology but should be placed in the context of patient predisposing risk factors and the constellation of other skin findings that may be suggestive of disordered eating behavior or other psychiatric illness. The observation of multiple signs and symptoms at the same time, especially of symptoms uncommonly encountered or suggestive of a severe and prolonged imbalance (eg, xanthoderma with vitamin A excess, aphthous stomatitis with vitamin B deficiency), should heighten clinical suspicion for an underlying ED. A clinician’s highest priority should be to resolve life-threatening medical emergencies and address nutritional derangements with the assistance of experts who are well versed in EDs. The patient should undergo workup to rule out organic causes of their nutritional dermatoses. Given the high psychiatric morbidity and mortality of patients with an ED and the demonstrated benefit of early intervention, recognition of cutaneous manifestations of malnutrition and EDs may be paramount to improving outcomes.

Eating disorders (EDs) and feeding disorders refer to a wide spectrum of complex biopsychosocial illnesses. The spectrum of EDs encompasses anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder, and other specified feeding or eating disorders. Feeding disorders, distinguished from EDs based on the absence of body image disturbance, include pica, rumination syndrome, and avoidant/restrictive food intake disorder (ARFID).¹

This spectrum of illnesses predominantly affect young females aged 15 to 45 years, with recent increases in the rates of EDs among males, patients with skin of color, and adolescent females.^2-5 Patients with EDs are at an elevated lifetime risk of suicidal ideation, suicide attempts, and other psychiatric comorbidities compared to the general population.⁶ Specifically, AN and BN are associated with high psychiatric morbidity and mortality. A meta-analysis by Arcelus et al⁷ demonstrated the weighted annual mortality for AN was 5.10 deaths per 1000 person-years (95% CI, 3.57-7.59) among patients with EDs and 4.55 deaths for studies that selected inpatients (95% CI, 3.09-6.28); for BN, the weighted mortality was 1.74 deaths per 1000 person-years (95% CI, 1.09-2.44). Unfortunately, ED diagnoses often are delayed or missed in clinical settings. Patients may lack insight into the severity of their illness, experience embarrassment about their eating behaviors, or actively avoid treatment for their ED.⁸

Pica—compulsive eating of nonnutritive substances outside the cultural norm—and rumination syndrome—regurgitation of undigested food—are feeding disorders more commonly recognized in childhood.^9-11 Pregnancy, intellectual disability, iron deficiency, and lead poisoning are other conditions associated with pica.^6,9,10 Avoidant/restrictive food intake disorder, a new diagnosis added to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)¹ in 2013, is an eating or feeding disturbance resulting in persistent failure to meet nutritional or energy needs. Etiologies of ARFID may include sensory sensitivities and/or a traumatic event related to eating, leading to avoidance of associated foods.¹²

Patients with an ED or a feeding disorder frequently experience malnutrition, including deficiencies, excesses, or imbalances in nutritional intake, which may lead to nutritional dermatoses.¹³ As a result, the skin may present the first visible clues to an ED diagnosis.^8,14-19 Gupta et al¹⁸ organized the skin signs of EDs into 4 categories: (1) those secondary to starvation or malnutrition; (2) cutaneous injury related to self-induced vomiting; (3) dermatoses due to laxative, diuretic, or emetic use; and (4) other concomitant psychiatric illnesses (eg, hand dermatitis from compulsive handwashing, dermatodaxia, onychophagia, trichotillomania). This review will focus on the effects of malnutrition and starvation on the skin.

Skin findings in patients with EDs offer the treating dermatologist a special opportunity for early diagnosis and appropriate consultation with specialists trained in ED treatment. It is important for dermatologists to be vigilant in looking for skin findings of nutritional dermatoses, especially in populations at an increased risk for developing an ED, such as young female patients. The approach to therapy and treatment must occur through a collaborative multidisciplinary effort in a thoughtful and nonjudgmental environment.

Xerosis

Xerosis, or dry skin, is the most common dermatologic finding in both adult and pediatric patients with AN and BN.^14,19 It presents as skin roughness, tightness, flaking, and scaling, which may be complicated by fissuring, itching, and bleeding.²⁰ In healthy skin, moisture is maintained by the stratum corneum and its lipids such as ceramides, cholesterol, and free fatty acids.²¹ Natural moisturizing factor (NMF) within the skin is composed of amino acids, ammonia, urea, uric acid, inorganic salts, lactic acid derivatives, and pyrrolidine-3-carboxylic acid.^20-22 Disruptions to this system result in increased transepidermal water loss and impaired barrier function.²³

In patients with ED, xerosis arises through several mechanisms. Chronic illness or starvation can lead to euthyroid sick syndrome with decreased peripheral conversion of thyroxine (T₄) to triiodothyronine (T₃).^24,25 In the context of functional hypothyroidism, xerosis can arise from decreased eccrine gland secretion.²⁶ Secretions of water, lactate, urea, sodium, and potassium from eccrine glands help to maintain NMF for skin hydration.²⁷ Persistent laxative or diuretic abuse and fluid intake restriction, which are common behaviors across the spectrum of EDs, lead to dehydration and electrolyte imbalances that can manifest as skin dryness.²⁰ Disrupted keratinocyte differentiation due to insufficient stores of vitamins and minerals involved in keratinocyte differentiation, such as vitamins A and C, selenium, and zinc, also may contribute to xerosis.^25,28,29

Severely restrictive eating patterns may lead to development of protein energy malnutrition (PEM). Cutaneous findings in PEM occur due to dysmaturation of epidermal keratinocytes and epidermal atrophy.³⁰ Patients with severe persistent depletion of macronutrients—carbohydrates, fat, and protein—may experience marasmus, resulting in loss of subcutaneous fat that causes the appearance of dry loose skin.^29,31

Xerosis is exceedingly common in the general population and has no predictive value in ED diagnosis; however, this finding should be noted in the context of other signs suggestive of an ED. Treatment of xerosis in the setting of an ED should focus on correction of the underlying malnutrition. Symptomatic alleviation requires improving skin hydration and repairing barrier function. Mild xerosis may not need treatment or can be ameliorated with over-the-counter moisturizers and emollients. Scaling secondary to dry skin can be improved by ingredients such as glycerol, urea, lactic acid, and dexpanthenol.^20,32 Glycerol and urea are small hydrophilic molecules that penetrate the stratum corneum and help to bind moisture within the skin to reduce transepidermal water loss. Urea and lactic acid are keratolytics of NMF commonly found in moisturizers and emollients.^33,34 Dexpanthenol may be used for soothing fissures and pruritus; in vitro and in vivo studies have demonstrated its ability to upregulate dermal fibroblast proliferation and epidermal re-epithelization to promote faster wound healing.³⁵

Lanugo

Lanugo is clinically apparent as a layer of fine, minimally pigmented hair. It is physiologically present on the skin surface of fetuses and newborns. In utero, lanugo plays an essential role in fetal skin protection from amniotic fluid, as well as promotion of proper hydration, thermoregulation, and innate immune development.^36-38 Although it may be found on approximately 30% of newborns as normal variation, its presence beyond the neonatal period signals underlying systemic disease and severe undernutrition.^16,36,39 Rarely, hypertrichosis lanuginosa acquisita has been reported in association with malignancy.^40,41 The finding of lanugo beyond the neonatal period should prompt exclusion of other medical disorders, including neoplasms, chronic infections, hyperthyroidism, malabsorption syndromes, and inflammatory bowel disease.^41-47

There is a limited understanding of the pathomechanism behind lanugo development in the context of malnutrition. Intentional starvation leads to loss of subcutaneous fat and a state of functional hypothyroidism.⁴⁸ Studies hypothesize that lanugo develops as a response to hypothermia, regulated by dermal papillae cell–derived exosomes that may stimulate hair growth via paracrine signaling to outer root sheath cells.^36,49 Molecular studies have found that T₃ impacts skin and hair differentiation and proliferation by modulating thyroid hormone receptor regulation of keratin expression in epithelial cells.^50,51 Lanugo may be a clinical indicator of severe malnutrition among ED patients, especially children and adolescents. A study of 30 patients aged 8 to 17 years with AN and BN who underwent a standard dermatologic examination found significant positive correlation between the presence of lanugo hair growth and concomitant amenorrhea (P<.01) as well as between lanugo hair and body mass index lower than 16 kg/m² (P<.05).¹⁹ Discovery of lanugo in the dermatology clinical setting should prompt a thorough history, including screening questions about eating patterns; attitudes on eating, exercise, and appearance; personal and family history of EDs or other psychiatric disorders; and screening for depression and anxiety. Given its association with other signs of severe malnutrition, a clinical finding of lanugo should prompt close physical examination for other potential signs of an ED and laboratory evaluation for electrolyte levels and blood counts.⁵² Resolution of lanugo secondary to an ED is achieved with restoration of normal total body fat.¹⁸ Treatment should be focused on appropriate weight gain with the guidance of an ED specialist.

Pruritus

The prevalence and pathomechanism of pruritus secondary to EDs remains unclear.^16,53,54 There have been limited reports of pruritus secondary to ED, with Gupta et al⁵³ providing a case series of 6 patients with generalized pruritus in association with starvation and/or rapid weight loss. The study reported remission of pruritus with nutritional rehabilitation and/or weight gain of 5 to 10 pounds. Laboratory evaluation ruled out other causes of pruritus such as cholestasis and uremia.⁵³ Other case reports have associated pruritus with iron deficiency, with anecdotal evidence of pruritus resolution following iron supplementation.^55-59 Although we found no studies specifically relating iron deficiency, EDs, and pruritus, iron deficiency routinely is seen in ED patients and has a known association with pica.^9,10,60 As such, iron deficiency may be a contributing factor in pruritus in ED patients. A UK study of 19 women with AN and a body mass index lower than 16 kg/m² found that more than half of the patients (11/19 [57.9%]) described pruritus on the St. Thomas’ Itch Questionnaire, postulating that pruritus may be a clinical feature of AN.⁶¹ Limited studies with small samples make it difficult to conclude whether pruritus arises as a direct consequence of malnutrition.

Treatment of pruritus should address the underlying ED, as the pathophysiology of itch as it relates to malnutrition is poorly understood. Correction of existing nutritional imbalances by iron supplementation and appropriate weight gain may lead to symptom resolution. Because xerosis may be a contributing factor to pruritus, correction of the xerosis also may be therapeutic. More studies are needed on the connection between pruritus and the nutritional imbalances encountered in patients with EDs.

Acrocyanosis

Acrocyanosis is clinically seen as bluish-dusky discoloration most commonly affecting the hands and feet but also may affect the nose, ears, and nipples. Acrocyanosis typically is a sign of cold intolerance, hypothesized to occur in the context of AN due to shunting of blood centrally in response to hypothermia.^39,62 The diminished oxyhemoglobin delivery to extremity sites leads to the characteristic blue color.⁶³ In a study of 211 adolescent females (age range, 13–17 years) with AN, physical examination revealed peripheral hypothermia and peripheral cyanosis in 80% and 43% of patients, respectively.⁴⁸ Cold intolerance seen in EDs may be secondary to a functional hypothyroid state similar to euthyroid sick syndrome seen in conditions of severe caloric deficit.²⁵

It is possible that anemia and dehydration can worsen acrocyanosis due to impaired delivery of oxyhemoglobin to the body’s periphery.⁶³ In a study of 14 ED patients requiring inpatient care, 6 were found to have underlying anemia following intravenous fluid supplementation.⁶⁴ On admission, the mean (SD) hemoglobin and hematocrit across 14 patients was 12.74 (2.19) and 37.42 (5.99), respectively. Following intravenous fluid supplementation, the mean (SD) hemoglobin and hematocrit decreased to 9.88 (1.79)(P<.001) and 29.56 (4.91)(P=.008), respectively. Most cases reported intentional restriction of dietary sodium and fluid intake, with 2 patients reporting a history of diuretic misuse.⁶⁴ These findings demonstrate that hemoglobin and hematocrit may be falsely normal in patients with AN due to hemoconcentration, suggesting that anemia may be underdiagnosed in inpatients with AN.

Beyond treatment of the underlying ED, acrocyanosis therapy is focused on improvement of circulation and avoidance of exacerbating factors. Pharmacologic intervention rarely is needed. Patients should be reassured that acrocyanosis is a benign condition and often can be improved by dressing warmly and avoiding exposure to cold. Severe cases may warrant trial treatment with nicotinic acid derivatives, α-adrenergic blockade, and topical minoxidil, which have demonstrated limited benefit in treating primary idiopathic acrocyanosis.⁶³

Carotenoderma

Carotenoderma—the presence of a yellow discoloration to skin secondary to hypercarotenemia—has been described in patients with EDs since the 1960s.^65,66 Beyond its clinical appearance, carotenoderma is asymptomatic. Carotenoids are lipid-soluble compounds present in the diet that are metabolized by the intestinal mucosa and liver to the primary conversion product, retinaldehyde, which is further converted to retinol, retinyl esters, and other retinoid metabolites.^67,68 Retinol is bound by lipoproteins and transported in the plasma, then deposited in peripheral tissues,⁶⁹ including in intercellular lipids in the stratum corneum, resulting in an orange hue that is most apparent in sites of increased skin thickness and sweating (eg, palms, soles, nasolabial folds).⁷⁰ In an observational study of ED patients, Glorio et al¹⁴ found that carotenoderma was present in 23.77% (29/122) and 25% (4/16) of patients with BN and other specified feeding or eating disorder, respectively; it was not noted among patients with AN. Prior case reports have provided anecdotal evidence of carotenoderma in AN patients.^66,71 In the setting of an ED, increased serum carotenoids likely are due to increased ingestion of carotene-rich foods, leading to increased levels of carotenoid-bound lipoproteins in the serum.⁷⁰ Resolution of xanthoderma requires restriction of carotenoid intake and may take 2 to 3 months to be clinically apparent. The lipophilic nature of carotenoids allows storage in body fat, prolonging resolution.⁷¹

Hair Changes

Telogen effluvium (TE) and hair pigmentary changes are clinical findings that have been reported in association with EDs.^14,16,19,72 Telogen effluvium occurs when physiologic stress causes a large portion of hairs in the anagen phase of growth to prematurely shift into the catagen then telogen phase. Approximately 2 to 3 months following the initial insult, there is clinically apparent excessive hair shedding compared to baseline.⁷³ Studies have demonstrated that patients with EDs commonly have psychiatric comorbidities such as mood and anxiety disorders, obsessive compulsive disorder, posttraumatic stress disorder, and panic disorder compared to the general population.^6,74-76 As such, stress experienced by ED patients may contribute to TE. Despite TE being commonly reported in ED patients,^16-18 there is a lack of controlled studies of TE in human subjects with ED. An animal model for TE demonstrated that stressed mice exhibited further progression in the hair cycle compared with nonstressed mice (P<.01); the majority of hair follicles in stressed mice were in the catagen phase, while the majority of hair follicles in nonstressed mice were in the anagen phase.⁷⁷ Stressed mice demonstrated an increased number of major histocompatibility complex class II⁺ cell clusters, composed mostly of activated macrophages, per 12.5-mm epidermal length compared to nonstressed mice (mean [SEM], 7.0 [1.1] vs 2.0 [0.3][P<.05]). This study illustrated that stress can lead to inflammatory cell recruitment and activation in the hair follicle microenvironment with growth-inhibitory effects.⁷⁷

The flag sign, or alternating bands of lesser and greater pigmentation in the hair, has been reported in cases of severe PEM.³¹ In addition, PEM may lead to scalp alopecia, dry and brittle hair, and/or hypopigmentation with periods of inadequate nutrition.^29,78 Scalp hair hypopigmentation, brittleness, and alopecia have been reported in pediatric patients with highly selective eating and/or ARFID.^79,80 Maruo et al⁸⁰ described a 3-year-old boy with ASD who consumed only potato chips for more than a year. Physical examination revealed reduced skin turgor overall and sparse red-brown hair on the scalp; laboratory testing showed deficiencies of protein, vitamin A, vitamin D, copper, and zinc. The patient was admitted for nutritional rehabilitation via nasogastric tube feeding, leading to resolution of laboratory abnormalities and growth of thicker black scalp hair over the course of several months.⁸⁰

Neuroendocrine control of keratin expression by thyroid-stimulating hormone (TSH) and thyroid hormones likely plays a role in the regulation of hair follicle activities, including hair growth, structure, and stem cell differentiation.^81,82 Altered thyroid hormone activity, which commonly is seen in patients with EDs,^24,25 may contribute to impaired hair growth and pigmentation.^26,51,83-85 Using tissue cultures of human anagen hair follicles, van Beek et al⁸⁵ provided in vitro evidence that T₃ and T₄ modulate scalp hair follicle growth and pigmentation. Both T₃- and T₄-treated tissue exhibited increased numbers of anagen and decreased numbers of catagen hair follicles in organ cultures compared with control (P<.01); on quantitative Fontana-Masson histochemistry, T₃ and T₄ significantly stimulated hair follicle melanin synthesis compared with control (P<.001 and P<.01, respectively).⁸⁵ Molecular studies by Bodó et al⁸³ have shown that the human scalp epidermis expresses TSH at the messenger RNA and protein levels. Both studies showed that intraepidermal TSH expression is downregulated by thyroid hormones.^83,85 Further studies are needed to examine the impact of malnutrition on local thyroid hormone signaling and action at the level of the dermis, epidermis, and hair follicle.

Discovery of TE, hair loss, and/or hair hypopigmentation should prompt close investigation for other signs of thyroid dysfunction, specifically secondary to malnutrition. Imbalances in TSH, T₃, and T₄ should be corrected. Nutritional deficiencies and dietary habits should be addressed through careful nutritional rehabilitation and targeted ED treatment.

Oral and Mucosal Symptoms

Symptoms of the oral cavity that may arise secondary to EDs and feeding disorders include glossitis, stomatitis, cheilitis, and dental erosions. Mucosal symptoms have been observed in patients with vitamin B deficiencies, inflammatory bowel disease, and other malabsorptive disorders, including patients with EDs.^86-88 Patients following restrictive diets, specifically strict vegan diets, without additional supplementation are at risk for developing vitamin B₁₂ deficiency. Because vitamin B₁₂ is stored in the liver, symptoms of deficiency appear when hepatic stores are depleted over the course of several years.⁸⁹ Insufficient vitamin B₁₂ prevents the proper functioning of methionine synthase, which is required for the conversion of homocysteine to methionine and for the conversion of methyl-tetrahydrofolate to tetrahydrofolate.⁸⁹ Impairment of this process impedes the synthesis of pyrimidine bases of DNA, disrupting the production of rapidly proliferating cells such as myeloid cells or mucosal lining cells. In cases of glossitis and/or stomatitis due to vitamin B₁₂ deficiency, resolution of lesions was achieved within 4 weeks of daily oral supplementation with vitamin B₁₂ at 2 μg daily.^90,91 Iron deficiency, a common finding in EDs, also may contribute to glossitis and angular cheilitis.²⁹ If uncovered, iron deficiency should be corrected by supplementation based on total deficit, age, and sex. Oral supplementation may be done with oral ferrous sulfate (325 mg provides 65 mg elemental iron) or with other iron salts such as ferrous gluconate (325 mg provides 38 mg elemental iron).²⁹ Mucosal symptoms of cheilitis and labial erythema may arise from irritation due to self-induced vomiting.⁸⁸

Dental erosion refers to loss of tooth structure via a chemical process that does not involve bacteria; in contrast, dental caries refer to tooth damage secondary to bacterial acid production. Patients with EDs who repeatedly self-induce vomiting have persistent introduction of gastric acids into the oral cavity, resulting in dissolution of the tooth enamel, which occurs when teeth are persistently exposed to a pH less than 5.5.⁹² Feeding disorders also may predispose patients to dental pathology. In a study of 60 pediatric patients, those with rumination syndrome were significantly more likely to have dental erosions than age- and sex-matched healthy controls (23/30 [77%] vs 4/30 [13%][P<.001]). The same study found no difference in the frequency of dental caries between children with and without rumination syndrome.⁹² These findings suggest that rumination syndrome increases the risk for dental erosions but not dental caries. The distribution of teeth affected by dental erosions may differ between EDs and feeding disorders. Patients with BN are more likely to experience involvement of the palatal surfaces of maxillary teeth, while patients with rumination syndrome had equal involvement of maxillary and mandibular teeth.⁹²

There is limited literature on the role of dentists in the care of patients with EDs and feeding disorders, though existing studies suggest inclusion of a dental care professional in multidisciplinary treatment along with emphasis on education around a home dental care regimen and frequent dental follow-up.^76,93,94 Prevention of further damage requires correction of the underlying behaviors and ED.

Other Dermatologic Findings

Russell sign refers to the development of calluses on the dorsal metacarpophalangeal joints of the dominant hand due to self-induced vomiting. Due to its specificity in purging-type EDs, the discovery of Russell sign should greatly increase suspicion for an ED.¹⁷ Patients with EDs also are at an increased risk for self-harming and body-focused repetitive behaviors, including skin cutting, superficial burning, onychophagia, and trichotillomania.¹⁹ It is important to recognize these signs in patients for whom an ED is suspected. The role of the dermatologist should include careful examination of the skin and documentation of findings that may aid in the diagnosis of an underlying ED.

Final Thoughts

A major limitation of this review is the reliance on small case reports and case series reporting cutaneous manifestations of ED. Controlled studies with larger cohorts are challenging in this population but are needed to substantiate the dermatologic signs commonly associated with EDs. Translational studies may help elucidate the pathomechanisms underlying dermatologic diseases such as lanugo, pruritus, and alopecia in the context of EDs and malnutrition. The known association between thyroid dysfunction and skin disease has been substantiated by clinical and basic science investigation, suggesting a notable role of thyroid hormone and TSH signaling in the skin local environment. Further investigation into nutritional and neuroendocrine regulation of skin health will aid in the diagnosis and treatment of patients impacted by EDs.

The treatment of the underlying ED is key in correcting associated skin disease, which requires interdisciplinary collaboration that addresses the psychological, behavioral, and social components of the condition. Following a diagnosis of ED, assessment should be made of the nutritional rehabilitation required to restore weight and nutritional status. Inpatient treatment may be indicated for patients requiring close monitoring to avoid refeeding syndrome, or those who meet the criteria for extreme AN in the DSM-5 (ie, body mass index <15 kg/m²),¹ or demonstrate signs of medical instability or organ failure secondary to malnutrition.⁶² Long-term recovery for ED patients should focus on behavioral therapy with a multidisciplinary team consisting of a psychiatrist, therapist, dietitian, and primary care provider. Comparative studies in large-scale trials of cognitive behavioral therapy, focal psychodynamic psychotherapy, and specialist supportive clinical management have shown little to no difference in efficacy in treating EDs.^75,95,96

Dermatologists may be the first providers to observe sequelae of nutritional and behavioral derangement in patients with EDs. Existing literature on the dermatologic findings of EDs report great heterogeneity of skin signs, with a very limited number of controlled studies available. Each cutaneous symptom described in this review should not be interpreted as an isolated pathology but should be placed in the context of patient predisposing risk factors and the constellation of other skin findings that may be suggestive of disordered eating behavior or other psychiatric illness. The observation of multiple signs and symptoms at the same time, especially of symptoms uncommonly encountered or suggestive of a severe and prolonged imbalance (eg, xanthoderma with vitamin A excess, aphthous stomatitis with vitamin B deficiency), should heighten clinical suspicion for an underlying ED. A clinician’s highest priority should be to resolve life-threatening medical emergencies and address nutritional derangements with the assistance of experts who are well versed in EDs. The patient should undergo workup to rule out organic causes of their nutritional dermatoses. Given the high psychiatric morbidity and mortality of patients with an ED and the demonstrated benefit of early intervention, recognition of cutaneous manifestations of malnutrition and EDs may be paramount to improving outcomes.

Eating disorders (EDs) and feeding disorders refer to a wide spectrum of complex biopsychosocial illnesses. The spectrum of EDs encompasses anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder, and other specified feeding or eating disorders. Feeding disorders, distinguished from EDs based on the absence of body image disturbance, include pica, rumination syndrome, and avoidant/restrictive food intake disorder (ARFID).¹

This spectrum of illnesses predominantly affect young females aged 15 to 45 years, with recent increases in the rates of EDs among males, patients with skin of color, and adolescent females.^2-5 Patients with EDs are at an elevated lifetime risk of suicidal ideation, suicide attempts, and other psychiatric comorbidities compared to the general population.⁶ Specifically, AN and BN are associated with high psychiatric morbidity and mortality. A meta-analysis by Arcelus et al⁷ demonstrated the weighted annual mortality for AN was 5.10 deaths per 1000 person-years (95% CI, 3.57-7.59) among patients with EDs and 4.55 deaths for studies that selected inpatients (95% CI, 3.09-6.28); for BN, the weighted mortality was 1.74 deaths per 1000 person-years (95% CI, 1.09-2.44). Unfortunately, ED diagnoses often are delayed or missed in clinical settings. Patients may lack insight into the severity of their illness, experience embarrassment about their eating behaviors, or actively avoid treatment for their ED.⁸

Pica—compulsive eating of nonnutritive substances outside the cultural norm—and rumination syndrome—regurgitation of undigested food—are feeding disorders more commonly recognized in childhood.^9-11 Pregnancy, intellectual disability, iron deficiency, and lead poisoning are other conditions associated with pica.^6,9,10 Avoidant/restrictive food intake disorder, a new diagnosis added to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)¹ in 2013, is an eating or feeding disturbance resulting in persistent failure to meet nutritional or energy needs. Etiologies of ARFID may include sensory sensitivities and/or a traumatic event related to eating, leading to avoidance of associated foods.¹²

Patients with an ED or a feeding disorder frequently experience malnutrition, including deficiencies, excesses, or imbalances in nutritional intake, which may lead to nutritional dermatoses.¹³ As a result, the skin may present the first visible clues to an ED diagnosis.^8,14-19 Gupta et al¹⁸ organized the skin signs of EDs into 4 categories: (1) those secondary to starvation or malnutrition; (2) cutaneous injury related to self-induced vomiting; (3) dermatoses due to laxative, diuretic, or emetic use; and (4) other concomitant psychiatric illnesses (eg, hand dermatitis from compulsive handwashing, dermatodaxia, onychophagia, trichotillomania). This review will focus on the effects of malnutrition and starvation on the skin.

Skin findings in patients with EDs offer the treating dermatologist a special opportunity for early diagnosis and appropriate consultation with specialists trained in ED treatment. It is important for dermatologists to be vigilant in looking for skin findings of nutritional dermatoses, especially in populations at an increased risk for developing an ED, such as young female patients. The approach to therapy and treatment must occur through a collaborative multidisciplinary effort in a thoughtful and nonjudgmental environment.

Xerosis

Xerosis, or dry skin, is the most common dermatologic finding in both adult and pediatric patients with AN and BN.^14,19 It presents as skin roughness, tightness, flaking, and scaling, which may be complicated by fissuring, itching, and bleeding.²⁰ In healthy skin, moisture is maintained by the stratum corneum and its lipids such as ceramides, cholesterol, and free fatty acids.²¹ Natural moisturizing factor (NMF) within the skin is composed of amino acids, ammonia, urea, uric acid, inorganic salts, lactic acid derivatives, and pyrrolidine-3-carboxylic acid.^20-22 Disruptions to this system result in increased transepidermal water loss and impaired barrier function.²³

In patients with ED, xerosis arises through several mechanisms. Chronic illness or starvation can lead to euthyroid sick syndrome with decreased peripheral conversion of thyroxine (T₄) to triiodothyronine (T₃).^24,25 In the context of functional hypothyroidism, xerosis can arise from decreased eccrine gland secretion.²⁶ Secretions of water, lactate, urea, sodium, and potassium from eccrine glands help to maintain NMF for skin hydration.²⁷ Persistent laxative or diuretic abuse and fluid intake restriction, which are common behaviors across the spectrum of EDs, lead to dehydration and electrolyte imbalances that can manifest as skin dryness.²⁰ Disrupted keratinocyte differentiation due to insufficient stores of vitamins and minerals involved in keratinocyte differentiation, such as vitamins A and C, selenium, and zinc, also may contribute to xerosis.^25,28,29

Severely restrictive eating patterns may lead to development of protein energy malnutrition (PEM). Cutaneous findings in PEM occur due to dysmaturation of epidermal keratinocytes and epidermal atrophy.³⁰ Patients with severe persistent depletion of macronutrients—carbohydrates, fat, and protein—may experience marasmus, resulting in loss of subcutaneous fat that causes the appearance of dry loose skin.^29,31

Xerosis is exceedingly common in the general population and has no predictive value in ED diagnosis; however, this finding should be noted in the context of other signs suggestive of an ED. Treatment of xerosis in the setting of an ED should focus on correction of the underlying malnutrition. Symptomatic alleviation requires improving skin hydration and repairing barrier function. Mild xerosis may not need treatment or can be ameliorated with over-the-counter moisturizers and emollients. Scaling secondary to dry skin can be improved by ingredients such as glycerol, urea, lactic acid, and dexpanthenol.^20,32 Glycerol and urea are small hydrophilic molecules that penetrate the stratum corneum and help to bind moisture within the skin to reduce transepidermal water loss. Urea and lactic acid are keratolytics of NMF commonly found in moisturizers and emollients.^33,34 Dexpanthenol may be used for soothing fissures and pruritus; in vitro and in vivo studies have demonstrated its ability to upregulate dermal fibroblast proliferation and epidermal re-epithelization to promote faster wound healing.³⁵

Lanugo

Lanugo is clinically apparent as a layer of fine, minimally pigmented hair. It is physiologically present on the skin surface of fetuses and newborns. In utero, lanugo plays an essential role in fetal skin protection from amniotic fluid, as well as promotion of proper hydration, thermoregulation, and innate immune development.^36-38 Although it may be found on approximately 30% of newborns as normal variation, its presence beyond the neonatal period signals underlying systemic disease and severe undernutrition.^16,36,39 Rarely, hypertrichosis lanuginosa acquisita has been reported in association with malignancy.^40,41 The finding of lanugo beyond the neonatal period should prompt exclusion of other medical disorders, including neoplasms, chronic infections, hyperthyroidism, malabsorption syndromes, and inflammatory bowel disease.^41-47

There is a limited understanding of the pathomechanism behind lanugo development in the context of malnutrition. Intentional starvation leads to loss of subcutaneous fat and a state of functional hypothyroidism.⁴⁸ Studies hypothesize that lanugo develops as a response to hypothermia, regulated by dermal papillae cell–derived exosomes that may stimulate hair growth via paracrine signaling to outer root sheath cells.^36,49 Molecular studies have found that T₃ impacts skin and hair differentiation and proliferation by modulating thyroid hormone receptor regulation of keratin expression in epithelial cells.^50,51 Lanugo may be a clinical indicator of severe malnutrition among ED patients, especially children and adolescents. A study of 30 patients aged 8 to 17 years with AN and BN who underwent a standard dermatologic examination found significant positive correlation between the presence of lanugo hair growth and concomitant amenorrhea (P<.01) as well as between lanugo hair and body mass index lower than 16 kg/m² (P<.05).¹⁹ Discovery of lanugo in the dermatology clinical setting should prompt a thorough history, including screening questions about eating patterns; attitudes on eating, exercise, and appearance; personal and family history of EDs or other psychiatric disorders; and screening for depression and anxiety. Given its association with other signs of severe malnutrition, a clinical finding of lanugo should prompt close physical examination for other potential signs of an ED and laboratory evaluation for electrolyte levels and blood counts.⁵² Resolution of lanugo secondary to an ED is achieved with restoration of normal total body fat.¹⁸ Treatment should be focused on appropriate weight gain with the guidance of an ED specialist.

Pruritus

The prevalence and pathomechanism of pruritus secondary to EDs remains unclear.^16,53,54 There have been limited reports of pruritus secondary to ED, with Gupta et al⁵³ providing a case series of 6 patients with generalized pruritus in association with starvation and/or rapid weight loss. The study reported remission of pruritus with nutritional rehabilitation and/or weight gain of 5 to 10 pounds. Laboratory evaluation ruled out other causes of pruritus such as cholestasis and uremia.⁵³ Other case reports have associated pruritus with iron deficiency, with anecdotal evidence of pruritus resolution following iron supplementation.^55-59 Although we found no studies specifically relating iron deficiency, EDs, and pruritus, iron deficiency routinely is seen in ED patients and has a known association with pica.^9,10,60 As such, iron deficiency may be a contributing factor in pruritus in ED patients. A UK study of 19 women with AN and a body mass index lower than 16 kg/m² found that more than half of the patients (11/19 [57.9%]) described pruritus on the St. Thomas’ Itch Questionnaire, postulating that pruritus may be a clinical feature of AN.⁶¹ Limited studies with small samples make it difficult to conclude whether pruritus arises as a direct consequence of malnutrition.

Treatment of pruritus should address the underlying ED, as the pathophysiology of itch as it relates to malnutrition is poorly understood. Correction of existing nutritional imbalances by iron supplementation and appropriate weight gain may lead to symptom resolution. Because xerosis may be a contributing factor to pruritus, correction of the xerosis also may be therapeutic. More studies are needed on the connection between pruritus and the nutritional imbalances encountered in patients with EDs.

Acrocyanosis

Acrocyanosis is clinically seen as bluish-dusky discoloration most commonly affecting the hands and feet but also may affect the nose, ears, and nipples. Acrocyanosis typically is a sign of cold intolerance, hypothesized to occur in the context of AN due to shunting of blood centrally in response to hypothermia.^39,62 The diminished oxyhemoglobin delivery to extremity sites leads to the characteristic blue color.⁶³ In a study of 211 adolescent females (age range, 13–17 years) with AN, physical examination revealed peripheral hypothermia and peripheral cyanosis in 80% and 43% of patients, respectively.⁴⁸ Cold intolerance seen in EDs may be secondary to a functional hypothyroid state similar to euthyroid sick syndrome seen in conditions of severe caloric deficit.²⁵

It is possible that anemia and dehydration can worsen acrocyanosis due to impaired delivery of oxyhemoglobin to the body’s periphery.⁶³ In a study of 14 ED patients requiring inpatient care, 6 were found to have underlying anemia following intravenous fluid supplementation.⁶⁴ On admission, the mean (SD) hemoglobin and hematocrit across 14 patients was 12.74 (2.19) and 37.42 (5.99), respectively. Following intravenous fluid supplementation, the mean (SD) hemoglobin and hematocrit decreased to 9.88 (1.79)(P<.001) and 29.56 (4.91)(P=.008), respectively. Most cases reported intentional restriction of dietary sodium and fluid intake, with 2 patients reporting a history of diuretic misuse.⁶⁴ These findings demonstrate that hemoglobin and hematocrit may be falsely normal in patients with AN due to hemoconcentration, suggesting that anemia may be underdiagnosed in inpatients with AN.

Beyond treatment of the underlying ED, acrocyanosis therapy is focused on improvement of circulation and avoidance of exacerbating factors. Pharmacologic intervention rarely is needed. Patients should be reassured that acrocyanosis is a benign condition and often can be improved by dressing warmly and avoiding exposure to cold. Severe cases may warrant trial treatment with nicotinic acid derivatives, α-adrenergic blockade, and topical minoxidil, which have demonstrated limited benefit in treating primary idiopathic acrocyanosis.⁶³

Carotenoderma

Carotenoderma—the presence of a yellow discoloration to skin secondary to hypercarotenemia—has been described in patients with EDs since the 1960s.^65,66 Beyond its clinical appearance, carotenoderma is asymptomatic. Carotenoids are lipid-soluble compounds present in the diet that are metabolized by the intestinal mucosa and liver to the primary conversion product, retinaldehyde, which is further converted to retinol, retinyl esters, and other retinoid metabolites.^67,68 Retinol is bound by lipoproteins and transported in the plasma, then deposited in peripheral tissues,⁶⁹ including in intercellular lipids in the stratum corneum, resulting in an orange hue that is most apparent in sites of increased skin thickness and sweating (eg, palms, soles, nasolabial folds).⁷⁰ In an observational study of ED patients, Glorio et al¹⁴ found that carotenoderma was present in 23.77% (29/122) and 25% (4/16) of patients with BN and other specified feeding or eating disorder, respectively; it was not noted among patients with AN. Prior case reports have provided anecdotal evidence of carotenoderma in AN patients.^66,71 In the setting of an ED, increased serum carotenoids likely are due to increased ingestion of carotene-rich foods, leading to increased levels of carotenoid-bound lipoproteins in the serum.⁷⁰ Resolution of xanthoderma requires restriction of carotenoid intake and may take 2 to 3 months to be clinically apparent. The lipophilic nature of carotenoids allows storage in body fat, prolonging resolution.⁷¹

Hair Changes

Telogen effluvium (TE) and hair pigmentary changes are clinical findings that have been reported in association with EDs.^14,16,19,72 Telogen effluvium occurs when physiologic stress causes a large portion of hairs in the anagen phase of growth to prematurely shift into the catagen then telogen phase. Approximately 2 to 3 months following the initial insult, there is clinically apparent excessive hair shedding compared to baseline.⁷³ Studies have demonstrated that patients with EDs commonly have psychiatric comorbidities such as mood and anxiety disorders, obsessive compulsive disorder, posttraumatic stress disorder, and panic disorder compared to the general population.^6,74-76 As such, stress experienced by ED patients may contribute to TE. Despite TE being commonly reported in ED patients,^16-18 there is a lack of controlled studies of TE in human subjects with ED. An animal model for TE demonstrated that stressed mice exhibited further progression in the hair cycle compared with nonstressed mice (P<.01); the majority of hair follicles in stressed mice were in the catagen phase, while the majority of hair follicles in nonstressed mice were in the anagen phase.⁷⁷ Stressed mice demonstrated an increased number of major histocompatibility complex class II⁺ cell clusters, composed mostly of activated macrophages, per 12.5-mm epidermal length compared to nonstressed mice (mean [SEM], 7.0 [1.1] vs 2.0 [0.3][P<.05]). This study illustrated that stress can lead to inflammatory cell recruitment and activation in the hair follicle microenvironment with growth-inhibitory effects.⁷⁷

The flag sign, or alternating bands of lesser and greater pigmentation in the hair, has been reported in cases of severe PEM.³¹ In addition, PEM may lead to scalp alopecia, dry and brittle hair, and/or hypopigmentation with periods of inadequate nutrition.^29,78 Scalp hair hypopigmentation, brittleness, and alopecia have been reported in pediatric patients with highly selective eating and/or ARFID.^79,80 Maruo et al⁸⁰ described a 3-year-old boy with ASD who consumed only potato chips for more than a year. Physical examination revealed reduced skin turgor overall and sparse red-brown hair on the scalp; laboratory testing showed deficiencies of protein, vitamin A, vitamin D, copper, and zinc. The patient was admitted for nutritional rehabilitation via nasogastric tube feeding, leading to resolution of laboratory abnormalities and growth of thicker black scalp hair over the course of several months.⁸⁰

Neuroendocrine control of keratin expression by thyroid-stimulating hormone (TSH) and thyroid hormones likely plays a role in the regulation of hair follicle activities, including hair growth, structure, and stem cell differentiation.^81,82 Altered thyroid hormone activity, which commonly is seen in patients with EDs,^24,25 may contribute to impaired hair growth and pigmentation.^26,51,83-85 Using tissue cultures of human anagen hair follicles, van Beek et al⁸⁵ provided in vitro evidence that T₃ and T₄ modulate scalp hair follicle growth and pigmentation. Both T₃- and T₄-treated tissue exhibited increased numbers of anagen and decreased numbers of catagen hair follicles in organ cultures compared with control (P<.01); on quantitative Fontana-Masson histochemistry, T₃ and T₄ significantly stimulated hair follicle melanin synthesis compared with control (P<.001 and P<.01, respectively).⁸⁵ Molecular studies by Bodó et al⁸³ have shown that the human scalp epidermis expresses TSH at the messenger RNA and protein levels. Both studies showed that intraepidermal TSH expression is downregulated by thyroid hormones.^83,85 Further studies are needed to examine the impact of malnutrition on local thyroid hormone signaling and action at the level of the dermis, epidermis, and hair follicle.

Discovery of TE, hair loss, and/or hair hypopigmentation should prompt close investigation for other signs of thyroid dysfunction, specifically secondary to malnutrition. Imbalances in TSH, T₃, and T₄ should be corrected. Nutritional deficiencies and dietary habits should be addressed through careful nutritional rehabilitation and targeted ED treatment.

Oral and Mucosal Symptoms

Symptoms of the oral cavity that may arise secondary to EDs and feeding disorders include glossitis, stomatitis, cheilitis, and dental erosions. Mucosal symptoms have been observed in patients with vitamin B deficiencies, inflammatory bowel disease, and other malabsorptive disorders, including patients with EDs.^86-88 Patients following restrictive diets, specifically strict vegan diets, without additional supplementation are at risk for developing vitamin B₁₂ deficiency. Because vitamin B₁₂ is stored in the liver, symptoms of deficiency appear when hepatic stores are depleted over the course of several years.⁸⁹ Insufficient vitamin B₁₂ prevents the proper functioning of methionine synthase, which is required for the conversion of homocysteine to methionine and for the conversion of methyl-tetrahydrofolate to tetrahydrofolate.⁸⁹ Impairment of this process impedes the synthesis of pyrimidine bases of DNA, disrupting the production of rapidly proliferating cells such as myeloid cells or mucosal lining cells. In cases of glossitis and/or stomatitis due to vitamin B₁₂ deficiency, resolution of lesions was achieved within 4 weeks of daily oral supplementation with vitamin B₁₂ at 2 μg daily.^90,91 Iron deficiency, a common finding in EDs, also may contribute to glossitis and angular cheilitis.²⁹ If uncovered, iron deficiency should be corrected by supplementation based on total deficit, age, and sex. Oral supplementation may be done with oral ferrous sulfate (325 mg provides 65 mg elemental iron) or with other iron salts such as ferrous gluconate (325 mg provides 38 mg elemental iron).²⁹ Mucosal symptoms of cheilitis and labial erythema may arise from irritation due to self-induced vomiting.⁸⁸

Dental erosion refers to loss of tooth structure via a chemical process that does not involve bacteria; in contrast, dental caries refer to tooth damage secondary to bacterial acid production. Patients with EDs who repeatedly self-induce vomiting have persistent introduction of gastric acids into the oral cavity, resulting in dissolution of the tooth enamel, which occurs when teeth are persistently exposed to a pH less than 5.5.⁹² Feeding disorders also may predispose patients to dental pathology. In a study of 60 pediatric patients, those with rumination syndrome were significantly more likely to have dental erosions than age- and sex-matched healthy controls (23/30 [77%] vs 4/30 [13%][P<.001]). The same study found no difference in the frequency of dental caries between children with and without rumination syndrome.⁹² These findings suggest that rumination syndrome increases the risk for dental erosions but not dental caries. The distribution of teeth affected by dental erosions may differ between EDs and feeding disorders. Patients with BN are more likely to experience involvement of the palatal surfaces of maxillary teeth, while patients with rumination syndrome had equal involvement of maxillary and mandibular teeth.⁹²

There is limited literature on the role of dentists in the care of patients with EDs and feeding disorders, though existing studies suggest inclusion of a dental care professional in multidisciplinary treatment along with emphasis on education around a home dental care regimen and frequent dental follow-up.^76,93,94 Prevention of further damage requires correction of the underlying behaviors and ED.

Other Dermatologic Findings

Russell sign refers to the development of calluses on the dorsal metacarpophalangeal joints of the dominant hand due to self-induced vomiting. Due to its specificity in purging-type EDs, the discovery of Russell sign should greatly increase suspicion for an ED.¹⁷ Patients with EDs also are at an increased risk for self-harming and body-focused repetitive behaviors, including skin cutting, superficial burning, onychophagia, and trichotillomania.¹⁹ It is important to recognize these signs in patients for whom an ED is suspected. The role of the dermatologist should include careful examination of the skin and documentation of findings that may aid in the diagnosis of an underlying ED.

Final Thoughts

A major limitation of this review is the reliance on small case reports and case series reporting cutaneous manifestations of ED. Controlled studies with larger cohorts are challenging in this population but are needed to substantiate the dermatologic signs commonly associated with EDs. Translational studies may help elucidate the pathomechanisms underlying dermatologic diseases such as lanugo, pruritus, and alopecia in the context of EDs and malnutrition. The known association between thyroid dysfunction and skin disease has been substantiated by clinical and basic science investigation, suggesting a notable role of thyroid hormone and TSH signaling in the skin local environment. Further investigation into nutritional and neuroendocrine regulation of skin health will aid in the diagnosis and treatment of patients impacted by EDs.

The treatment of the underlying ED is key in correcting associated skin disease, which requires interdisciplinary collaboration that addresses the psychological, behavioral, and social components of the condition. Following a diagnosis of ED, assessment should be made of the nutritional rehabilitation required to restore weight and nutritional status. Inpatient treatment may be indicated for patients requiring close monitoring to avoid refeeding syndrome, or those who meet the criteria for extreme AN in the DSM-5 (ie, body mass index <15 kg/m²),¹ or demonstrate signs of medical instability or organ failure secondary to malnutrition.⁶² Long-term recovery for ED patients should focus on behavioral therapy with a multidisciplinary team consisting of a psychiatrist, therapist, dietitian, and primary care provider. Comparative studies in large-scale trials of cognitive behavioral therapy, focal psychodynamic psychotherapy, and specialist supportive clinical management have shown little to no difference in efficacy in treating EDs.^75,95,96

Dermatologists may be the first providers to observe sequelae of nutritional and behavioral derangement in patients with EDs. Existing literature on the dermatologic findings of EDs report great heterogeneity of skin signs, with a very limited number of controlled studies available. Each cutaneous symptom described in this review should not be interpreted as an isolated pathology but should be placed in the context of patient predisposing risk factors and the constellation of other skin findings that may be suggestive of disordered eating behavior or other psychiatric illness. The observation of multiple signs and symptoms at the same time, especially of symptoms uncommonly encountered or suggestive of a severe and prolonged imbalance (eg, xanthoderma with vitamin A excess, aphthous stomatitis with vitamin B deficiency), should heighten clinical suspicion for an underlying ED. A clinician’s highest priority should be to resolve life-threatening medical emergencies and address nutritional derangements with the assistance of experts who are well versed in EDs. The patient should undergo workup to rule out organic causes of their nutritional dermatoses. Given the high psychiatric morbidity and mortality of patients with an ED and the demonstrated benefit of early intervention, recognition of cutaneous manifestations of malnutrition and EDs may be paramount to improving outcomes.

On January 1, 2021, the Current Procedural Terminology (CPT) evaluation and management (E/M) reporting rules changed dramatically, with “bullet counting” no longer necessary and the coding level now based on either the new medical decision making (MDM) table or time spent on all activities relating to the care of the patient on the day of the encounter.¹ This is described in the CPT Professional Edition 2023, a book every practitioner should review annually.² In particular, every provider should read and reread pages 1 to 14—and beyond if you provide services beyond standard office visits. These changes were made with the intent to simplify the process of documentation and allow a provider to spend more time with patients, though there is still a paucity of data related to whether the new system achieves these aims.

The general rule of reporting work with CPT codes can be simply stated—“Document what you did, do what you documented, and report that which is medically necessary” (David McCafferey, MD, personal communication)—and you should never have any difficulty with audits. Unfortunately, the new system does not let an auditor, who typically lacks a medical degree, audit effectively unless they have a clear understanding of diseases and their stages. Many medical societies, including the American Medical Association³ and American Academy of Dermatology,⁴ have provided education that focuses on how to report a given vignette, but specific examples of documentation with commentary are uncommon.

To make your documentation more likely to pass audits, explicitly link parts of your documentation to CPT MDM descriptors. We offer scenarios and tips. In part 1 of this series, we discuss how to approach the “spot check,” a commonly encountered chief concern (CC) within dermatology.

Scenario 1: A Funny-Looking New Spot

A 34-year-old presents with a new spot on the left cheek that seems to be growing and changing shape rapidly. You examine the patient and discuss treatment options. The documentation reads as follows:

• CC: New spot on left cheek that seems to be growing and changing shape rapidly.

• History: No family history of skin cancer; concerned about scarring, no blood thinner.

• Examination: Irregular tan to brown to black 8-mm macule. No lymphadenopathy.

• Impression: rule out melanoma.

• Plan: Consent, biopsy via shave technique. Lidocaine hydrochloride 1% with epinephrine, 1 cc, prepare and drape, hemostasis obtained, ointment and bandage applied, and care instructions provided.

As was the case before 2021, you still need a CC, along with a medically (and medicolegally) appropriate history and physical examination. A diagnostic impression and treatment plan also should be included.

In this situation, reporting is straightforward. There is no separate E/M visit; only the CPT code 11102 for tangential biopsy is reported. An International Classification of Diseases, Tenth Revision code of D48.5 (neoplasm of uncertain behavior of skin) will be included.

Why no E/M code? This is because the biopsy includes preservice and postservice time and work that would be double reported with the E/M. Remember that the preservice work would include any history and physical examination related to the area to be biopsied.

Specifically, preservice work includes:

Inspect and palpate lesion to assess surface size, subcutaneous depth and extension, and whether fixed to underlying structures. Select the most representative and appropriate site to obtain specimen. Examine draining lymph node basins. Discuss need for skin biopsy and biopsy technique options. Describe the tangential biopsy procedure method and expected result and the potential for inconclusive pathology result. Review procedural risks, including bleeding, pain, edema, infection, delayed healing, scarring, and hyper- or hypopigmentation.⁵

Postservice work includes:

Instruct patient and family on postoperative wound care and dressing changes, as well as problems such as bleeding or pain and restrictions on activities, and follow-up care. Provide prescriptions for pain and antibiotics as necessary. Advise patient and family when results will be available and how they will be communicated. The pathology request form is filled out and signed by the physician. Complete medical record and communicate procedure/results to referring physician as appropriate.⁵

The Takeaway—Procedure codes include preservice and postservice work. If additional work for the procedure is not documented beyond that, an E/M cannot be included in the encounter.

Scenario 2: What If We Don’t Biopsy?

A 34-year-old presents with a new spot on the left cheek that seems to be growing and changing shape rapidly. You examine the patient and discuss treatment options. The documentation reads as follows:

• CC: New spot on left cheek that seems to be growing and changing shape rapidly.

• History: No family history of skin cancer; concerned about scarring, no blood thinner.

• Examination: Irregular tan to brown to black 8-mm macule. No lymphadenopathy.

• Impression: rule out melanoma.

• Plan: Review risk, benefits, and alternative options. Schedule biopsy. Discuss unique risk factor of sebaceous peau d’orange skin more prone to contour defects after biopsy.

When determining the coding level for this scenario by MDM, 3 components must be considered: number and complexity of problems addressed at the encounter (column 1), amount and/or complexity of data to be reviewed and analyzed (column 2), and risk of complications and/or morbidity or mortality of patient management (column 3).¹ There are no data that are reviewed, so the auditor will assume minimal data to be reviewed and/or analyzed (level 2, row 2 in the MDM table). However, there may be a lot of variation in how an auditor would address the number and complexity of problems (level 1). Consider that you must explicitly state what you are thinking, as an auditor may not know melanoma is a life-threatening diagnosis. From the perspective of the auditor, could this be a:

• Self-limited or minor problem (level 2, or minimal problem in the MDM table)?¹

• Stable chronic illness (level 3, or low-level problem)?¹

• Undiagnosed new problem with uncertain prognosis (level 4, or moderate level problem)?¹

• Acute illness with systemic symptoms (level 4, or moderate level problem)?¹

• Acute or chronic illness or injury that poses a threat to life or bodily function (level 5, or high-level problem)?¹

• All of the above?

Similarly, there may be variation in how the risk (column 3) would be interpreted in this scenario. The treatment gives no guidance, so the auditor may assume this has a minimal risk of morbidity (level 2) or possibly a low risk of morbidity from additional diagnostic testing or treatment (level 3), as opposed to a moderate risk of morbidity (level 4).¹The Takeaway—In the auditor’s mind, this could be a straightforward (CPT codes 99202/99212) or lowlevel (99203/99213) visit as opposed to a moderate-level (99204/99214) visit. From the above documentation, an auditor would not be able to tell what you are thinking, and you can be assured they will not look further into the diagnosis or treatment to learn. That is not their job. So, let us clarify by explicitly stating what you are thinking in the context of the MDM grid.

Modified Scenario 2: A Funny-Looking New Spot With MDM Descriptors to Guide an Auditor

Below are modifications to the documentation for scenario 2 to guide an auditor:

• CC: New spot on left cheek that seems to be growing and changing shape rapidly.

• History: No family history of skin cancer; concerned about scarring, no blood thinner.

• Examination: Irregular tan to brown to black 8-mm macule. No lymphadenopathy.

• Impression: rule out melanoma (undiagnosed new problem with uncertain prognosis).

• Plan: Discuss risks, benefits, and alternatives, including biopsy (decision regarding minor surgery with identified patient or procedure risk factors) vs a noninvasive gene expression profiling melanoma rule-out test. Patient prefers the latter.

In this scenario, the level of MDM is much more clearly documented (as bolded above).

The number and complexity of problems would be an undiagnosed new problem with uncertain prognosis, which would be moderate complexity (column 1, level 4).¹ There are no data that are reviewed or analyzed, which would be straightforward (column 2, level 2). For risk, the discussion of the biopsy as part of the diagnostic choices should include discussion of possible scarring, bleeding, pain, and infection, which would be considered best described as a decision regarding minor surgery with identified patient or procedure risk factors, which would make this of moderate complexity (column 3, level 4).¹

Importantly, even if the procedure is not chosen as the final treatment plan, the discussion regarding the surgery, including the risks, benefits, and alternatives, can still count toward this category in the MDM table. Therefore, in this scenario with the updated and clarified documentation, this would be reported as CPT code 99204 for a new patient, while an established patient would be 99214.

Scenario 1 Revisited: A Funny-Looking New Spot

Below is scenario 1 with enhanced documentation, now applied to our procedure-only visit.

• CC: New spot on left cheek that seems to be growing and changing shape rapidly.

• History: No family history of skin cancer; concerned about scarring, no blood thinner.

• Examination: Irregular tan to brown to black 8-mm macule. No lymphadenopathy.

• Impression: rule out melanoma (undiagnosed new problem with uncertain prognosis).

• Plan: Discuss risks, benefits, and alternatives, including biopsy (decision regarding minor surgery with identified patient or procedure risk factors) vs a noninvasive 2 gene expression profiling melanoma rule-out test. Patient wants biopsy. Consent, biopsy via shave technique. Lidocaine hydrochloride 1% with epinephrine, 1 cc, prepare and drape, hemostasis obtained, ointment and bandage applied, and care instructions provided.

This documentation would only allow reporting the biopsy as in Scenario 1, as the decision to perform a 0- or 10-day global procedure is bundled with the procedure if performed on the same date of service.

Final Thoughts

Spot checks are commonly encountered dermatologic visits. With the updated E/M guidelines, clarifying and streamlining your documentation is crucial. In particular, utilizing language that clearly defines number and complexity of problems, amount and/or complexity of data to be reviewed and analyzed, and appropriate risk stratification is crucial to ensuring appropriate reimbursement and minimizing your pain with audits.

On January 1, 2021, the Current Procedural Terminology (CPT) evaluation and management (E/M) reporting rules changed dramatically, with “bullet counting” no longer necessary and the coding level now based on either the new medical decision making (MDM) table or time spent on all activities relating to the care of the patient on the day of the encounter.¹ This is described in the CPT Professional Edition 2023, a book every practitioner should review annually.² In particular, every provider should read and reread pages 1 to 14—and beyond if you provide services beyond standard office visits. These changes were made with the intent to simplify the process of documentation and allow a provider to spend more time with patients, though there is still a paucity of data related to whether the new system achieves these aims.

The general rule of reporting work with CPT codes can be simply stated—“Document what you did, do what you documented, and report that which is medically necessary” (David McCafferey, MD, personal communication)—and you should never have any difficulty with audits. Unfortunately, the new system does not let an auditor, who typically lacks a medical degree, audit effectively unless they have a clear understanding of diseases and their stages. Many medical societies, including the American Medical Association³ and American Academy of Dermatology,⁴ have provided education that focuses on how to report a given vignette, but specific examples of documentation with commentary are uncommon.

To make your documentation more likely to pass audits, explicitly link parts of your documentation to CPT MDM descriptors. We offer scenarios and tips. In part 1 of this series, we discuss how to approach the “spot check,” a commonly encountered chief concern (CC) within dermatology.

Scenario 1: A Funny-Looking New Spot

A 34-year-old presents with a new spot on the left cheek that seems to be growing and changing shape rapidly. You examine the patient and discuss treatment options. The documentation reads as follows:

• CC: New spot on left cheek that seems to be growing and changing shape rapidly.

• History: No family history of skin cancer; concerned about scarring, no blood thinner.

• Examination: Irregular tan to brown to black 8-mm macule. No lymphadenopathy.

• Impression: rule out melanoma.

• Plan: Consent, biopsy via shave technique. Lidocaine hydrochloride 1% with epinephrine, 1 cc, prepare and drape, hemostasis obtained, ointment and bandage applied, and care instructions provided.

As was the case before 2021, you still need a CC, along with a medically (and medicolegally) appropriate history and physical examination. A diagnostic impression and treatment plan also should be included.

In this situation, reporting is straightforward. There is no separate E/M visit; only the CPT code 11102 for tangential biopsy is reported. An International Classification of Diseases, Tenth Revision code of D48.5 (neoplasm of uncertain behavior of skin) will be included.

Why no E/M code? This is because the biopsy includes preservice and postservice time and work that would be double reported with the E/M. Remember that the preservice work would include any history and physical examination related to the area to be biopsied.

Specifically, preservice work includes:

Inspect and palpate lesion to assess surface size, subcutaneous depth and extension, and whether fixed to underlying structures. Select the most representative and appropriate site to obtain specimen. Examine draining lymph node basins. Discuss need for skin biopsy and biopsy technique options. Describe the tangential biopsy procedure method and expected result and the potential for inconclusive pathology result. Review procedural risks, including bleeding, pain, edema, infection, delayed healing, scarring, and hyper- or hypopigmentation.⁵

Postservice work includes:

Instruct patient and family on postoperative wound care and dressing changes, as well as problems such as bleeding or pain and restrictions on activities, and follow-up care. Provide prescriptions for pain and antibiotics as necessary. Advise patient and family when results will be available and how they will be communicated. The pathology request form is filled out and signed by the physician. Complete medical record and communicate procedure/results to referring physician as appropriate.⁵

The Takeaway—Procedure codes include preservice and postservice work. If additional work for the procedure is not documented beyond that, an E/M cannot be included in the encounter.

Scenario 2: What If We Don’t Biopsy?

A 34-year-old presents with a new spot on the left cheek that seems to be growing and changing shape rapidly. You examine the patient and discuss treatment options. The documentation reads as follows:

• CC: New spot on left cheek that seems to be growing and changing shape rapidly.

• History: No family history of skin cancer; concerned about scarring, no blood thinner.

• Examination: Irregular tan to brown to black 8-mm macule. No lymphadenopathy.

• Impression: rule out melanoma.

• Plan: Review risk, benefits, and alternative options. Schedule biopsy. Discuss unique risk factor of sebaceous peau d’orange skin more prone to contour defects after biopsy.

When determining the coding level for this scenario by MDM, 3 components must be considered: number and complexity of problems addressed at the encounter (column 1), amount and/or complexity of data to be reviewed and analyzed (column 2), and risk of complications and/or morbidity or mortality of patient management (column 3).¹ There are no data that are reviewed, so the auditor will assume minimal data to be reviewed and/or analyzed (level 2, row 2 in the MDM table). However, there may be a lot of variation in how an auditor would address the number and complexity of problems (level 1). Consider that you must explicitly state what you are thinking, as an auditor may not know melanoma is a life-threatening diagnosis. From the perspective of the auditor, could this be a:

• Self-limited or minor problem (level 2, or minimal problem in the MDM table)?¹

• Stable chronic illness (level 3, or low-level problem)?¹

• Undiagnosed new problem with uncertain prognosis (level 4, or moderate level problem)?¹

• Acute illness with systemic symptoms (level 4, or moderate level problem)?¹

• Acute or chronic illness or injury that poses a threat to life or bodily function (level 5, or high-level problem)?¹

• All of the above?

Similarly, there may be variation in how the risk (column 3) would be interpreted in this scenario. The treatment gives no guidance, so the auditor may assume this has a minimal risk of morbidity (level 2) or possibly a low risk of morbidity from additional diagnostic testing or treatment (level 3), as opposed to a moderate risk of morbidity (level 4).¹The Takeaway—In the auditor’s mind, this could be a straightforward (CPT codes 99202/99212) or lowlevel (99203/99213) visit as opposed to a moderate-level (99204/99214) visit. From the above documentation, an auditor would not be able to tell what you are thinking, and you can be assured they will not look further into the diagnosis or treatment to learn. That is not their job. So, let us clarify by explicitly stating what you are thinking in the context of the MDM grid.

Modified Scenario 2: A Funny-Looking New Spot With MDM Descriptors to Guide an Auditor

Below are modifications to the documentation for scenario 2 to guide an auditor:

• CC: New spot on left cheek that seems to be growing and changing shape rapidly.

• History: No family history of skin cancer; concerned about scarring, no blood thinner.

• Examination: Irregular tan to brown to black 8-mm macule. No lymphadenopathy.

• Impression: rule out melanoma (undiagnosed new problem with uncertain prognosis).

• Plan: Discuss risks, benefits, and alternatives, including biopsy (decision regarding minor surgery with identified patient or procedure risk factors) vs a noninvasive gene expression profiling melanoma rule-out test. Patient prefers the latter.

In this scenario, the level of MDM is much more clearly documented (as bolded above).

The number and complexity of problems would be an undiagnosed new problem with uncertain prognosis, which would be moderate complexity (column 1, level 4).¹ There are no data that are reviewed or analyzed, which would be straightforward (column 2, level 2). For risk, the discussion of the biopsy as part of the diagnostic choices should include discussion of possible scarring, bleeding, pain, and infection, which would be considered best described as a decision regarding minor surgery with identified patient or procedure risk factors, which would make this of moderate complexity (column 3, level 4).¹

Importantly, even if the procedure is not chosen as the final treatment plan, the discussion regarding the surgery, including the risks, benefits, and alternatives, can still count toward this category in the MDM table. Therefore, in this scenario with the updated and clarified documentation, this would be reported as CPT code 99204 for a new patient, while an established patient would be 99214.

Scenario 1 Revisited: A Funny-Looking New Spot

Below is scenario 1 with enhanced documentation, now applied to our procedure-only visit.

• CC: New spot on left cheek that seems to be growing and changing shape rapidly.

• History: No family history of skin cancer; concerned about scarring, no blood thinner.

• Examination: Irregular tan to brown to black 8-mm macule. No lymphadenopathy.

• Impression: rule out melanoma (undiagnosed new problem with uncertain prognosis).

• Plan: Discuss risks, benefits, and alternatives, including biopsy (decision regarding minor surgery with identified patient or procedure risk factors) vs a noninvasive 2 gene expression profiling melanoma rule-out test. Patient wants biopsy. Consent, biopsy via shave technique. Lidocaine hydrochloride 1% with epinephrine, 1 cc, prepare and drape, hemostasis obtained, ointment and bandage applied, and care instructions provided.

This documentation would only allow reporting the biopsy as in Scenario 1, as the decision to perform a 0- or 10-day global procedure is bundled with the procedure if performed on the same date of service.

Final Thoughts

Spot checks are commonly encountered dermatologic visits. With the updated E/M guidelines, clarifying and streamlining your documentation is crucial. In particular, utilizing language that clearly defines number and complexity of problems, amount and/or complexity of data to be reviewed and analyzed, and appropriate risk stratification is crucial to ensuring appropriate reimbursement and minimizing your pain with audits.

On January 1, 2021, the Current Procedural Terminology (CPT) evaluation and management (E/M) reporting rules changed dramatically, with “bullet counting” no longer necessary and the coding level now based on either the new medical decision making (MDM) table or time spent on all activities relating to the care of the patient on the day of the encounter.¹ This is described in the CPT Professional Edition 2023, a book every practitioner should review annually.² In particular, every provider should read and reread pages 1 to 14—and beyond if you provide services beyond standard office visits. These changes were made with the intent to simplify the process of documentation and allow a provider to spend more time with patients, though there is still a paucity of data related to whether the new system achieves these aims.

The general rule of reporting work with CPT codes can be simply stated—“Document what you did, do what you documented, and report that which is medically necessary” (David McCafferey, MD, personal communication)—and you should never have any difficulty with audits. Unfortunately, the new system does not let an auditor, who typically lacks a medical degree, audit effectively unless they have a clear understanding of diseases and their stages. Many medical societies, including the American Medical Association³ and American Academy of Dermatology,⁴ have provided education that focuses on how to report a given vignette, but specific examples of documentation with commentary are uncommon.

To make your documentation more likely to pass audits, explicitly link parts of your documentation to CPT MDM descriptors. We offer scenarios and tips. In part 1 of this series, we discuss how to approach the “spot check,” a commonly encountered chief concern (CC) within dermatology.

Scenario 1: A Funny-Looking New Spot

A 34-year-old presents with a new spot on the left cheek that seems to be growing and changing shape rapidly. You examine the patient and discuss treatment options. The documentation reads as follows:

• CC: New spot on left cheek that seems to be growing and changing shape rapidly.

• History: No family history of skin cancer; concerned about scarring, no blood thinner.

• Examination: Irregular tan to brown to black 8-mm macule. No lymphadenopathy.

• Impression: rule out melanoma.

• Plan: Consent, biopsy via shave technique. Lidocaine hydrochloride 1% with epinephrine, 1 cc, prepare and drape, hemostasis obtained, ointment and bandage applied, and care instructions provided.

As was the case before 2021, you still need a CC, along with a medically (and medicolegally) appropriate history and physical examination. A diagnostic impression and treatment plan also should be included.

In this situation, reporting is straightforward. There is no separate E/M visit; only the CPT code 11102 for tangential biopsy is reported. An International Classification of Diseases, Tenth Revision code of D48.5 (neoplasm of uncertain behavior of skin) will be included.

Why no E/M code? This is because the biopsy includes preservice and postservice time and work that would be double reported with the E/M. Remember that the preservice work would include any history and physical examination related to the area to be biopsied.

Specifically, preservice work includes:

Inspect and palpate lesion to assess surface size, subcutaneous depth and extension, and whether fixed to underlying structures. Select the most representative and appropriate site to obtain specimen. Examine draining lymph node basins. Discuss need for skin biopsy and biopsy technique options. Describe the tangential biopsy procedure method and expected result and the potential for inconclusive pathology result. Review procedural risks, including bleeding, pain, edema, infection, delayed healing, scarring, and hyper- or hypopigmentation.⁵

Postservice work includes:

Instruct patient and family on postoperative wound care and dressing changes, as well as problems such as bleeding or pain and restrictions on activities, and follow-up care. Provide prescriptions for pain and antibiotics as necessary. Advise patient and family when results will be available and how they will be communicated. The pathology request form is filled out and signed by the physician. Complete medical record and communicate procedure/results to referring physician as appropriate.⁵

The Takeaway—Procedure codes include preservice and postservice work. If additional work for the procedure is not documented beyond that, an E/M cannot be included in the encounter.

Scenario 2: What If We Don’t Biopsy?

A 34-year-old presents with a new spot on the left cheek that seems to be growing and changing shape rapidly. You examine the patient and discuss treatment options. The documentation reads as follows:

• CC: New spot on left cheek that seems to be growing and changing shape rapidly.

• History: No family history of skin cancer; concerned about scarring, no blood thinner.

• Examination: Irregular tan to brown to black 8-mm macule. No lymphadenopathy.

• Impression: rule out melanoma.

• Plan: Review risk, benefits, and alternative options. Schedule biopsy. Discuss unique risk factor of sebaceous peau d’orange skin more prone to contour defects after biopsy.

When determining the coding level for this scenario by MDM, 3 components must be considered: number and complexity of problems addressed at the encounter (column 1), amount and/or complexity of data to be reviewed and analyzed (column 2), and risk of complications and/or morbidity or mortality of patient management (column 3).¹ There are no data that are reviewed, so the auditor will assume minimal data to be reviewed and/or analyzed (level 2, row 2 in the MDM table). However, there may be a lot of variation in how an auditor would address the number and complexity of problems (level 1). Consider that you must explicitly state what you are thinking, as an auditor may not know melanoma is a life-threatening diagnosis. From the perspective of the auditor, could this be a:

• Self-limited or minor problem (level 2, or minimal problem in the MDM table)?¹

• Stable chronic illness (level 3, or low-level problem)?¹

• Undiagnosed new problem with uncertain prognosis (level 4, or moderate level problem)?¹

• Acute illness with systemic symptoms (level 4, or moderate level problem)?¹

• Acute or chronic illness or injury that poses a threat to life or bodily function (level 5, or high-level problem)?¹

• All of the above?

Similarly, there may be variation in how the risk (column 3) would be interpreted in this scenario. The treatment gives no guidance, so the auditor may assume this has a minimal risk of morbidity (level 2) or possibly a low risk of morbidity from additional diagnostic testing or treatment (level 3), as opposed to a moderate risk of morbidity (level 4).¹The Takeaway—In the auditor’s mind, this could be a straightforward (CPT codes 99202/99212) or lowlevel (99203/99213) visit as opposed to a moderate-level (99204/99214) visit. From the above documentation, an auditor would not be able to tell what you are thinking, and you can be assured they will not look further into the diagnosis or treatment to learn. That is not their job. So, let us clarify by explicitly stating what you are thinking in the context of the MDM grid.

Modified Scenario 2: A Funny-Looking New Spot With MDM Descriptors to Guide an Auditor

Below are modifications to the documentation for scenario 2 to guide an auditor:

• CC: New spot on left cheek that seems to be growing and changing shape rapidly.

• History: No family history of skin cancer; concerned about scarring, no blood thinner.

• Examination: Irregular tan to brown to black 8-mm macule. No lymphadenopathy.

• Impression: rule out melanoma (undiagnosed new problem with uncertain prognosis).

• Plan: Discuss risks, benefits, and alternatives, including biopsy (decision regarding minor surgery with identified patient or procedure risk factors) vs a noninvasive gene expression profiling melanoma rule-out test. Patient prefers the latter.

In this scenario, the level of MDM is much more clearly documented (as bolded above).

The number and complexity of problems would be an undiagnosed new problem with uncertain prognosis, which would be moderate complexity (column 1, level 4).¹ There are no data that are reviewed or analyzed, which would be straightforward (column 2, level 2). For risk, the discussion of the biopsy as part of the diagnostic choices should include discussion of possible scarring, bleeding, pain, and infection, which would be considered best described as a decision regarding minor surgery with identified patient or procedure risk factors, which would make this of moderate complexity (column 3, level 4).¹

Importantly, even if the procedure is not chosen as the final treatment plan, the discussion regarding the surgery, including the risks, benefits, and alternatives, can still count toward this category in the MDM table. Therefore, in this scenario with the updated and clarified documentation, this would be reported as CPT code 99204 for a new patient, while an established patient would be 99214.

Scenario 1 Revisited: A Funny-Looking New Spot

Below is scenario 1 with enhanced documentation, now applied to our procedure-only visit.

• CC: New spot on left cheek that seems to be growing and changing shape rapidly.

• History: No family history of skin cancer; concerned about scarring, no blood thinner.

• Examination: Irregular tan to brown to black 8-mm macule. No lymphadenopathy.

• Impression: rule out melanoma (undiagnosed new problem with uncertain prognosis).

• Plan: Discuss risks, benefits, and alternatives, including biopsy (decision regarding minor surgery with identified patient or procedure risk factors) vs a noninvasive 2 gene expression profiling melanoma rule-out test. Patient wants biopsy. Consent, biopsy via shave technique. Lidocaine hydrochloride 1% with epinephrine, 1 cc, prepare and drape, hemostasis obtained, ointment and bandage applied, and care instructions provided.

This documentation would only allow reporting the biopsy as in Scenario 1, as the decision to perform a 0- or 10-day global procedure is bundled with the procedure if performed on the same date of service.

Final Thoughts

Spot checks are commonly encountered dermatologic visits. With the updated E/M guidelines, clarifying and streamlining your documentation is crucial. In particular, utilizing language that clearly defines number and complexity of problems, amount and/or complexity of data to be reviewed and analyzed, and appropriate risk stratification is crucial to ensuring appropriate reimbursement and minimizing your pain with audits.

Dermatology certainly is the most visual medical specialty. In the current era of powerful electronic imaging and laboratory techniques, the skills of physical diagnosis seem to have become less important in medicine—not so in dermatology, in which the experienced clinician is able to identify many conditions by simply looking at the skin. Of course, dermatologists do heavily rely on dermatopathologists to microscopically visualize biopsies to distinguish diseases. Even as we acknowledge the dominant role of visual recognition, there is increasing progress in making clinical determinations based on molecular events. The era of genomic dermatology is here.

The Genodermatoses

There are more than 500 dermatologic conditions resulting from heritable mutational events.¹ The rarity of most of these diseases and variability in phenotypic manifestations presents considerable diagnostic challenges, typically the province of a select group of clinical pediatric dermatologists whose abilities have been developed by experience.² However, the addition of genomic analysis has now made reliable identification more accessible to a wider group of clinicians.³ The Human Genome Project was arguably the most successful health policy endeavor in human history, promoting the development of massive automated, information theory–driven applications to analyze DNA sequences.⁴ We all think of DNA analysis as the ultimate means to detect mutations by sequencing whole exomes—and in fact the entire genome of affected individuals searching for mutations—but DNA sequencing often is insufficient to detect mutations in noncoding regions of genes and to identify abnormalities of gene expression (eg, splice variants). Building on the advances in high-throughput nucleic acid sequencing and massive computerized analysis, the field has now taken a quantum leap further to sequence transcribed RNA to detect abnormalities.⁵

The techniques are straightforward: RNA is isolated and reverse transcribed to complementary DNA. The complementary DNA is amplified and then processed by high-throughput sequencers. The sequences are then identified by computer algorithms. It is possible to fully define the transcriptomes of multiple genes, even reaching the threshold of resolution of gene expression emanating from a single cell.⁶

Studying Gene Expression for Malignant Melanoma

As much as we rely on visual interpretations, we acknowledge that many conditions look very similar, whether to the naked eye or under the microscope. This is true for rare diseases but also for the rashes we routinely see. A group of investigators recently used RNA transcriptome sequencing to analyze differences between atopic dermatitis and psoriasis, permitting better differentiation of these 2 common conditions.⁷

One of the greatest challenges confronting dermatologists and their dermatopathologist partners is to distinguish malignant melanoma from benign nevi.⁸ Despite staining for a number of molecular markers, some lesions defy histopathology, such as distinguishing benign and malignant Spitz nevi; however, recent work on RNA transcriptomes suggests that gene expression may increase confidence in assessing atypical Spitz nevi.⁹ A 23-gene expression panel has yielded a sensitivity of 91.5% and a specificity of 92.5% in differentiating benign nevi from malignant melanoma.¹⁰

From the Research Laboratory to Routine Clinical Use

Undoubtedly, it is a large step from proof-of-concept studies to accepted clinical use. The ultimate achievement for a laboratory technique is to enter approved clinical use. Gene expression panels have now been approved by numerous third-party insurers to help predict future clinical evolution of biopsied melanomas. Although early in situ melanomas are eminently curable by wide excision, lesions that have more concerning characteristics (eg, depth >0.8 mm, ulceration) may progress to metastatic disease. The gratifying success of checkpoint inhibitor therapy has improved the previously dismal outlook for advanced melanomas.¹¹ Dermatologists search for clues to suggest which patients may benefit from adjuvant therapy. Sentinel lymph node biopsy (SLNB) has been a standard-of-care technique to help make this determination.¹²

It has now been demonstrated that gene expression array analysis can provide evidence complementing SLNB results or even independent of SLNB results. In extensive validation studies, a 31-gene expression panel analyzing initial melanoma biopsy specimens showed predictive value for later recurrence and development of metastatic disease.^13,14 The gene expression studies have identified patients with negative SLNBs who have gone on to develop metastatic melanomas.¹⁵ It has been suggested that gene expression panel diagnosis may reduce the need for invasive SLNBs in patients in whom the surgical procedure may involve risk.¹⁶

Looking to the Future

The progress of science is the result of many small steps building on prior work. The terms breakthrough and game changer in medicine have been popularized by the media and rarely are valid. On the contrary, sequential development of methods over many years has preceded the acclaimed successes of medical research; for example, the best-known medical breakthrough—that of Salk’s inactivated polio vaccine—was preceded by the use of an inactivated polio vaccine by Brodie and Park¹⁷ in 1935. However, it was the development of tissue culture of poliomyelitis virus by Enders et al¹⁸ that provided the methodology to Salk’s group to produce their inactivated polio vaccine.

The ability to go beyond our visual senses will be of great importance in characterizing the variability of skin diseases, especially in skin of color patients; for example, acral melanoma is perhaps the primary melanocytic malignancy in darker-skinned patients and is the target of RNA transcriptomic research.¹⁹ Progress is continuing on gene therapy for a growing number of skin conditions.^20,21 In vivo correction of abnormal genes is being attempted for a number of inherited cutaneous diseases,²² notably for disorders of skin fragility.²³ For now, we welcome the addition of genomic capabilities to the visual practice of dermatology and the capability to go beyond that which we can see with our eyes.

Dermatology certainly is the most visual medical specialty. In the current era of powerful electronic imaging and laboratory techniques, the skills of physical diagnosis seem to have become less important in medicine—not so in dermatology, in which the experienced clinician is able to identify many conditions by simply looking at the skin. Of course, dermatologists do heavily rely on dermatopathologists to microscopically visualize biopsies to distinguish diseases. Even as we acknowledge the dominant role of visual recognition, there is increasing progress in making clinical determinations based on molecular events. The era of genomic dermatology is here.

The Genodermatoses

There are more than 500 dermatologic conditions resulting from heritable mutational events.¹ The rarity of most of these diseases and variability in phenotypic manifestations presents considerable diagnostic challenges, typically the province of a select group of clinical pediatric dermatologists whose abilities have been developed by experience.² However, the addition of genomic analysis has now made reliable identification more accessible to a wider group of clinicians.³ The Human Genome Project was arguably the most successful health policy endeavor in human history, promoting the development of massive automated, information theory–driven applications to analyze DNA sequences.⁴ We all think of DNA analysis as the ultimate means to detect mutations by sequencing whole exomes—and in fact the entire genome of affected individuals searching for mutations—but DNA sequencing often is insufficient to detect mutations in noncoding regions of genes and to identify abnormalities of gene expression (eg, splice variants). Building on the advances in high-throughput nucleic acid sequencing and massive computerized analysis, the field has now taken a quantum leap further to sequence transcribed RNA to detect abnormalities.⁵

The techniques are straightforward: RNA is isolated and reverse transcribed to complementary DNA. The complementary DNA is amplified and then processed by high-throughput sequencers. The sequences are then identified by computer algorithms. It is possible to fully define the transcriptomes of multiple genes, even reaching the threshold of resolution of gene expression emanating from a single cell.⁶

Studying Gene Expression for Malignant Melanoma

As much as we rely on visual interpretations, we acknowledge that many conditions look very similar, whether to the naked eye or under the microscope. This is true for rare diseases but also for the rashes we routinely see. A group of investigators recently used RNA transcriptome sequencing to analyze differences between atopic dermatitis and psoriasis, permitting better differentiation of these 2 common conditions.⁷

One of the greatest challenges confronting dermatologists and their dermatopathologist partners is to distinguish malignant melanoma from benign nevi.⁸ Despite staining for a number of molecular markers, some lesions defy histopathology, such as distinguishing benign and malignant Spitz nevi; however, recent work on RNA transcriptomes suggests that gene expression may increase confidence in assessing atypical Spitz nevi.⁹ A 23-gene expression panel has yielded a sensitivity of 91.5% and a specificity of 92.5% in differentiating benign nevi from malignant melanoma.¹⁰

From the Research Laboratory to Routine Clinical Use

Undoubtedly, it is a large step from proof-of-concept studies to accepted clinical use. The ultimate achievement for a laboratory technique is to enter approved clinical use. Gene expression panels have now been approved by numerous third-party insurers to help predict future clinical evolution of biopsied melanomas. Although early in situ melanomas are eminently curable by wide excision, lesions that have more concerning characteristics (eg, depth >0.8 mm, ulceration) may progress to metastatic disease. The gratifying success of checkpoint inhibitor therapy has improved the previously dismal outlook for advanced melanomas.¹¹ Dermatologists search for clues to suggest which patients may benefit from adjuvant therapy. Sentinel lymph node biopsy (SLNB) has been a standard-of-care technique to help make this determination.¹²

It has now been demonstrated that gene expression array analysis can provide evidence complementing SLNB results or even independent of SLNB results. In extensive validation studies, a 31-gene expression panel analyzing initial melanoma biopsy specimens showed predictive value for later recurrence and development of metastatic disease.^13,14 The gene expression studies have identified patients with negative SLNBs who have gone on to develop metastatic melanomas.¹⁵ It has been suggested that gene expression panel diagnosis may reduce the need for invasive SLNBs in patients in whom the surgical procedure may involve risk.¹⁶

Looking to the Future

The progress of science is the result of many small steps building on prior work. The terms breakthrough and game changer in medicine have been popularized by the media and rarely are valid. On the contrary, sequential development of methods over many years has preceded the acclaimed successes of medical research; for example, the best-known medical breakthrough—that of Salk’s inactivated polio vaccine—was preceded by the use of an inactivated polio vaccine by Brodie and Park¹⁷ in 1935. However, it was the development of tissue culture of poliomyelitis virus by Enders et al¹⁸ that provided the methodology to Salk’s group to produce their inactivated polio vaccine.

The ability to go beyond our visual senses will be of great importance in characterizing the variability of skin diseases, especially in skin of color patients; for example, acral melanoma is perhaps the primary melanocytic malignancy in darker-skinned patients and is the target of RNA transcriptomic research.¹⁹ Progress is continuing on gene therapy for a growing number of skin conditions.^20,21 In vivo correction of abnormal genes is being attempted for a number of inherited cutaneous diseases,²² notably for disorders of skin fragility.²³ For now, we welcome the addition of genomic capabilities to the visual practice of dermatology and the capability to go beyond that which we can see with our eyes.

Dermatology certainly is the most visual medical specialty. In the current era of powerful electronic imaging and laboratory techniques, the skills of physical diagnosis seem to have become less important in medicine—not so in dermatology, in which the experienced clinician is able to identify many conditions by simply looking at the skin. Of course, dermatologists do heavily rely on dermatopathologists to microscopically visualize biopsies to distinguish diseases. Even as we acknowledge the dominant role of visual recognition, there is increasing progress in making clinical determinations based on molecular events. The era of genomic dermatology is here.

The Genodermatoses

There are more than 500 dermatologic conditions resulting from heritable mutational events.¹ The rarity of most of these diseases and variability in phenotypic manifestations presents considerable diagnostic challenges, typically the province of a select group of clinical pediatric dermatologists whose abilities have been developed by experience.² However, the addition of genomic analysis has now made reliable identification more accessible to a wider group of clinicians.³ The Human Genome Project was arguably the most successful health policy endeavor in human history, promoting the development of massive automated, information theory–driven applications to analyze DNA sequences.⁴ We all think of DNA analysis as the ultimate means to detect mutations by sequencing whole exomes—and in fact the entire genome of affected individuals searching for mutations—but DNA sequencing often is insufficient to detect mutations in noncoding regions of genes and to identify abnormalities of gene expression (eg, splice variants). Building on the advances in high-throughput nucleic acid sequencing and massive computerized analysis, the field has now taken a quantum leap further to sequence transcribed RNA to detect abnormalities.⁵

The techniques are straightforward: RNA is isolated and reverse transcribed to complementary DNA. The complementary DNA is amplified and then processed by high-throughput sequencers. The sequences are then identified by computer algorithms. It is possible to fully define the transcriptomes of multiple genes, even reaching the threshold of resolution of gene expression emanating from a single cell.⁶

Studying Gene Expression for Malignant Melanoma

As much as we rely on visual interpretations, we acknowledge that many conditions look very similar, whether to the naked eye or under the microscope. This is true for rare diseases but also for the rashes we routinely see. A group of investigators recently used RNA transcriptome sequencing to analyze differences between atopic dermatitis and psoriasis, permitting better differentiation of these 2 common conditions.⁷

One of the greatest challenges confronting dermatologists and their dermatopathologist partners is to distinguish malignant melanoma from benign nevi.⁸ Despite staining for a number of molecular markers, some lesions defy histopathology, such as distinguishing benign and malignant Spitz nevi; however, recent work on RNA transcriptomes suggests that gene expression may increase confidence in assessing atypical Spitz nevi.⁹ A 23-gene expression panel has yielded a sensitivity of 91.5% and a specificity of 92.5% in differentiating benign nevi from malignant melanoma.¹⁰

From the Research Laboratory to Routine Clinical Use

Undoubtedly, it is a large step from proof-of-concept studies to accepted clinical use. The ultimate achievement for a laboratory technique is to enter approved clinical use. Gene expression panels have now been approved by numerous third-party insurers to help predict future clinical evolution of biopsied melanomas. Although early in situ melanomas are eminently curable by wide excision, lesions that have more concerning characteristics (eg, depth >0.8 mm, ulceration) may progress to metastatic disease. The gratifying success of checkpoint inhibitor therapy has improved the previously dismal outlook for advanced melanomas.¹¹ Dermatologists search for clues to suggest which patients may benefit from adjuvant therapy. Sentinel lymph node biopsy (SLNB) has been a standard-of-care technique to help make this determination.¹²

It has now been demonstrated that gene expression array analysis can provide evidence complementing SLNB results or even independent of SLNB results. In extensive validation studies, a 31-gene expression panel analyzing initial melanoma biopsy specimens showed predictive value for later recurrence and development of metastatic disease.^13,14 The gene expression studies have identified patients with negative SLNBs who have gone on to develop metastatic melanomas.¹⁵ It has been suggested that gene expression panel diagnosis may reduce the need for invasive SLNBs in patients in whom the surgical procedure may involve risk.¹⁶

Looking to the Future

The progress of science is the result of many small steps building on prior work. The terms breakthrough and game changer in medicine have been popularized by the media and rarely are valid. On the contrary, sequential development of methods over many years has preceded the acclaimed successes of medical research; for example, the best-known medical breakthrough—that of Salk’s inactivated polio vaccine—was preceded by the use of an inactivated polio vaccine by Brodie and Park¹⁷ in 1935. However, it was the development of tissue culture of poliomyelitis virus by Enders et al¹⁸ that provided the methodology to Salk’s group to produce their inactivated polio vaccine.

The ability to go beyond our visual senses will be of great importance in characterizing the variability of skin diseases, especially in skin of color patients; for example, acral melanoma is perhaps the primary melanocytic malignancy in darker-skinned patients and is the target of RNA transcriptomic research.¹⁹ Progress is continuing on gene therapy for a growing number of skin conditions.^20,21 In vivo correction of abnormal genes is being attempted for a number of inherited cutaneous diseases,²² notably for disorders of skin fragility.²³ For now, we welcome the addition of genomic capabilities to the visual practice of dermatology and the capability to go beyond that which we can see with our eyes.

Practice Gap

Nail matrix and nail bed injections with triamcinolone acetonide are used to treat trachyonychia and inflammatory nail conditions, including nail psoriasis and nail lichen planus. The procedure should be quick in well-trained hands, with each nail injection taking only seconds to perform. Typically, patients have multiple nails involved, requiring at least 1 injection into the nail matrix or the nail bed (or both) in each nail at each visit. Patients often are anxious when undergoing nail injections; the nail unit is highly innervated and vascular, which can cause notable transient discomfort during the procedure^1,2 as well as postoperative pain.³

Nail injections must be repeated every 4 to 6 weeks to sustain clinical benefit and maximize outcomes, which can lead to heightened anxiety and apprehension before and during the visit. Furthermore, pain and anxiety associated with the procedure may deter patients from returning for follow-up injections, which can impact treatment adherence and clinical outcomes.

Dermatologists should implement strategies to decrease periprocedural anxiety to improve the nail injection experience. In our practice, we routinely incorporate stress-reducing techniques—music, talkesthesia, a sleep mask, cool air, ethyl chloride, and squeezing a stress ball—into the clinical workflow of the procedure. The goal of these techniques is to divert attention away from painful stimuli. Most patients, however, receive injections in both hands, making it impractical to employ some of these techniques, particularly squeezing a stress ball. We employed a unique method involving polyurethane tubing to reduce stress and anxiety during nail procedures.

The Technique

A patient was receiving treatment with intralesional triamcinolone injections to the nail matrix for trachyonychia involving all of the fingernails. He worked as an equipment and facilities manager, giving him access to polyurethane tubing, which is routinely used in the manufacture of some medical devices that require gas or liquid to operate. He found the nail injections to be painful but was motivated to proceed with treatment. He brought in a piece of polyurethane tubing to a subsequent visit to bite on during the injections (Figure) and reported considerable relief of pain.

What you were not taught in United States history class was that this method—clenching an object orally—dates to the era before the Civil War, before appropriate anesthetics and analgesics were developed, when patients and soldiers bit on a bullet or leather strap during surgical procedures.⁴ Clenching and chewing have been shown to promote relaxation and reduce acute pain and stress.⁵

Practical Implications

Polyurethane tubing can be purchased in bulk, is inexpensive ($0.30/foot on Amazon), and unlikely to damage teeth due to its flexibility. It can be cut into 6-inch pieces and given to the patient at their first nail injection appointment. The patient can then bring the tubing to subsequent appointments to use as a mastication tool during nail injections.

We instruct the patient to disinfect the dedicated piece of tubing after the initial visit and each subsequent visit by soaking it for 15 minutes in either a 3% hydrogen peroxide solution, antibacterial mouthwash, a solution of baking soda (bicarbonate of soda) and water (1 cup of water to 2 teaspoons of baking soda), or white vinegar. We instruct them to thoroughly dry the disinfected polyurethane tube and store it in a clean, reusable, resealable zipper storage bag between appointments.

In addition to reducing anxiety and pain, this method also distracts the patient and therefore promotes patient and physician safety. Patients are less likely to jump or startle during the injection, thereby reducing the risk of physically interfering with the nail surgeon or making an unanticipated advance into the surgical field.

Although frustrated patients with nail disease may need to “bite the bullet” when they accept treatment with nail injections, lessons from our patient and from United States history offer a safe and cost-effective pain management strategy. Minimizing discomfort and anxiety during the first nail injection is crucial because doing so is likely to promote adherence with follow-up injections and therefore improve clinical outcomes.

Future clinical studies should validate the clinical utility of oral mastication and clenching during nail procedures compared to other perioperative stress- and anxiety-reducing techniques.

Practice Gap

Nail matrix and nail bed injections with triamcinolone acetonide are used to treat trachyonychia and inflammatory nail conditions, including nail psoriasis and nail lichen planus. The procedure should be quick in well-trained hands, with each nail injection taking only seconds to perform. Typically, patients have multiple nails involved, requiring at least 1 injection into the nail matrix or the nail bed (or both) in each nail at each visit. Patients often are anxious when undergoing nail injections; the nail unit is highly innervated and vascular, which can cause notable transient discomfort during the procedure^1,2 as well as postoperative pain.³

Nail injections must be repeated every 4 to 6 weeks to sustain clinical benefit and maximize outcomes, which can lead to heightened anxiety and apprehension before and during the visit. Furthermore, pain and anxiety associated with the procedure may deter patients from returning for follow-up injections, which can impact treatment adherence and clinical outcomes.

Dermatologists should implement strategies to decrease periprocedural anxiety to improve the nail injection experience. In our practice, we routinely incorporate stress-reducing techniques—music, talkesthesia, a sleep mask, cool air, ethyl chloride, and squeezing a stress ball—into the clinical workflow of the procedure. The goal of these techniques is to divert attention away from painful stimuli. Most patients, however, receive injections in both hands, making it impractical to employ some of these techniques, particularly squeezing a stress ball. We employed a unique method involving polyurethane tubing to reduce stress and anxiety during nail procedures.

The Technique

A patient was receiving treatment with intralesional triamcinolone injections to the nail matrix for trachyonychia involving all of the fingernails. He worked as an equipment and facilities manager, giving him access to polyurethane tubing, which is routinely used in the manufacture of some medical devices that require gas or liquid to operate. He found the nail injections to be painful but was motivated to proceed with treatment. He brought in a piece of polyurethane tubing to a subsequent visit to bite on during the injections (Figure) and reported considerable relief of pain.

What you were not taught in United States history class was that this method—clenching an object orally—dates to the era before the Civil War, before appropriate anesthetics and analgesics were developed, when patients and soldiers bit on a bullet or leather strap during surgical procedures.⁴ Clenching and chewing have been shown to promote relaxation and reduce acute pain and stress.⁵

Practical Implications

Polyurethane tubing can be purchased in bulk, is inexpensive ($0.30/foot on Amazon), and unlikely to damage teeth due to its flexibility. It can be cut into 6-inch pieces and given to the patient at their first nail injection appointment. The patient can then bring the tubing to subsequent appointments to use as a mastication tool during nail injections.

We instruct the patient to disinfect the dedicated piece of tubing after the initial visit and each subsequent visit by soaking it for 15 minutes in either a 3% hydrogen peroxide solution, antibacterial mouthwash, a solution of baking soda (bicarbonate of soda) and water (1 cup of water to 2 teaspoons of baking soda), or white vinegar. We instruct them to thoroughly dry the disinfected polyurethane tube and store it in a clean, reusable, resealable zipper storage bag between appointments.

In addition to reducing anxiety and pain, this method also distracts the patient and therefore promotes patient and physician safety. Patients are less likely to jump or startle during the injection, thereby reducing the risk of physically interfering with the nail surgeon or making an unanticipated advance into the surgical field.

Although frustrated patients with nail disease may need to “bite the bullet” when they accept treatment with nail injections, lessons from our patient and from United States history offer a safe and cost-effective pain management strategy. Minimizing discomfort and anxiety during the first nail injection is crucial because doing so is likely to promote adherence with follow-up injections and therefore improve clinical outcomes.

Future clinical studies should validate the clinical utility of oral mastication and clenching during nail procedures compared to other perioperative stress- and anxiety-reducing techniques.

Practice Gap

Nail matrix and nail bed injections with triamcinolone acetonide are used to treat trachyonychia and inflammatory nail conditions, including nail psoriasis and nail lichen planus. The procedure should be quick in well-trained hands, with each nail injection taking only seconds to perform. Typically, patients have multiple nails involved, requiring at least 1 injection into the nail matrix or the nail bed (or both) in each nail at each visit. Patients often are anxious when undergoing nail injections; the nail unit is highly innervated and vascular, which can cause notable transient discomfort during the procedure^1,2 as well as postoperative pain.³

Nail injections must be repeated every 4 to 6 weeks to sustain clinical benefit and maximize outcomes, which can lead to heightened anxiety and apprehension before and during the visit. Furthermore, pain and anxiety associated with the procedure may deter patients from returning for follow-up injections, which can impact treatment adherence and clinical outcomes.

Dermatologists should implement strategies to decrease periprocedural anxiety to improve the nail injection experience. In our practice, we routinely incorporate stress-reducing techniques—music, talkesthesia, a sleep mask, cool air, ethyl chloride, and squeezing a stress ball—into the clinical workflow of the procedure. The goal of these techniques is to divert attention away from painful stimuli. Most patients, however, receive injections in both hands, making it impractical to employ some of these techniques, particularly squeezing a stress ball. We employed a unique method involving polyurethane tubing to reduce stress and anxiety during nail procedures.

The Technique

A patient was receiving treatment with intralesional triamcinolone injections to the nail matrix for trachyonychia involving all of the fingernails. He worked as an equipment and facilities manager, giving him access to polyurethane tubing, which is routinely used in the manufacture of some medical devices that require gas or liquid to operate. He found the nail injections to be painful but was motivated to proceed with treatment. He brought in a piece of polyurethane tubing to a subsequent visit to bite on during the injections (Figure) and reported considerable relief of pain.

What you were not taught in United States history class was that this method—clenching an object orally—dates to the era before the Civil War, before appropriate anesthetics and analgesics were developed, when patients and soldiers bit on a bullet or leather strap during surgical procedures.⁴ Clenching and chewing have been shown to promote relaxation and reduce acute pain and stress.⁵

Practical Implications

Polyurethane tubing can be purchased in bulk, is inexpensive ($0.30/foot on Amazon), and unlikely to damage teeth due to its flexibility. It can be cut into 6-inch pieces and given to the patient at their first nail injection appointment. The patient can then bring the tubing to subsequent appointments to use as a mastication tool during nail injections.

We instruct the patient to disinfect the dedicated piece of tubing after the initial visit and each subsequent visit by soaking it for 15 minutes in either a 3% hydrogen peroxide solution, antibacterial mouthwash, a solution of baking soda (bicarbonate of soda) and water (1 cup of water to 2 teaspoons of baking soda), or white vinegar. We instruct them to thoroughly dry the disinfected polyurethane tube and store it in a clean, reusable, resealable zipper storage bag between appointments.

In addition to reducing anxiety and pain, this method also distracts the patient and therefore promotes patient and physician safety. Patients are less likely to jump or startle during the injection, thereby reducing the risk of physically interfering with the nail surgeon or making an unanticipated advance into the surgical field.

Although frustrated patients with nail disease may need to “bite the bullet” when they accept treatment with nail injections, lessons from our patient and from United States history offer a safe and cost-effective pain management strategy. Minimizing discomfort and anxiety during the first nail injection is crucial because doing so is likely to promote adherence with follow-up injections and therefore improve clinical outcomes.

Future clinical studies should validate the clinical utility of oral mastication and clenching during nail procedures compared to other perioperative stress- and anxiety-reducing techniques.