MDedge Dermatology

Fragrances are complex organic compounds that are sufficiently volatile to produce an odor—most often a pleasant one—or at times intended to neutralize unpleasant odors. They can be further divided into natural fragrances (eg, essential oils) and synthetic ones. Fragrances are found in abundance in our daily lives: in perfumes; colognes; lotions; shampoos; and an array of other personal, household, and even industrial products (Table). These exposures include products directly applied to the skin, rinsed off, or aerosolized. A single product often contains a multitude of different fragrances to create the scents we know and love. To many, fragrances can be an important part of everyday life or even a part of one’s identity. But that once-intoxicating aroma can transform into an itchy skin nightmare; fragrances are among the most common contact allergens.

Given the widespread prevalence of fragrances in so many products, understanding fragrance allergy and skillful avoidance is imperative. In this review, we explore important aspects of fragrance allergic contact dermatitis (ACD), including chemistry, epidemiology, patch test considerations, and management strategies for patients, with the goal of providing valuable clinical insights for treating physicians on how patients can embrace a fragrance-free lifestyle.

How Fragrances Act as Allergens

A plethora of chemicals emit odors, of which more than 2000 are used to create the fragranced products we see on our shelves today.¹ For many of these fragrances, contact allergy develops because the fragrance acts as a hapten (ie, a small molecule that combines with a carrier protein to elicit an immune response).² Some fragrance molecules require “activation” to be able to bind to proteins; these are known as prehaptens.³ For example, the natural fragrance linalool is generally considered nonallergenic in its initial form. However, once it is exposed to air, it may undergo oxidation to become linalool hydroperoxides, a well-established contact allergen. Some fragrances can become allergenic in the skin itself, often secondary to enzymatic reactions—these are known as prohaptens.³ However, most fragrances are directly reactive to skin proteins on the basis of chemical reactions such as Michael addition and Schiff base formation.⁴ In either case, the end result is that fragrance allergens, including essential oils, may cause skin sensitization and subsequent ACD.^5,6

Epidemiology

Contact allergy to fragrances is not uncommon; in a multicenter cross-sectional study conducted in 5 European countries, the prevalence in the general population was estimated to be as high as 2.6% and 1.9% among 3119 patients patch tested to fragrance mix I (FMI) and fragrance mix II (FMII), respectively.⁷ Studies in patients referred for patch testing have shown a higher 5% to 25% prevalence of fragrance allergy, largely depending on what population was evaluated.¹ Factors such as sociocultural differences in frequency and types of fragrances used could contribute to this variation.

During patch testing, the primary fragrance screening allergens are FMI, FMII, and balsam of Peru (BOP)(Myroxylon pereirae resin).⁷ In recent years, hydroperoxides of linalool and limonene also have emerged as potentially important fragrance allergens.⁸ The frequencies of patch-test positivity of these allergens can be quite high in referral-based populations. In a study performed by the North American Contact Dermatitis Group (NACDG) from 2019 to 2020, frequencies of fragrance allergen positivity were 12.8% for FMI, 5.2% for FMII, 7.4% for BOP, 11.1% for hydroperoxides of linalool, and 3.5% for hydroperoxides of limonene.⁸ Additionally, it was noted that FMI and hydroperoxides of linalool were among the top 10 most frequently positive allergens.⁹ It should be kept in mind that NACDG studies are drawn from a referral population and not representative of the general population.

Allergic contact dermatitis to fragrances can manifest anywhere on the body, but certain patterns are characteristic. A study by the NACDG analyzed fragrance and botanical patch test results in 24,246 patients and found that fragrance/botanical-sensitive patients more commonly had dermatitis involving the face (odds ratio [OR], 1.12; 95% CI, 1.03-1.21), legs (OR, 1.22; 95% CI, 1.06-1.41), and anal/genital areas (OR, 1.26; 95% CI, 1.04-1.52) and were less likely to have hand dermatitis (OR, 0.88; 95% CI, 0.82-0.95) compared with non–fragrance/botanical-sensitive patients.¹⁰ However, other studies have found that hand dermatitis is common among fragrance-allergic individuals.^11-13

Fragrance allergy tends to be more common in women than men, which likely is attributable to differences in product use and exposure.¹⁰ The prevalence of fragrance allergy increases with age in both men and women, peaking at approximately 50 years of age, likely due to repeat exposure or age-related changes to the skin barrier or immune system.¹⁴

Occupational fragrance exposures are important to consider, and fragrance ACD is associated with hairdressers, beauticians, office workers exposed to aromatherapy diffusers, and food handlers.¹⁵ Less-obvious professions that involve exposure to fragrances used to cover up unwanted odors—such as working with industrial and cleaning chemicals or even metalworking—also have been reported to be associated with ACD.¹⁶

Patch Test Considerations

Patch testing is essential to confirm fragrance allergy and guide treatment, but because there are so many potential fragrance allergens, there is no perfect patch test strategy. In a standard patch test series, the most important screening allergens are considered to be FMI, FMII, and BOP; tested together, they are thought to detect a large proportion of cases of fragrance allergy. Strikingly, in a large European study (N=1951), patch testing with the fragrance markers in the baseline panel failed to detect more than 40% of cases of allergy compared to testing with 26 individual fragrance allergens.¹⁷ Other studies have reported that a smaller proportion of fragrance allergies are missed by using baseline screening allergens alone.^18,19 Limonene and linalool hydroperoxides also are potentially important fragrance allergens to consider adding to the patch test panel, as unoxidized limonene and linalool commonly are used in many products and could theoretically undergo auto-oxidation under use conditions.⁸ However, because of the high number of irritant, questionable, and potentially false-positive reactions, the Information Network of Departments of Dermatology has recommended against adding these hydroperoxides to a standard screening tray for patch testing.²⁰ It must be remembered that a positive patch test to a fragrance does not necessarily represent ACD unless the patient has a clinically relevant exposure to the allergen.²¹

In patients who test negative to the baseline ­fragrance-screening allergens and in whom a high degree of suspicion remains, further testing with supplemental fragrance allergens (commercially available from patch test suppliers) is warranted.¹⁷ The thin-layer rapid use epicutaneous (T.R.U.E.) test (SmartPractice) includes FMI and BOP but not FMII or linalool or limonene hydroperoxides. More comprehensive patch test panels are available that include additional fragrances, such as the North American 80 Comprehensive Series and the American Contact Dermatitis Society Core Allergen Series.^22-24 It is important to remain vigilant and consider expanded patch testing if patients initially test negative but suspicion remains.

Furthermore, patch testing with the patient’s own products is an important consideration. Uter et al²⁵ evaluated patch testing using patients’ perfumes, deodorants, and shaving lotions, and approximately 41% (53/129) of patients who tested positive to their own product tested negative for fragrance-screening allergens. Although it can be difficult to ascertain which exact component of a commercial product is the culprit, a positive patch test may still provide clinically relevant information for patients and treating physicians. In cases of questionable or weak-positive results, repeat testing or repeated open application tests can help re-evaluate suspected products.

Cross-reactivity should be considered when patch testing for fragrances. Atwater et al¹⁰ found that cross-reactivity between FMI, FMII, and BOP was common; for instance, approximately 40% of patients testing positive to FMII or BOP also had positive reactions to FMI (522/1182 and 768/1942, respectively). Understanding this concept is important because in some cases (as detailed below) patients will need to avoid all fragrances, not just the ones to which they have previously been exposed, given the limitations on fragrance labeling in the United States. However, this may change with the Modernization of Cosmetic Regulation Act of 2022.²⁶

Avoiding Fragrances: Improving Patient Education and Outcomes

Once a relevant contact allergy to fragrance is established after patch testing, successful avoidance is critical but challenging, as there are numerous potential pitfalls. Missing just 1 hidden source of fragrance exposure will often be the difference between success or failure. Dermatologists play a crucial role in guiding patients through the intricate process of identifying and avoiding potential allergens.

Optimal Safety: Embracing a Fragrance-Free Lifestyle

For fragrance-allergic patients, it generally is safest to completely avoid fragrance.

First, if a patient only shows positive patch-test reactions to fragrance screening mixes (and not to the particular fragrances in these mixes), there is no way to be certain which fragrances the patient needs to avoid.

Second, even if specific fragrance allergens are identified, numerous chemically related fragrances to which the patient may be allergic are not commercially available for patch testing. One review provided evidence of 162 fragrance allergens that have been documented to cause contact allergy.¹ Dermatologists generally patch test to screening mixtures and/or the 26 fragrance chemicals required on labels in European products (European Directive fragrance).²⁷ Therefore, there are more than 100 known fragrance allergens that are not routinely tested to which patients could be allergic.

Third, certain fragrances, such as limonene and linalool, are found in many products with fragrance, and it is difficult to find products without these substances. Limonene and linalool themselves are not potent allergens; however, upon air exposure, they may auto-oxidize to hydroperoxides of limonene and linalool, which are increasingly common positive patch tests.¹⁹

Additionally, patients should be advised that many products labeled “fragrance free,” “unscented,” or “free and clear” are not truly fragrance free, and patients should not choose products based on these claims. There are no legal definitions for these claims in the United States, and industries are allowed to choose the definition they prefer. Numerous products labeled “unscented” use this term to indicate that the product had an odor, the company used a masking fragrance to hide the odor, and then the product can be considered unscented. In many holistic stores, most products labeled “fragrance free” are only free of artificial fragrances but contain essential oils. Of the 162 documented fragrance allergens, 80 are essential oils.⁶ Essential oils are perceived to be safe by the vast majority of the population because they are viewed as “natural” and “unprocessed” sources of fragrance.²⁸ However, numerous allergenic terpenes have been discovered in essential oils, including functionalized variations of alcohols (eg, geraniol, bisabolol) and aldehydes (eg, citronellal).⁶ Essential oils also consist of nonterpenic compounds produced through the phenylpropanoids pathway, including eugenol and cinnamaldehyde. One review showed that most essential oils contain one or more European Directive fragrance.²⁹ Therefore, many products labeled “unscented,” “fragrance free,” or “natural” are not free of fragrance and may be unsafe for fragrance-allergic patients.

Although not required, manufacturers sometimes voluntarily list one or more of the 162 currently identified fragrance allergens on product labels. Also, there are more than 50 potentially allergenic essential oils that can be listed on labels by their common names or by genus or species. In addition, there are synonyms for fragrance, such as aroma, parfum, perfume, and scent. Therefore, there are several hundred different ingredient names on labels that indicate the presence of fragrance, and patients are very unlikely to successfully identify fragrance-free products by trying to read product labels on their own.

Lastly, in the United States product labels only require products to state that they contain “fragrance” and do not mandate the listing of specific fragrances. If a patient is allergic to a specific fragrance, there is no way to determine if that fragrance is present in these products. This will change with the enactment of Modernization of Cosmetics Regulation Act of 2022, which empowers the US Food and Drug Administration to require manufacturers to disclose many, but not all, fragrance allergens on the labels of cosmetic and topical products.²⁶

For all these reasons, patients should be advised to use a medical database to choose safe alternative products instead of trying to read labels themselves to avoid fragrance. The American Contact Dermatitis Society’s Contact Allergen Management Program (CAMP) database (https://www.contactderm.org/resources/acds-camp) is designed to identify safe alternative products for patients with contact allergies. When CAMP is programmed to avoid “fragrance,” it will list only “safe” products free of all fragrances found in a comprehensive fragrance cross-reactor group.³⁰ This customizable database is available as an application that can be downloaded onto a patient’s mobile device. Fragrance-allergic patients should be encouraged to use the CAMP application or other similar applications (eg, SkinSAFE)(https://www.skinsafeproducts­.com/) to find all the products they use.

Potential Pitfalls in Fragrance Avoidance

Most physicians, even dermatologists, will not know which products on the market are fragrance free from a contact allergy standpoint. Patients should instruct their physicians to use the allergen-avoidance application of choice whenever recommending new topical products, whether prescription or nonprescription. In 2009, Nardelli and colleagues³¹ found that 10% of topical pharmaceutical products contained a total of 66 different fragrance substances.

Individuals who are allergic to fragrance also can react to fragrances used by close contacts (ie, consort dermatitis).³² Therefore, fragrance-allergic individuals who do not improve after changing their personal products should consider urging their spouses or significant others to choose their personal care products using an allergen-avoidance application. Also, physical contact with pets can cause reactions, and the use of a fragrance-free pet shampoo is recommended. Additionally, allergic individuals who are providing care for small children should select fragrance-free products for them.

Some of the most heavily fragranced products on the market are found at hair salons. One exposure to an allergen often can keep patients broken out for up to 4 weeks and occasionally longer, a typical frequency for salon visits—even if the individual is taking great care to avoid fragrance at home. Patients should be instructed to bring their own shampoo, conditioner, and styling products to the salon. These patients also should bring safe moisturizer and nail polish remover for manicures. Additionally, aromatherapy used in most massages can cause flare-ups, and it is recommended that allergic patients purchase fragrance-free massage oil to bring to their sessions.

Fragranced soaps and cleansers can leave a residue on the palmar surface of the hands and fingers. This residue may not meet the threshold for causing a reaction on the thick skin of these surfaces, but it is sufficient to passively transfer fragrance to other more sensitive areas, such as the eyelids. Passive transfer of fragrance can be a major source of allergen exposure and should not be overlooked. Allergic patients should be instructed to bring safe hand cleansers to friends’ houses, restaurants, or work.

Airborne fragrances in a patient’s environment can reach sufficient concentration to cause airborne contact dermatitis. In one case report, an Uber driver developed facial airborne ACD from a fragrance diffuser in his vehicle and his condition improved upon removing the diffuser.³³ Therefore, patients should be instructed to avoid fragranced diffusers, scented candles, room deodorizers, incense, and wax melts.

Fragrance in household products also can be an issue. Fragrance-allergic patients should be instructed to choose fragrance-free cleaning products and to avoid fragranced wipes on surfaces that may be touched. In addition, they should be instructed to use fragrance-free laundry products. It is not required for household products in the United States to list their ingredients, and the majority do not have complete ingredient lists. Therefore, it is imperative that the patient use an allergen-avoidance application that identifies products that have full ingredient disclosure and are free of fragrance.

For individuals who enjoy perfume and/or cologne, it may be possible for them to resume use of these products in some cases after their condition has fully cleared with complete fragrance avoidance. They should avoid spraying products into the air or applying them directly onto the skin and should instead dip a cotton swab into the perfume/cologne and dab a small amount onto their clothing. This technique can sometimes satisfy the patient and improve compliance.

If a patient who is allergic to fragrance does not clear after 6 weeks of complete fragrance avoidance, it is worth considering systemic contact dermatitis due to ingestion of fragrance-related substances in foods.³⁴ A large number of fragrance materials also are food flavorings. For patients allergic to a specific fragrance(s), systemic avoidance needs to be specific to the allergen, and the Flavor and Extract Manufacturers Association’s flavor ingredient library is most helpful (https://www.femaflavor.org/flavor-library). If the patient is allergic to the complex mixture BOP, a balsam-free diet can be attempted.^35,36

Final Thoughts

Dermatologists must equip themselves with the knowledge to educate fragrance-allergic patients on proper avoidance. The multifaceted nature of fragrance avoidance requires a personalized approach, combining label scrutiny, utilization of a safe-product application, and tailored recommendations for specific situations. By guiding patients through these complexities, dermatologists can empower patients to manage their fragrance allergy and enhance their quality of life.

Fragrances are complex organic compounds that are sufficiently volatile to produce an odor—most often a pleasant one—or at times intended to neutralize unpleasant odors. They can be further divided into natural fragrances (eg, essential oils) and synthetic ones. Fragrances are found in abundance in our daily lives: in perfumes; colognes; lotions; shampoos; and an array of other personal, household, and even industrial products (Table). These exposures include products directly applied to the skin, rinsed off, or aerosolized. A single product often contains a multitude of different fragrances to create the scents we know and love. To many, fragrances can be an important part of everyday life or even a part of one’s identity. But that once-intoxicating aroma can transform into an itchy skin nightmare; fragrances are among the most common contact allergens.

Given the widespread prevalence of fragrances in so many products, understanding fragrance allergy and skillful avoidance is imperative. In this review, we explore important aspects of fragrance allergic contact dermatitis (ACD), including chemistry, epidemiology, patch test considerations, and management strategies for patients, with the goal of providing valuable clinical insights for treating physicians on how patients can embrace a fragrance-free lifestyle.

How Fragrances Act as Allergens

A plethora of chemicals emit odors, of which more than 2000 are used to create the fragranced products we see on our shelves today.¹ For many of these fragrances, contact allergy develops because the fragrance acts as a hapten (ie, a small molecule that combines with a carrier protein to elicit an immune response).² Some fragrance molecules require “activation” to be able to bind to proteins; these are known as prehaptens.³ For example, the natural fragrance linalool is generally considered nonallergenic in its initial form. However, once it is exposed to air, it may undergo oxidation to become linalool hydroperoxides, a well-established contact allergen. Some fragrances can become allergenic in the skin itself, often secondary to enzymatic reactions—these are known as prohaptens.³ However, most fragrances are directly reactive to skin proteins on the basis of chemical reactions such as Michael addition and Schiff base formation.⁴ In either case, the end result is that fragrance allergens, including essential oils, may cause skin sensitization and subsequent ACD.^5,6

Epidemiology

Contact allergy to fragrances is not uncommon; in a multicenter cross-sectional study conducted in 5 European countries, the prevalence in the general population was estimated to be as high as 2.6% and 1.9% among 3119 patients patch tested to fragrance mix I (FMI) and fragrance mix II (FMII), respectively.⁷ Studies in patients referred for patch testing have shown a higher 5% to 25% prevalence of fragrance allergy, largely depending on what population was evaluated.¹ Factors such as sociocultural differences in frequency and types of fragrances used could contribute to this variation.

During patch testing, the primary fragrance screening allergens are FMI, FMII, and balsam of Peru (BOP)(Myroxylon pereirae resin).⁷ In recent years, hydroperoxides of linalool and limonene also have emerged as potentially important fragrance allergens.⁸ The frequencies of patch-test positivity of these allergens can be quite high in referral-based populations. In a study performed by the North American Contact Dermatitis Group (NACDG) from 2019 to 2020, frequencies of fragrance allergen positivity were 12.8% for FMI, 5.2% for FMII, 7.4% for BOP, 11.1% for hydroperoxides of linalool, and 3.5% for hydroperoxides of limonene.⁸ Additionally, it was noted that FMI and hydroperoxides of linalool were among the top 10 most frequently positive allergens.⁹ It should be kept in mind that NACDG studies are drawn from a referral population and not representative of the general population.

Allergic contact dermatitis to fragrances can manifest anywhere on the body, but certain patterns are characteristic. A study by the NACDG analyzed fragrance and botanical patch test results in 24,246 patients and found that fragrance/botanical-sensitive patients more commonly had dermatitis involving the face (odds ratio [OR], 1.12; 95% CI, 1.03-1.21), legs (OR, 1.22; 95% CI, 1.06-1.41), and anal/genital areas (OR, 1.26; 95% CI, 1.04-1.52) and were less likely to have hand dermatitis (OR, 0.88; 95% CI, 0.82-0.95) compared with non–fragrance/botanical-sensitive patients.¹⁰ However, other studies have found that hand dermatitis is common among fragrance-allergic individuals.^11-13

Fragrance allergy tends to be more common in women than men, which likely is attributable to differences in product use and exposure.¹⁰ The prevalence of fragrance allergy increases with age in both men and women, peaking at approximately 50 years of age, likely due to repeat exposure or age-related changes to the skin barrier or immune system.¹⁴

Occupational fragrance exposures are important to consider, and fragrance ACD is associated with hairdressers, beauticians, office workers exposed to aromatherapy diffusers, and food handlers.¹⁵ Less-obvious professions that involve exposure to fragrances used to cover up unwanted odors—such as working with industrial and cleaning chemicals or even metalworking—also have been reported to be associated with ACD.¹⁶

Patch Test Considerations

Patch testing is essential to confirm fragrance allergy and guide treatment, but because there are so many potential fragrance allergens, there is no perfect patch test strategy. In a standard patch test series, the most important screening allergens are considered to be FMI, FMII, and BOP; tested together, they are thought to detect a large proportion of cases of fragrance allergy. Strikingly, in a large European study (N=1951), patch testing with the fragrance markers in the baseline panel failed to detect more than 40% of cases of allergy compared to testing with 26 individual fragrance allergens.¹⁷ Other studies have reported that a smaller proportion of fragrance allergies are missed by using baseline screening allergens alone.^18,19 Limonene and linalool hydroperoxides also are potentially important fragrance allergens to consider adding to the patch test panel, as unoxidized limonene and linalool commonly are used in many products and could theoretically undergo auto-oxidation under use conditions.⁸ However, because of the high number of irritant, questionable, and potentially false-positive reactions, the Information Network of Departments of Dermatology has recommended against adding these hydroperoxides to a standard screening tray for patch testing.²⁰ It must be remembered that a positive patch test to a fragrance does not necessarily represent ACD unless the patient has a clinically relevant exposure to the allergen.²¹

In patients who test negative to the baseline ­fragrance-screening allergens and in whom a high degree of suspicion remains, further testing with supplemental fragrance allergens (commercially available from patch test suppliers) is warranted.¹⁷ The thin-layer rapid use epicutaneous (T.R.U.E.) test (SmartPractice) includes FMI and BOP but not FMII or linalool or limonene hydroperoxides. More comprehensive patch test panels are available that include additional fragrances, such as the North American 80 Comprehensive Series and the American Contact Dermatitis Society Core Allergen Series.^22-24 It is important to remain vigilant and consider expanded patch testing if patients initially test negative but suspicion remains.

Furthermore, patch testing with the patient’s own products is an important consideration. Uter et al²⁵ evaluated patch testing using patients’ perfumes, deodorants, and shaving lotions, and approximately 41% (53/129) of patients who tested positive to their own product tested negative for fragrance-screening allergens. Although it can be difficult to ascertain which exact component of a commercial product is the culprit, a positive patch test may still provide clinically relevant information for patients and treating physicians. In cases of questionable or weak-positive results, repeat testing or repeated open application tests can help re-evaluate suspected products.

Cross-reactivity should be considered when patch testing for fragrances. Atwater et al¹⁰ found that cross-reactivity between FMI, FMII, and BOP was common; for instance, approximately 40% of patients testing positive to FMII or BOP also had positive reactions to FMI (522/1182 and 768/1942, respectively). Understanding this concept is important because in some cases (as detailed below) patients will need to avoid all fragrances, not just the ones to which they have previously been exposed, given the limitations on fragrance labeling in the United States. However, this may change with the Modernization of Cosmetic Regulation Act of 2022.²⁶

Avoiding Fragrances: Improving Patient Education and Outcomes

Once a relevant contact allergy to fragrance is established after patch testing, successful avoidance is critical but challenging, as there are numerous potential pitfalls. Missing just 1 hidden source of fragrance exposure will often be the difference between success or failure. Dermatologists play a crucial role in guiding patients through the intricate process of identifying and avoiding potential allergens.

Optimal Safety: Embracing a Fragrance-Free Lifestyle

For fragrance-allergic patients, it generally is safest to completely avoid fragrance.

First, if a patient only shows positive patch-test reactions to fragrance screening mixes (and not to the particular fragrances in these mixes), there is no way to be certain which fragrances the patient needs to avoid.

Second, even if specific fragrance allergens are identified, numerous chemically related fragrances to which the patient may be allergic are not commercially available for patch testing. One review provided evidence of 162 fragrance allergens that have been documented to cause contact allergy.¹ Dermatologists generally patch test to screening mixtures and/or the 26 fragrance chemicals required on labels in European products (European Directive fragrance).²⁷ Therefore, there are more than 100 known fragrance allergens that are not routinely tested to which patients could be allergic.

Third, certain fragrances, such as limonene and linalool, are found in many products with fragrance, and it is difficult to find products without these substances. Limonene and linalool themselves are not potent allergens; however, upon air exposure, they may auto-oxidize to hydroperoxides of limonene and linalool, which are increasingly common positive patch tests.¹⁹

Additionally, patients should be advised that many products labeled “fragrance free,” “unscented,” or “free and clear” are not truly fragrance free, and patients should not choose products based on these claims. There are no legal definitions for these claims in the United States, and industries are allowed to choose the definition they prefer. Numerous products labeled “unscented” use this term to indicate that the product had an odor, the company used a masking fragrance to hide the odor, and then the product can be considered unscented. In many holistic stores, most products labeled “fragrance free” are only free of artificial fragrances but contain essential oils. Of the 162 documented fragrance allergens, 80 are essential oils.⁶ Essential oils are perceived to be safe by the vast majority of the population because they are viewed as “natural” and “unprocessed” sources of fragrance.²⁸ However, numerous allergenic terpenes have been discovered in essential oils, including functionalized variations of alcohols (eg, geraniol, bisabolol) and aldehydes (eg, citronellal).⁶ Essential oils also consist of nonterpenic compounds produced through the phenylpropanoids pathway, including eugenol and cinnamaldehyde. One review showed that most essential oils contain one or more European Directive fragrance.²⁹ Therefore, many products labeled “unscented,” “fragrance free,” or “natural” are not free of fragrance and may be unsafe for fragrance-allergic patients.

Although not required, manufacturers sometimes voluntarily list one or more of the 162 currently identified fragrance allergens on product labels. Also, there are more than 50 potentially allergenic essential oils that can be listed on labels by their common names or by genus or species. In addition, there are synonyms for fragrance, such as aroma, parfum, perfume, and scent. Therefore, there are several hundred different ingredient names on labels that indicate the presence of fragrance, and patients are very unlikely to successfully identify fragrance-free products by trying to read product labels on their own.

Lastly, in the United States product labels only require products to state that they contain “fragrance” and do not mandate the listing of specific fragrances. If a patient is allergic to a specific fragrance, there is no way to determine if that fragrance is present in these products. This will change with the enactment of Modernization of Cosmetics Regulation Act of 2022, which empowers the US Food and Drug Administration to require manufacturers to disclose many, but not all, fragrance allergens on the labels of cosmetic and topical products.²⁶

For all these reasons, patients should be advised to use a medical database to choose safe alternative products instead of trying to read labels themselves to avoid fragrance. The American Contact Dermatitis Society’s Contact Allergen Management Program (CAMP) database (https://www.contactderm.org/resources/acds-camp) is designed to identify safe alternative products for patients with contact allergies. When CAMP is programmed to avoid “fragrance,” it will list only “safe” products free of all fragrances found in a comprehensive fragrance cross-reactor group.³⁰ This customizable database is available as an application that can be downloaded onto a patient’s mobile device. Fragrance-allergic patients should be encouraged to use the CAMP application or other similar applications (eg, SkinSAFE)(https://www.skinsafeproducts­.com/) to find all the products they use.

Potential Pitfalls in Fragrance Avoidance

Most physicians, even dermatologists, will not know which products on the market are fragrance free from a contact allergy standpoint. Patients should instruct their physicians to use the allergen-avoidance application of choice whenever recommending new topical products, whether prescription or nonprescription. In 2009, Nardelli and colleagues³¹ found that 10% of topical pharmaceutical products contained a total of 66 different fragrance substances.

Individuals who are allergic to fragrance also can react to fragrances used by close contacts (ie, consort dermatitis).³² Therefore, fragrance-allergic individuals who do not improve after changing their personal products should consider urging their spouses or significant others to choose their personal care products using an allergen-avoidance application. Also, physical contact with pets can cause reactions, and the use of a fragrance-free pet shampoo is recommended. Additionally, allergic individuals who are providing care for small children should select fragrance-free products for them.

Some of the most heavily fragranced products on the market are found at hair salons. One exposure to an allergen often can keep patients broken out for up to 4 weeks and occasionally longer, a typical frequency for salon visits—even if the individual is taking great care to avoid fragrance at home. Patients should be instructed to bring their own shampoo, conditioner, and styling products to the salon. These patients also should bring safe moisturizer and nail polish remover for manicures. Additionally, aromatherapy used in most massages can cause flare-ups, and it is recommended that allergic patients purchase fragrance-free massage oil to bring to their sessions.

Fragranced soaps and cleansers can leave a residue on the palmar surface of the hands and fingers. This residue may not meet the threshold for causing a reaction on the thick skin of these surfaces, but it is sufficient to passively transfer fragrance to other more sensitive areas, such as the eyelids. Passive transfer of fragrance can be a major source of allergen exposure and should not be overlooked. Allergic patients should be instructed to bring safe hand cleansers to friends’ houses, restaurants, or work.

Airborne fragrances in a patient’s environment can reach sufficient concentration to cause airborne contact dermatitis. In one case report, an Uber driver developed facial airborne ACD from a fragrance diffuser in his vehicle and his condition improved upon removing the diffuser.³³ Therefore, patients should be instructed to avoid fragranced diffusers, scented candles, room deodorizers, incense, and wax melts.

Fragrance in household products also can be an issue. Fragrance-allergic patients should be instructed to choose fragrance-free cleaning products and to avoid fragranced wipes on surfaces that may be touched. In addition, they should be instructed to use fragrance-free laundry products. It is not required for household products in the United States to list their ingredients, and the majority do not have complete ingredient lists. Therefore, it is imperative that the patient use an allergen-avoidance application that identifies products that have full ingredient disclosure and are free of fragrance.

For individuals who enjoy perfume and/or cologne, it may be possible for them to resume use of these products in some cases after their condition has fully cleared with complete fragrance avoidance. They should avoid spraying products into the air or applying them directly onto the skin and should instead dip a cotton swab into the perfume/cologne and dab a small amount onto their clothing. This technique can sometimes satisfy the patient and improve compliance.

If a patient who is allergic to fragrance does not clear after 6 weeks of complete fragrance avoidance, it is worth considering systemic contact dermatitis due to ingestion of fragrance-related substances in foods.³⁴ A large number of fragrance materials also are food flavorings. For patients allergic to a specific fragrance(s), systemic avoidance needs to be specific to the allergen, and the Flavor and Extract Manufacturers Association’s flavor ingredient library is most helpful (https://www.femaflavor.org/flavor-library). If the patient is allergic to the complex mixture BOP, a balsam-free diet can be attempted.^35,36

Final Thoughts

Dermatologists must equip themselves with the knowledge to educate fragrance-allergic patients on proper avoidance. The multifaceted nature of fragrance avoidance requires a personalized approach, combining label scrutiny, utilization of a safe-product application, and tailored recommendations for specific situations. By guiding patients through these complexities, dermatologists can empower patients to manage their fragrance allergy and enhance their quality of life.

Fragrances are complex organic compounds that are sufficiently volatile to produce an odor—most often a pleasant one—or at times intended to neutralize unpleasant odors. They can be further divided into natural fragrances (eg, essential oils) and synthetic ones. Fragrances are found in abundance in our daily lives: in perfumes; colognes; lotions; shampoos; and an array of other personal, household, and even industrial products (Table). These exposures include products directly applied to the skin, rinsed off, or aerosolized. A single product often contains a multitude of different fragrances to create the scents we know and love. To many, fragrances can be an important part of everyday life or even a part of one’s identity. But that once-intoxicating aroma can transform into an itchy skin nightmare; fragrances are among the most common contact allergens.

Given the widespread prevalence of fragrances in so many products, understanding fragrance allergy and skillful avoidance is imperative. In this review, we explore important aspects of fragrance allergic contact dermatitis (ACD), including chemistry, epidemiology, patch test considerations, and management strategies for patients, with the goal of providing valuable clinical insights for treating physicians on how patients can embrace a fragrance-free lifestyle.

How Fragrances Act as Allergens

A plethora of chemicals emit odors, of which more than 2000 are used to create the fragranced products we see on our shelves today.¹ For many of these fragrances, contact allergy develops because the fragrance acts as a hapten (ie, a small molecule that combines with a carrier protein to elicit an immune response).² Some fragrance molecules require “activation” to be able to bind to proteins; these are known as prehaptens.³ For example, the natural fragrance linalool is generally considered nonallergenic in its initial form. However, once it is exposed to air, it may undergo oxidation to become linalool hydroperoxides, a well-established contact allergen. Some fragrances can become allergenic in the skin itself, often secondary to enzymatic reactions—these are known as prohaptens.³ However, most fragrances are directly reactive to skin proteins on the basis of chemical reactions such as Michael addition and Schiff base formation.⁴ In either case, the end result is that fragrance allergens, including essential oils, may cause skin sensitization and subsequent ACD.^5,6

Epidemiology

Contact allergy to fragrances is not uncommon; in a multicenter cross-sectional study conducted in 5 European countries, the prevalence in the general population was estimated to be as high as 2.6% and 1.9% among 3119 patients patch tested to fragrance mix I (FMI) and fragrance mix II (FMII), respectively.⁷ Studies in patients referred for patch testing have shown a higher 5% to 25% prevalence of fragrance allergy, largely depending on what population was evaluated.¹ Factors such as sociocultural differences in frequency and types of fragrances used could contribute to this variation.

During patch testing, the primary fragrance screening allergens are FMI, FMII, and balsam of Peru (BOP)(Myroxylon pereirae resin).⁷ In recent years, hydroperoxides of linalool and limonene also have emerged as potentially important fragrance allergens.⁸ The frequencies of patch-test positivity of these allergens can be quite high in referral-based populations. In a study performed by the North American Contact Dermatitis Group (NACDG) from 2019 to 2020, frequencies of fragrance allergen positivity were 12.8% for FMI, 5.2% for FMII, 7.4% for BOP, 11.1% for hydroperoxides of linalool, and 3.5% for hydroperoxides of limonene.⁸ Additionally, it was noted that FMI and hydroperoxides of linalool were among the top 10 most frequently positive allergens.⁹ It should be kept in mind that NACDG studies are drawn from a referral population and not representative of the general population.

Allergic contact dermatitis to fragrances can manifest anywhere on the body, but certain patterns are characteristic. A study by the NACDG analyzed fragrance and botanical patch test results in 24,246 patients and found that fragrance/botanical-sensitive patients more commonly had dermatitis involving the face (odds ratio [OR], 1.12; 95% CI, 1.03-1.21), legs (OR, 1.22; 95% CI, 1.06-1.41), and anal/genital areas (OR, 1.26; 95% CI, 1.04-1.52) and were less likely to have hand dermatitis (OR, 0.88; 95% CI, 0.82-0.95) compared with non–fragrance/botanical-sensitive patients.¹⁰ However, other studies have found that hand dermatitis is common among fragrance-allergic individuals.^11-13

Fragrance allergy tends to be more common in women than men, which likely is attributable to differences in product use and exposure.¹⁰ The prevalence of fragrance allergy increases with age in both men and women, peaking at approximately 50 years of age, likely due to repeat exposure or age-related changes to the skin barrier or immune system.¹⁴

Occupational fragrance exposures are important to consider, and fragrance ACD is associated with hairdressers, beauticians, office workers exposed to aromatherapy diffusers, and food handlers.¹⁵ Less-obvious professions that involve exposure to fragrances used to cover up unwanted odors—such as working with industrial and cleaning chemicals or even metalworking—also have been reported to be associated with ACD.¹⁶

Patch Test Considerations

Patch testing is essential to confirm fragrance allergy and guide treatment, but because there are so many potential fragrance allergens, there is no perfect patch test strategy. In a standard patch test series, the most important screening allergens are considered to be FMI, FMII, and BOP; tested together, they are thought to detect a large proportion of cases of fragrance allergy. Strikingly, in a large European study (N=1951), patch testing with the fragrance markers in the baseline panel failed to detect more than 40% of cases of allergy compared to testing with 26 individual fragrance allergens.¹⁷ Other studies have reported that a smaller proportion of fragrance allergies are missed by using baseline screening allergens alone.^18,19 Limonene and linalool hydroperoxides also are potentially important fragrance allergens to consider adding to the patch test panel, as unoxidized limonene and linalool commonly are used in many products and could theoretically undergo auto-oxidation under use conditions.⁸ However, because of the high number of irritant, questionable, and potentially false-positive reactions, the Information Network of Departments of Dermatology has recommended against adding these hydroperoxides to a standard screening tray for patch testing.²⁰ It must be remembered that a positive patch test to a fragrance does not necessarily represent ACD unless the patient has a clinically relevant exposure to the allergen.²¹

In patients who test negative to the baseline ­fragrance-screening allergens and in whom a high degree of suspicion remains, further testing with supplemental fragrance allergens (commercially available from patch test suppliers) is warranted.¹⁷ The thin-layer rapid use epicutaneous (T.R.U.E.) test (SmartPractice) includes FMI and BOP but not FMII or linalool or limonene hydroperoxides. More comprehensive patch test panels are available that include additional fragrances, such as the North American 80 Comprehensive Series and the American Contact Dermatitis Society Core Allergen Series.^22-24 It is important to remain vigilant and consider expanded patch testing if patients initially test negative but suspicion remains.

Furthermore, patch testing with the patient’s own products is an important consideration. Uter et al²⁵ evaluated patch testing using patients’ perfumes, deodorants, and shaving lotions, and approximately 41% (53/129) of patients who tested positive to their own product tested negative for fragrance-screening allergens. Although it can be difficult to ascertain which exact component of a commercial product is the culprit, a positive patch test may still provide clinically relevant information for patients and treating physicians. In cases of questionable or weak-positive results, repeat testing or repeated open application tests can help re-evaluate suspected products.

Cross-reactivity should be considered when patch testing for fragrances. Atwater et al¹⁰ found that cross-reactivity between FMI, FMII, and BOP was common; for instance, approximately 40% of patients testing positive to FMII or BOP also had positive reactions to FMI (522/1182 and 768/1942, respectively). Understanding this concept is important because in some cases (as detailed below) patients will need to avoid all fragrances, not just the ones to which they have previously been exposed, given the limitations on fragrance labeling in the United States. However, this may change with the Modernization of Cosmetic Regulation Act of 2022.²⁶

Avoiding Fragrances: Improving Patient Education and Outcomes

Once a relevant contact allergy to fragrance is established after patch testing, successful avoidance is critical but challenging, as there are numerous potential pitfalls. Missing just 1 hidden source of fragrance exposure will often be the difference between success or failure. Dermatologists play a crucial role in guiding patients through the intricate process of identifying and avoiding potential allergens.

Optimal Safety: Embracing a Fragrance-Free Lifestyle

For fragrance-allergic patients, it generally is safest to completely avoid fragrance.

First, if a patient only shows positive patch-test reactions to fragrance screening mixes (and not to the particular fragrances in these mixes), there is no way to be certain which fragrances the patient needs to avoid.

Second, even if specific fragrance allergens are identified, numerous chemically related fragrances to which the patient may be allergic are not commercially available for patch testing. One review provided evidence of 162 fragrance allergens that have been documented to cause contact allergy.¹ Dermatologists generally patch test to screening mixtures and/or the 26 fragrance chemicals required on labels in European products (European Directive fragrance).²⁷ Therefore, there are more than 100 known fragrance allergens that are not routinely tested to which patients could be allergic.

Third, certain fragrances, such as limonene and linalool, are found in many products with fragrance, and it is difficult to find products without these substances. Limonene and linalool themselves are not potent allergens; however, upon air exposure, they may auto-oxidize to hydroperoxides of limonene and linalool, which are increasingly common positive patch tests.¹⁹

Additionally, patients should be advised that many products labeled “fragrance free,” “unscented,” or “free and clear” are not truly fragrance free, and patients should not choose products based on these claims. There are no legal definitions for these claims in the United States, and industries are allowed to choose the definition they prefer. Numerous products labeled “unscented” use this term to indicate that the product had an odor, the company used a masking fragrance to hide the odor, and then the product can be considered unscented. In many holistic stores, most products labeled “fragrance free” are only free of artificial fragrances but contain essential oils. Of the 162 documented fragrance allergens, 80 are essential oils.⁶ Essential oils are perceived to be safe by the vast majority of the population because they are viewed as “natural” and “unprocessed” sources of fragrance.²⁸ However, numerous allergenic terpenes have been discovered in essential oils, including functionalized variations of alcohols (eg, geraniol, bisabolol) and aldehydes (eg, citronellal).⁶ Essential oils also consist of nonterpenic compounds produced through the phenylpropanoids pathway, including eugenol and cinnamaldehyde. One review showed that most essential oils contain one or more European Directive fragrance.²⁹ Therefore, many products labeled “unscented,” “fragrance free,” or “natural” are not free of fragrance and may be unsafe for fragrance-allergic patients.

Although not required, manufacturers sometimes voluntarily list one or more of the 162 currently identified fragrance allergens on product labels. Also, there are more than 50 potentially allergenic essential oils that can be listed on labels by their common names or by genus or species. In addition, there are synonyms for fragrance, such as aroma, parfum, perfume, and scent. Therefore, there are several hundred different ingredient names on labels that indicate the presence of fragrance, and patients are very unlikely to successfully identify fragrance-free products by trying to read product labels on their own.

Lastly, in the United States product labels only require products to state that they contain “fragrance” and do not mandate the listing of specific fragrances. If a patient is allergic to a specific fragrance, there is no way to determine if that fragrance is present in these products. This will change with the enactment of Modernization of Cosmetics Regulation Act of 2022, which empowers the US Food and Drug Administration to require manufacturers to disclose many, but not all, fragrance allergens on the labels of cosmetic and topical products.²⁶

For all these reasons, patients should be advised to use a medical database to choose safe alternative products instead of trying to read labels themselves to avoid fragrance. The American Contact Dermatitis Society’s Contact Allergen Management Program (CAMP) database (https://www.contactderm.org/resources/acds-camp) is designed to identify safe alternative products for patients with contact allergies. When CAMP is programmed to avoid “fragrance,” it will list only “safe” products free of all fragrances found in a comprehensive fragrance cross-reactor group.³⁰ This customizable database is available as an application that can be downloaded onto a patient’s mobile device. Fragrance-allergic patients should be encouraged to use the CAMP application or other similar applications (eg, SkinSAFE)(https://www.skinsafeproducts­.com/) to find all the products they use.

Potential Pitfalls in Fragrance Avoidance

Most physicians, even dermatologists, will not know which products on the market are fragrance free from a contact allergy standpoint. Patients should instruct their physicians to use the allergen-avoidance application of choice whenever recommending new topical products, whether prescription or nonprescription. In 2009, Nardelli and colleagues³¹ found that 10% of topical pharmaceutical products contained a total of 66 different fragrance substances.

Individuals who are allergic to fragrance also can react to fragrances used by close contacts (ie, consort dermatitis).³² Therefore, fragrance-allergic individuals who do not improve after changing their personal products should consider urging their spouses or significant others to choose their personal care products using an allergen-avoidance application. Also, physical contact with pets can cause reactions, and the use of a fragrance-free pet shampoo is recommended. Additionally, allergic individuals who are providing care for small children should select fragrance-free products for them.

Some of the most heavily fragranced products on the market are found at hair salons. One exposure to an allergen often can keep patients broken out for up to 4 weeks and occasionally longer, a typical frequency for salon visits—even if the individual is taking great care to avoid fragrance at home. Patients should be instructed to bring their own shampoo, conditioner, and styling products to the salon. These patients also should bring safe moisturizer and nail polish remover for manicures. Additionally, aromatherapy used in most massages can cause flare-ups, and it is recommended that allergic patients purchase fragrance-free massage oil to bring to their sessions.

Fragranced soaps and cleansers can leave a residue on the palmar surface of the hands and fingers. This residue may not meet the threshold for causing a reaction on the thick skin of these surfaces, but it is sufficient to passively transfer fragrance to other more sensitive areas, such as the eyelids. Passive transfer of fragrance can be a major source of allergen exposure and should not be overlooked. Allergic patients should be instructed to bring safe hand cleansers to friends’ houses, restaurants, or work.

Airborne fragrances in a patient’s environment can reach sufficient concentration to cause airborne contact dermatitis. In one case report, an Uber driver developed facial airborne ACD from a fragrance diffuser in his vehicle and his condition improved upon removing the diffuser.³³ Therefore, patients should be instructed to avoid fragranced diffusers, scented candles, room deodorizers, incense, and wax melts.

Fragrance in household products also can be an issue. Fragrance-allergic patients should be instructed to choose fragrance-free cleaning products and to avoid fragranced wipes on surfaces that may be touched. In addition, they should be instructed to use fragrance-free laundry products. It is not required for household products in the United States to list their ingredients, and the majority do not have complete ingredient lists. Therefore, it is imperative that the patient use an allergen-avoidance application that identifies products that have full ingredient disclosure and are free of fragrance.

For individuals who enjoy perfume and/or cologne, it may be possible for them to resume use of these products in some cases after their condition has fully cleared with complete fragrance avoidance. They should avoid spraying products into the air or applying them directly onto the skin and should instead dip a cotton swab into the perfume/cologne and dab a small amount onto their clothing. This technique can sometimes satisfy the patient and improve compliance.

If a patient who is allergic to fragrance does not clear after 6 weeks of complete fragrance avoidance, it is worth considering systemic contact dermatitis due to ingestion of fragrance-related substances in foods.³⁴ A large number of fragrance materials also are food flavorings. For patients allergic to a specific fragrance(s), systemic avoidance needs to be specific to the allergen, and the Flavor and Extract Manufacturers Association’s flavor ingredient library is most helpful (https://www.femaflavor.org/flavor-library). If the patient is allergic to the complex mixture BOP, a balsam-free diet can be attempted.^35,36

Final Thoughts

Dermatologists must equip themselves with the knowledge to educate fragrance-allergic patients on proper avoidance. The multifaceted nature of fragrance avoidance requires a personalized approach, combining label scrutiny, utilization of a safe-product application, and tailored recommendations for specific situations. By guiding patients through these complexities, dermatologists can empower patients to manage their fragrance allergy and enhance their quality of life.

Vulvar dermatoses continue to be an overlooked aspect of medical care, highlighting the necessity for enhanced diagnosis and management of these conditions. Here, we address recent advancements in understanding vulvar inflammatory dermatoses other than lichen sclerosus (LS), which was discussed in a prior Guest Editorial¹—specifically vulvovaginal lichen planus (VLP), plasma cell vulvitis (PCV), and vulvar lichen simplex chronicus (LSC).

Vulvar Inflammatory Skin Disease and Quality of Life

There is an increased awareness of the impact vulvar skin disease has on quality of life and its association with anxiety and depression.^2-5 Evaluating the burden of vulvar dermatoses remains an active area of research due to its significance in monitoring disease progression and assessing therapeutic effectiveness. Despite the existence of various dermatology quality-of-life assessment tools, many fail to adequately capture the unique impacts of vulvovaginal diseases, such as sexual or urinary dysfunction. The vulvar quality of life index, which was developed and validated by Saunderson et al⁶ in 2020, consists of a 15-item questionnaire spanning 4 domains: symptoms, anxiety, activities of daily living, and sexuality. This tool has been utilized to gauge treatment response in vulvar conditions and to compare disease burden of various vulvar dermatoses.^7,8 Moving forward, integrating this tool into clinical studies on vulvar skin disease holds promise for enhancing our understanding and management of these conditions.

Vulvovaginal Lichen Planus

Vulvovaginal lichen planus is unique among several prevalent vulvar inflammatory skin disorders encountered by dermatologists—primarily due to its erosive form, which can extend to the vagina, resulting in noninfectious vaginitis and potential vaginal stenosis.^9,10 Managing VLP poses a notable challenge, even when it is confined to the vulva, as it often proves resistant to topical therapies.¹¹

Evaluation for Vaginal Mucosal Disease—In contrast to LS, which typically spares the vaginal mucosa, VLP can involve mucosal sites.^9,12,13 Therefore, it is imperative that all patients with a diagnosis of vulvar VLP undergo evaluation for potential vaginal involvement through speculum examination, wet mount, or vaginal biopsy. Strategies to manage vaginal involvement include use of dilators and pelvic floor physical therapy, lysis of adhesions (if present), topical estrogen, and intravaginal corticosteroids—all tailored to the severity of the disease.^9,11,14

Management of VLP—Approximately 20% to 40% of patients with VLP may require systemic therapy for disease management, including those who are younger, those of non-White ethnicity, and those presenting with vulvar pruritus.¹¹ Various systemic immunosuppressants have been used for VLP, with a recent retrospective study revealing similar response rates for both methotrexate and mycophenolate mofetil in the treatment of VLP.¹⁵ Another retrospective study found hydroxychloroquine to be safe and effective for VLP but noted a slow onset of action, with approximately 70% responding at 9 months following initiation of therapy.¹⁶

Recent attention has shifted to use of targeted therapies for VLP. For instance, apremilast has shown efficacy in a single-center, nonrandomized, open-label pilot study.¹⁷ Tildrakizumab, an IL-23 inhibitor, demonstrated efficacy in a case series involving 24 patients with VLP.¹⁸ Moreover, recent case reports and series have highlighted the potential of oral Janus kinase (JAK) ­inhibitors, such as tofacitinib, in VLP treatment.¹⁹ Clinical trials are ongoing to evaluate the safety and efficacy of topical ruxolitinib and deucravacitinib (a tyrosine kinase 2 inhibitor) in VLP.^20-22 Systemic therapies for VLP currently are used off label, emphasizing the need for future randomized controlled trials to ascertain the optimal therapies for patients affected by erosive and nonerosive forms of this disease.

Plasma Cell Vulvitis

Plasma cell vulvitis is a chronic inflammatory disorder with an unknown etiology that some consider to be a variant of VLP.²³ Others have observed an overlap with desquamative inflammatory vaginitis, categorizing PCV as a hemorrhagic vestibulovaginitis.²⁴ Although its classification as a distinct entity remains under scrutiny, studies indicate a predilection for the nonkeratinized or partially keratinized vulva. A systematic review outlining common clinical findings reported that the most common anatomic sites included the vulvar vestibule, periurethral area, and labia minora.²³ Additionally, reports have emphasized the association between PCV and other inflammatory vulvar skin conditions, including LS.²⁵

Clinical Variants of PCV—A retrospective review proposed 2 clinical phenotypes for PCV: (1) primary non–lichen-associated PCV and (2) secondary lichen-associated PCV, which is linked to LS.²⁶ The primary form is reported to be restricted to the vestibule, and the authors considered this a vulvar counterpart of atrophic vaginitis due to estrogen deficiency (now known as postmenopausal genitourinary syndrome). The secondary phenotype more commonly involved the vestibular and extravestibular epithelium.²⁶

Management of PCV—Recognizing PCV in the context of LS may be important for identifying comorbid conditions and guiding treatment. However, evidence-based guidelines for PCV treatment are lacking. Commonly reported treatment modalities include clobetasol ointment 0.05% and tacrolimus ointment 0.1%.²³ Successful treatment with hydrocortisone suppositories alternating with estradiol vaginal cream was reported in a recent case series.²⁷ Crisaborole also has been reported as a treatment in 1 case of PCV.²⁸ A recent case report found abrocitinib to be effective for the treatment of plasma cell balanitis in the setting of male genital LS,²⁹ but there are limited data on the use of JAK inhibitors for PCV. Further research is necessary to ascertain the incidence, prevalence, clinical subtypes, and optimal management strategies for PCV to effectively treat patients with this condition.

Vulvar LSC

Similar to extragenital LSC, the evaluation of vulvar LSC should prioritize identification of underlying ­etiologies that contribute to the itch-scratch cycle, which may include psoriasis, atopic dermatitis, neurologic conditions, and allergic or irritant contact dermatitis.^30,31 Although treatment strategies may vary based on underlying ­conditions, we will concentrate on updates in managing vulvar LSC and pruritus associated with an atopic ­diathesis or resulting from chronic contact dermatitis, which is prevalent in vulvar skin areas. Finally, we highlight some emerging vulvar allergens for consideration in clinical practice.

Management of Vulvar LSC—The advent of targeted therapies, including biologics and small-molecule inhibitors, for atopic dermatitis and prurigo nodularis in recent years presents potential options for treatment of individuals with vulvar LSC. However, studies on the use of these therapies specifically for vulvar LSC are limited, necessitating thorough discussions with patients. Given the debilitating nature of vulvar pruritus that may be seen in vulvar LSC and the potential inadequacy of topical steroids as monotherapy, systemic therapies may serve as alternative options for patients with refractory disease.³⁰

Dupilumab, a dual inhibitor of IL-4 and IL-13 signaling, has shown rapid and sustained disease improvement in patients with atopic dermatitis, prurigo nodularis, and pruritus.^32,33 Although data on its role in managing vulvar LSC are scarce, a recent case series reported improvement of vulvar pruritus with dupilumab.³⁴ Similarly, tralokinumab, an IL-13 inhibitor approved by the US Food and Drug Administration (FDA) for atopic dermatitis, has shown efficacy in prurigo nodularis³⁵ and may benefit patients with vulvar LSC, though studies on cutaneous outcomes in those with genital involvement specifically are lacking. Oral JAK inhibitors such as upadacitinib and abrocitinib—both FDA approved for atopic dermatitis—have demonstrated efficacy in treating LSC and itch, potentially serving as management options for vulvar LSC in cases resistant to topical steroids or in which steroid atrophy or other steroid adverse effects may preclude continued use of such agents.^36,37 Finally, IL-31 inhibitors such as nemolizumab, which reduced the signs and symptoms of prurigo nodularis in a recent phase 3 clinical trial, may hold utility in addressing vulvar LSC and associated pruritus.³⁸

The topical JAK inhibitor ruxolitinib, which is FDA approved for atopic dermatitis and vitiligo, holds promise for managing LSC on vulvar skin while mitigating the risk for steroid-induced atrophy.³⁹ Additionally, nonsteroidal topicals including roflumilast cream 0.3% and tapinarof cream 1%, both FDA approved for psoriasis, are being evaluated in studies for their safety and efficacy in atopic dermatitis.^40,41 These agents may have the potential to improve signs and symptoms of vulvar LSC, but further studies are necessary.

Vulvar Allergens and LSC—When assessing patients with vulvar LSC, it is crucial to recognize that allergic contact dermatitis is a common primary vulvar dermatosis but can coexist with other vulvar dermatoses such as LS.^13,30 The vulvar skin’s susceptibly to allergic contact dermatitis is attributed to factors such as a higher ratio of antigen-presenting cells in the vulvar skin, the nonkeratinized nature of certain sites, and frequent contact with potential allergens.^42,43 Therefore, incorporating patch testing into the diagnostic process should be considered when evaluating patients with vulvar skin conditions.⁴³

A systemic review identified multiple vulvar allergens, including metals, topical medicaments, fragrances, preservatives, cosmetic constituents, and rubber components that led to contact dermatitis.⁴⁴ Moreover, a recent analysis of topical preparations recommended by women with LS on social media found a high prevalence of known vulvar allergens in these agents, including botanical extracts/spices.⁴⁵ Personal-care wipes marketed for vulvar care and hygiene are known to contain a variety of allergens, with a recent study finding numerous allergens in commercially available wipes including fragrances, scented botanicals in the form of essences, oils, fruit juices, and vitamin E.⁴⁶ These findings underscore the importance of considering potential allergens when caring for patients with vulvar LSC and counseling patients about the potential allergens in many commercially available products that may be recommended on social media sites or by other sources.

Final Thoughts

Vulvar inflammatory dermatoses are becoming increasingly recognized, and there is a need to develop more effective diagnostic and treatment approaches. Recent literature has shed light on some of the challenges in the management of VLP, particularly its resistance to topical therapies and the importance of assessing and managing both cutaneous and vaginal involvement. Efforts have been made to refine the classification of PCV, with studies suggesting a variant that coexists with LS. Although evidence for vulvar-specific treatment of LSC is limited, the emergence of biologics and small-molecule inhibitors that are FDA approved for atopic dermatitis and prurigo nodularis offer promise for certain cases of vulvar LSC and vulvar pruritus. Moreover, recent developments in steroid-sparing topical agents warrant further investigation for their potential efficacy in treating vulvar LSC and possibly other vulvar inflammatory conditions in the future.

Vulvar dermatoses continue to be an overlooked aspect of medical care, highlighting the necessity for enhanced diagnosis and management of these conditions. Here, we address recent advancements in understanding vulvar inflammatory dermatoses other than lichen sclerosus (LS), which was discussed in a prior Guest Editorial¹—specifically vulvovaginal lichen planus (VLP), plasma cell vulvitis (PCV), and vulvar lichen simplex chronicus (LSC).

Vulvar Inflammatory Skin Disease and Quality of Life

There is an increased awareness of the impact vulvar skin disease has on quality of life and its association with anxiety and depression.^2-5 Evaluating the burden of vulvar dermatoses remains an active area of research due to its significance in monitoring disease progression and assessing therapeutic effectiveness. Despite the existence of various dermatology quality-of-life assessment tools, many fail to adequately capture the unique impacts of vulvovaginal diseases, such as sexual or urinary dysfunction. The vulvar quality of life index, which was developed and validated by Saunderson et al⁶ in 2020, consists of a 15-item questionnaire spanning 4 domains: symptoms, anxiety, activities of daily living, and sexuality. This tool has been utilized to gauge treatment response in vulvar conditions and to compare disease burden of various vulvar dermatoses.^7,8 Moving forward, integrating this tool into clinical studies on vulvar skin disease holds promise for enhancing our understanding and management of these conditions.

Vulvovaginal Lichen Planus

Vulvovaginal lichen planus is unique among several prevalent vulvar inflammatory skin disorders encountered by dermatologists—primarily due to its erosive form, which can extend to the vagina, resulting in noninfectious vaginitis and potential vaginal stenosis.^9,10 Managing VLP poses a notable challenge, even when it is confined to the vulva, as it often proves resistant to topical therapies.¹¹

Evaluation for Vaginal Mucosal Disease—In contrast to LS, which typically spares the vaginal mucosa, VLP can involve mucosal sites.^9,12,13 Therefore, it is imperative that all patients with a diagnosis of vulvar VLP undergo evaluation for potential vaginal involvement through speculum examination, wet mount, or vaginal biopsy. Strategies to manage vaginal involvement include use of dilators and pelvic floor physical therapy, lysis of adhesions (if present), topical estrogen, and intravaginal corticosteroids—all tailored to the severity of the disease.^9,11,14

Management of VLP—Approximately 20% to 40% of patients with VLP may require systemic therapy for disease management, including those who are younger, those of non-White ethnicity, and those presenting with vulvar pruritus.¹¹ Various systemic immunosuppressants have been used for VLP, with a recent retrospective study revealing similar response rates for both methotrexate and mycophenolate mofetil in the treatment of VLP.¹⁵ Another retrospective study found hydroxychloroquine to be safe and effective for VLP but noted a slow onset of action, with approximately 70% responding at 9 months following initiation of therapy.¹⁶

Recent attention has shifted to use of targeted therapies for VLP. For instance, apremilast has shown efficacy in a single-center, nonrandomized, open-label pilot study.¹⁷ Tildrakizumab, an IL-23 inhibitor, demonstrated efficacy in a case series involving 24 patients with VLP.¹⁸ Moreover, recent case reports and series have highlighted the potential of oral Janus kinase (JAK) ­inhibitors, such as tofacitinib, in VLP treatment.¹⁹ Clinical trials are ongoing to evaluate the safety and efficacy of topical ruxolitinib and deucravacitinib (a tyrosine kinase 2 inhibitor) in VLP.^20-22 Systemic therapies for VLP currently are used off label, emphasizing the need for future randomized controlled trials to ascertain the optimal therapies for patients affected by erosive and nonerosive forms of this disease.

Plasma Cell Vulvitis

Plasma cell vulvitis is a chronic inflammatory disorder with an unknown etiology that some consider to be a variant of VLP.²³ Others have observed an overlap with desquamative inflammatory vaginitis, categorizing PCV as a hemorrhagic vestibulovaginitis.²⁴ Although its classification as a distinct entity remains under scrutiny, studies indicate a predilection for the nonkeratinized or partially keratinized vulva. A systematic review outlining common clinical findings reported that the most common anatomic sites included the vulvar vestibule, periurethral area, and labia minora.²³ Additionally, reports have emphasized the association between PCV and other inflammatory vulvar skin conditions, including LS.²⁵

Clinical Variants of PCV—A retrospective review proposed 2 clinical phenotypes for PCV: (1) primary non–lichen-associated PCV and (2) secondary lichen-associated PCV, which is linked to LS.²⁶ The primary form is reported to be restricted to the vestibule, and the authors considered this a vulvar counterpart of atrophic vaginitis due to estrogen deficiency (now known as postmenopausal genitourinary syndrome). The secondary phenotype more commonly involved the vestibular and extravestibular epithelium.²⁶

Management of PCV—Recognizing PCV in the context of LS may be important for identifying comorbid conditions and guiding treatment. However, evidence-based guidelines for PCV treatment are lacking. Commonly reported treatment modalities include clobetasol ointment 0.05% and tacrolimus ointment 0.1%.²³ Successful treatment with hydrocortisone suppositories alternating with estradiol vaginal cream was reported in a recent case series.²⁷ Crisaborole also has been reported as a treatment in 1 case of PCV.²⁸ A recent case report found abrocitinib to be effective for the treatment of plasma cell balanitis in the setting of male genital LS,²⁹ but there are limited data on the use of JAK inhibitors for PCV. Further research is necessary to ascertain the incidence, prevalence, clinical subtypes, and optimal management strategies for PCV to effectively treat patients with this condition.

Vulvar LSC

Similar to extragenital LSC, the evaluation of vulvar LSC should prioritize identification of underlying ­etiologies that contribute to the itch-scratch cycle, which may include psoriasis, atopic dermatitis, neurologic conditions, and allergic or irritant contact dermatitis.^30,31 Although treatment strategies may vary based on underlying ­conditions, we will concentrate on updates in managing vulvar LSC and pruritus associated with an atopic ­diathesis or resulting from chronic contact dermatitis, which is prevalent in vulvar skin areas. Finally, we highlight some emerging vulvar allergens for consideration in clinical practice.

Management of Vulvar LSC—The advent of targeted therapies, including biologics and small-molecule inhibitors, for atopic dermatitis and prurigo nodularis in recent years presents potential options for treatment of individuals with vulvar LSC. However, studies on the use of these therapies specifically for vulvar LSC are limited, necessitating thorough discussions with patients. Given the debilitating nature of vulvar pruritus that may be seen in vulvar LSC and the potential inadequacy of topical steroids as monotherapy, systemic therapies may serve as alternative options for patients with refractory disease.³⁰

Dupilumab, a dual inhibitor of IL-4 and IL-13 signaling, has shown rapid and sustained disease improvement in patients with atopic dermatitis, prurigo nodularis, and pruritus.^32,33 Although data on its role in managing vulvar LSC are scarce, a recent case series reported improvement of vulvar pruritus with dupilumab.³⁴ Similarly, tralokinumab, an IL-13 inhibitor approved by the US Food and Drug Administration (FDA) for atopic dermatitis, has shown efficacy in prurigo nodularis³⁵ and may benefit patients with vulvar LSC, though studies on cutaneous outcomes in those with genital involvement specifically are lacking. Oral JAK inhibitors such as upadacitinib and abrocitinib—both FDA approved for atopic dermatitis—have demonstrated efficacy in treating LSC and itch, potentially serving as management options for vulvar LSC in cases resistant to topical steroids or in which steroid atrophy or other steroid adverse effects may preclude continued use of such agents.^36,37 Finally, IL-31 inhibitors such as nemolizumab, which reduced the signs and symptoms of prurigo nodularis in a recent phase 3 clinical trial, may hold utility in addressing vulvar LSC and associated pruritus.³⁸

The topical JAK inhibitor ruxolitinib, which is FDA approved for atopic dermatitis and vitiligo, holds promise for managing LSC on vulvar skin while mitigating the risk for steroid-induced atrophy.³⁹ Additionally, nonsteroidal topicals including roflumilast cream 0.3% and tapinarof cream 1%, both FDA approved for psoriasis, are being evaluated in studies for their safety and efficacy in atopic dermatitis.^40,41 These agents may have the potential to improve signs and symptoms of vulvar LSC, but further studies are necessary.

Vulvar Allergens and LSC—When assessing patients with vulvar LSC, it is crucial to recognize that allergic contact dermatitis is a common primary vulvar dermatosis but can coexist with other vulvar dermatoses such as LS.^13,30 The vulvar skin’s susceptibly to allergic contact dermatitis is attributed to factors such as a higher ratio of antigen-presenting cells in the vulvar skin, the nonkeratinized nature of certain sites, and frequent contact with potential allergens.^42,43 Therefore, incorporating patch testing into the diagnostic process should be considered when evaluating patients with vulvar skin conditions.⁴³

A systemic review identified multiple vulvar allergens, including metals, topical medicaments, fragrances, preservatives, cosmetic constituents, and rubber components that led to contact dermatitis.⁴⁴ Moreover, a recent analysis of topical preparations recommended by women with LS on social media found a high prevalence of known vulvar allergens in these agents, including botanical extracts/spices.⁴⁵ Personal-care wipes marketed for vulvar care and hygiene are known to contain a variety of allergens, with a recent study finding numerous allergens in commercially available wipes including fragrances, scented botanicals in the form of essences, oils, fruit juices, and vitamin E.⁴⁶ These findings underscore the importance of considering potential allergens when caring for patients with vulvar LSC and counseling patients about the potential allergens in many commercially available products that may be recommended on social media sites or by other sources.

Final Thoughts

Vulvar inflammatory dermatoses are becoming increasingly recognized, and there is a need to develop more effective diagnostic and treatment approaches. Recent literature has shed light on some of the challenges in the management of VLP, particularly its resistance to topical therapies and the importance of assessing and managing both cutaneous and vaginal involvement. Efforts have been made to refine the classification of PCV, with studies suggesting a variant that coexists with LS. Although evidence for vulvar-specific treatment of LSC is limited, the emergence of biologics and small-molecule inhibitors that are FDA approved for atopic dermatitis and prurigo nodularis offer promise for certain cases of vulvar LSC and vulvar pruritus. Moreover, recent developments in steroid-sparing topical agents warrant further investigation for their potential efficacy in treating vulvar LSC and possibly other vulvar inflammatory conditions in the future.

Vulvar dermatoses continue to be an overlooked aspect of medical care, highlighting the necessity for enhanced diagnosis and management of these conditions. Here, we address recent advancements in understanding vulvar inflammatory dermatoses other than lichen sclerosus (LS), which was discussed in a prior Guest Editorial¹—specifically vulvovaginal lichen planus (VLP), plasma cell vulvitis (PCV), and vulvar lichen simplex chronicus (LSC).

Vulvar Inflammatory Skin Disease and Quality of Life

There is an increased awareness of the impact vulvar skin disease has on quality of life and its association with anxiety and depression.^2-5 Evaluating the burden of vulvar dermatoses remains an active area of research due to its significance in monitoring disease progression and assessing therapeutic effectiveness. Despite the existence of various dermatology quality-of-life assessment tools, many fail to adequately capture the unique impacts of vulvovaginal diseases, such as sexual or urinary dysfunction. The vulvar quality of life index, which was developed and validated by Saunderson et al⁶ in 2020, consists of a 15-item questionnaire spanning 4 domains: symptoms, anxiety, activities of daily living, and sexuality. This tool has been utilized to gauge treatment response in vulvar conditions and to compare disease burden of various vulvar dermatoses.^7,8 Moving forward, integrating this tool into clinical studies on vulvar skin disease holds promise for enhancing our understanding and management of these conditions.

Vulvovaginal Lichen Planus

Vulvovaginal lichen planus is unique among several prevalent vulvar inflammatory skin disorders encountered by dermatologists—primarily due to its erosive form, which can extend to the vagina, resulting in noninfectious vaginitis and potential vaginal stenosis.^9,10 Managing VLP poses a notable challenge, even when it is confined to the vulva, as it often proves resistant to topical therapies.¹¹

Evaluation for Vaginal Mucosal Disease—In contrast to LS, which typically spares the vaginal mucosa, VLP can involve mucosal sites.^9,12,13 Therefore, it is imperative that all patients with a diagnosis of vulvar VLP undergo evaluation for potential vaginal involvement through speculum examination, wet mount, or vaginal biopsy. Strategies to manage vaginal involvement include use of dilators and pelvic floor physical therapy, lysis of adhesions (if present), topical estrogen, and intravaginal corticosteroids—all tailored to the severity of the disease.^9,11,14

Management of VLP—Approximately 20% to 40% of patients with VLP may require systemic therapy for disease management, including those who are younger, those of non-White ethnicity, and those presenting with vulvar pruritus.¹¹ Various systemic immunosuppressants have been used for VLP, with a recent retrospective study revealing similar response rates for both methotrexate and mycophenolate mofetil in the treatment of VLP.¹⁵ Another retrospective study found hydroxychloroquine to be safe and effective for VLP but noted a slow onset of action, with approximately 70% responding at 9 months following initiation of therapy.¹⁶

Recent attention has shifted to use of targeted therapies for VLP. For instance, apremilast has shown efficacy in a single-center, nonrandomized, open-label pilot study.¹⁷ Tildrakizumab, an IL-23 inhibitor, demonstrated efficacy in a case series involving 24 patients with VLP.¹⁸ Moreover, recent case reports and series have highlighted the potential of oral Janus kinase (JAK) ­inhibitors, such as tofacitinib, in VLP treatment.¹⁹ Clinical trials are ongoing to evaluate the safety and efficacy of topical ruxolitinib and deucravacitinib (a tyrosine kinase 2 inhibitor) in VLP.^20-22 Systemic therapies for VLP currently are used off label, emphasizing the need for future randomized controlled trials to ascertain the optimal therapies for patients affected by erosive and nonerosive forms of this disease.

Plasma Cell Vulvitis

Plasma cell vulvitis is a chronic inflammatory disorder with an unknown etiology that some consider to be a variant of VLP.²³ Others have observed an overlap with desquamative inflammatory vaginitis, categorizing PCV as a hemorrhagic vestibulovaginitis.²⁴ Although its classification as a distinct entity remains under scrutiny, studies indicate a predilection for the nonkeratinized or partially keratinized vulva. A systematic review outlining common clinical findings reported that the most common anatomic sites included the vulvar vestibule, periurethral area, and labia minora.²³ Additionally, reports have emphasized the association between PCV and other inflammatory vulvar skin conditions, including LS.²⁵

Clinical Variants of PCV—A retrospective review proposed 2 clinical phenotypes for PCV: (1) primary non–lichen-associated PCV and (2) secondary lichen-associated PCV, which is linked to LS.²⁶ The primary form is reported to be restricted to the vestibule, and the authors considered this a vulvar counterpart of atrophic vaginitis due to estrogen deficiency (now known as postmenopausal genitourinary syndrome). The secondary phenotype more commonly involved the vestibular and extravestibular epithelium.²⁶

Management of PCV—Recognizing PCV in the context of LS may be important for identifying comorbid conditions and guiding treatment. However, evidence-based guidelines for PCV treatment are lacking. Commonly reported treatment modalities include clobetasol ointment 0.05% and tacrolimus ointment 0.1%.²³ Successful treatment with hydrocortisone suppositories alternating with estradiol vaginal cream was reported in a recent case series.²⁷ Crisaborole also has been reported as a treatment in 1 case of PCV.²⁸ A recent case report found abrocitinib to be effective for the treatment of plasma cell balanitis in the setting of male genital LS,²⁹ but there are limited data on the use of JAK inhibitors for PCV. Further research is necessary to ascertain the incidence, prevalence, clinical subtypes, and optimal management strategies for PCV to effectively treat patients with this condition.

Vulvar LSC

Similar to extragenital LSC, the evaluation of vulvar LSC should prioritize identification of underlying ­etiologies that contribute to the itch-scratch cycle, which may include psoriasis, atopic dermatitis, neurologic conditions, and allergic or irritant contact dermatitis.^30,31 Although treatment strategies may vary based on underlying ­conditions, we will concentrate on updates in managing vulvar LSC and pruritus associated with an atopic ­diathesis or resulting from chronic contact dermatitis, which is prevalent in vulvar skin areas. Finally, we highlight some emerging vulvar allergens for consideration in clinical practice.

Management of Vulvar LSC—The advent of targeted therapies, including biologics and small-molecule inhibitors, for atopic dermatitis and prurigo nodularis in recent years presents potential options for treatment of individuals with vulvar LSC. However, studies on the use of these therapies specifically for vulvar LSC are limited, necessitating thorough discussions with patients. Given the debilitating nature of vulvar pruritus that may be seen in vulvar LSC and the potential inadequacy of topical steroids as monotherapy, systemic therapies may serve as alternative options for patients with refractory disease.³⁰

Dupilumab, a dual inhibitor of IL-4 and IL-13 signaling, has shown rapid and sustained disease improvement in patients with atopic dermatitis, prurigo nodularis, and pruritus.^32,33 Although data on its role in managing vulvar LSC are scarce, a recent case series reported improvement of vulvar pruritus with dupilumab.³⁴ Similarly, tralokinumab, an IL-13 inhibitor approved by the US Food and Drug Administration (FDA) for atopic dermatitis, has shown efficacy in prurigo nodularis³⁵ and may benefit patients with vulvar LSC, though studies on cutaneous outcomes in those with genital involvement specifically are lacking. Oral JAK inhibitors such as upadacitinib and abrocitinib—both FDA approved for atopic dermatitis—have demonstrated efficacy in treating LSC and itch, potentially serving as management options for vulvar LSC in cases resistant to topical steroids or in which steroid atrophy or other steroid adverse effects may preclude continued use of such agents.^36,37 Finally, IL-31 inhibitors such as nemolizumab, which reduced the signs and symptoms of prurigo nodularis in a recent phase 3 clinical trial, may hold utility in addressing vulvar LSC and associated pruritus.³⁸

The topical JAK inhibitor ruxolitinib, which is FDA approved for atopic dermatitis and vitiligo, holds promise for managing LSC on vulvar skin while mitigating the risk for steroid-induced atrophy.³⁹ Additionally, nonsteroidal topicals including roflumilast cream 0.3% and tapinarof cream 1%, both FDA approved for psoriasis, are being evaluated in studies for their safety and efficacy in atopic dermatitis.^40,41 These agents may have the potential to improve signs and symptoms of vulvar LSC, but further studies are necessary.

Vulvar Allergens and LSC—When assessing patients with vulvar LSC, it is crucial to recognize that allergic contact dermatitis is a common primary vulvar dermatosis but can coexist with other vulvar dermatoses such as LS.^13,30 The vulvar skin’s susceptibly to allergic contact dermatitis is attributed to factors such as a higher ratio of antigen-presenting cells in the vulvar skin, the nonkeratinized nature of certain sites, and frequent contact with potential allergens.^42,43 Therefore, incorporating patch testing into the diagnostic process should be considered when evaluating patients with vulvar skin conditions.⁴³

A systemic review identified multiple vulvar allergens, including metals, topical medicaments, fragrances, preservatives, cosmetic constituents, and rubber components that led to contact dermatitis.⁴⁴ Moreover, a recent analysis of topical preparations recommended by women with LS on social media found a high prevalence of known vulvar allergens in these agents, including botanical extracts/spices.⁴⁵ Personal-care wipes marketed for vulvar care and hygiene are known to contain a variety of allergens, with a recent study finding numerous allergens in commercially available wipes including fragrances, scented botanicals in the form of essences, oils, fruit juices, and vitamin E.⁴⁶ These findings underscore the importance of considering potential allergens when caring for patients with vulvar LSC and counseling patients about the potential allergens in many commercially available products that may be recommended on social media sites or by other sources.

Final Thoughts

Vulvar inflammatory dermatoses are becoming increasingly recognized, and there is a need to develop more effective diagnostic and treatment approaches. Recent literature has shed light on some of the challenges in the management of VLP, particularly its resistance to topical therapies and the importance of assessing and managing both cutaneous and vaginal involvement. Efforts have been made to refine the classification of PCV, with studies suggesting a variant that coexists with LS. Although evidence for vulvar-specific treatment of LSC is limited, the emergence of biologics and small-molecule inhibitors that are FDA approved for atopic dermatitis and prurigo nodularis offer promise for certain cases of vulvar LSC and vulvar pruritus. Moreover, recent developments in steroid-sparing topical agents warrant further investigation for their potential efficacy in treating vulvar LSC and possibly other vulvar inflammatory conditions in the future.

A surprising therapy is showing promise for chronic pain, vision loss, and muscle recovery, among other conditions.

It’s not a pill, an injection, or surgery.

It’s light.

Yes, light. The thing that appears when you open the curtains, flip a switch, or strike a match.

Light illuminates our world and helps us see. Early human trials suggest it may help us heal in new ways as well.

“Phototherapy is still in its infancy,” said Mohab Ibrahim, MD, PhD, a professor of anesthesiology at the University of Arizona, Tucson, who studies the effects of light on chronic pain. “There are so many questions, a lot of things we do not understand yet. But that’s where it gets interesting. What we can conclude is that different colors of light can influence different biological functions.”

This growing field goes by several names. Light therapy. Phototherapy. Photobiomodulation.

It leverages known effects of light on human health — such as skin exposure to ultraviolet light producing vitamin D or blue light’s power to regulate human body clocks — to take light as medicine in surprising new directions.
 

New Science, Old Idea

The science is young, but the concept of using light to restore health is thousands of years old.

Hippocrates prescribed sunbathing to patients at his medical center on the Greek island of Kos in 400 BC. Florence Nightingale promoted sunshine, along with fresh air, as prerequisites for recovery in hospitals during the Civil War. A Danish doctor, Niels Finsen, won the Nobel Prize in 1903 for developing ultraviolet lamps to treat a tuberculosis-related skin condition. And worried parents of the 1930s sat their babies in front of mercury arc lamps, bought at the drugstore, to discourage rickets.

Today, light therapy is widely used in medicine for newborn jaundice, psoriasis, and seasonal affective disorder and in light-activated treatments for cancers of the esophagus and lungs, as well as for actinic keratosis, a skin condition that can lead to cancer.

But researchers are finding that light may be capable of far more, particularly in conditions with few treatment options or where available drugs have unwanted side effects.
 

How Red Light Could Restore Vision

When 100 midlife and older adults, aged 53-91, with the dry form of age-related macular degeneration (AMD) were treated with an experimental red-light therapy or a sham therapy, the light treatment group showed signs of improved vision, as measured on a standard eye chart.

Volunteers received the therapy three times a week for 3-5 weeks, every 4 months for 2 years. By the study’s end, 67% of those treated with light could read an additional five letters on the chart, and 20% could read 10 or more. About 7% developed geographic atrophy — the most advanced, vision-threatening stage of dry AMD — compared with 24% in the sham group.

The study, called LIGHTSITE III, was conducted at 10 ophthalmology centers across the United States. The device they used — the Valeda Light Delivery System from medical device company LumiThera — is available in Europe and now being reviewed by the Food and Drug Administration (FDA).

courtesy LumiThera

Exposure to red light at the wavelengths used in the study likely revitalizes failing mitochondria — the power plants inside cells — so they produce more energy, the researchers say.

“This is the first therapy for dry AMD that’s actually shown a benefit in improving vision,” said study coauthor Richard Rosen, MD, chair of ophthalmology at the Icahn School of Medicine at Mount Sinai and chief of Retinal Services at the New York Eye and Ear Infirmary in New York City. “Supplements called AREDS can reduce progression, and in wet AMD we can improve vision loss with injections. But in dry AMD, none of the treatments studied in the past have improved it.”

AMD develops when the eyes can’t break down natural by-products, which glom together as clumps of protein called drusen. Drusen can lodge under the retina, eventually damaging tissue.

“Retinal epithelial cells, a single layer of cells that cares for the photoreceptors in the eyes, are there for life,” Dr. Rosen said. “They have a tremendous capacity to repair themselves, but things [such as aging and smoking] get in the way.”

“I’m proposing,” Dr. Rosen said, “that by boosting energy levels in cells [with red light], we’re improving normal repair mechanisms.”

Lab studies support this idea.

In a 2017 mouse study from the University College London Institute of Ophthalmology in England, retinal function improved by 25% in old mice exposed to red light. And a 2019 study from the Ophthalmological Research Foundation, Oviedo, Spain, found that exposure to blue light harmed the mitochondria in retina cells, while red light somewhat counteracted the losses.

If cleared by the FDA — which the company anticipated could happen in 2024 — LumiThera’s light delivery device will likely be most useful in the beginning stages of dry AMD, Dr. Rosen said. “I think treatment of early dry AMD will be huge.”

Eventually, light therapy may also be valuable in treating or managing glaucoma and diabetic retinopathy.

For now, Dr. Rosen recommended that clinicians and consumers with AMD skip over-the-counter (OTC) red-light therapy devices currently on the market.

“We don’t know what kind of light the devices produce,” he said. “The wavelengths can vary. The eyes are delicate. Experimenting on your own may be hazardous to your vision.”
 

Green Light for Pain Relief

On his way to the pharmacy to pick up pain relievers for a headache, Dr. Ibrahim passed Gene C. Reid Park in Tucson. Recalling how his brother eased headaches by sitting in his backyard, Dr. Ibrahim pulled over.

“Reid Park is probably one of the greenest areas of Tucson,” said Dr. Ibrahim, who also serves as medical director of the Comprehensive Center for Pain & Addiction at Banner-University Medical Center Phoenix in Arizona. “I spent a half hour or 40 minutes there, and my headache felt better.”

Being outdoors in a green space may be soothing for lots of reasons, like the quiet or the fresh air. But there’s also sunlight reflected off and shining through greenery. The experience inspired Dr. Ibrahim to take a closer look at the effects of green light on chronic pain.

In his 2021 study of 29 people with migraines, participants reported that, after daily exposure to green light for 10 weeks, the number of days per month when they had headaches fell from 7.9 to 2.4 for those who had episodic migraines and from 22.3 to 9.4 for those with chronic migraines. In another 2021 study, 21 people with fibromyalgia who had green light therapy for 10 weeks said their average, self-reported pain intensity fell from 8.4 to 4.9 on a 10-point scale used at the University of Arizona’s pain clinic.

Volunteers in both studies got their light therapy at home, switching on green LED lights while they listened to music, read a book, relaxed, or exercised for 1 or 2 hours daily. The lights were within their field of vision, but they did not look directly at them.

Dr. Ibrahim now has funding from the Department of Defense and Department of Veterans Affairs to find out why green light alters pain perception.

“What we know is that the visual system is connected to certain areas of the brain that also modulate pain,” he said. “We are trying to understand the connection.”

Padma Gulur, MD, a professor of anesthesiology and population health and director of Pain Management Strategy and Opioid Surveillance at Duke University, Durham, North Carolina, saw similar results in a 2023 study of 45 people with fibromyalgia. But instead of using a light source, volunteers wore glasses with clear, green, or blue lenses for 4 hours a day.

After 2 weeks, 33% in the green lens group reduced their use of opioids by 10% or more, compared with 11% in the blue lens group and 8% who wore clear lenses. Previous studies have found green light affects levels of the feel-good brain chemical serotonin and stimulates the body’s own opioid system, the authors noted.

“Green light helps your body control and reduce pain,” Dr. Gulur said. It “seems to help with pain relief by affecting the body’s natural pain management system. This effect appears to play a crucial role in antinociception — reducing the sensation of pain; antiallodynia — preventing normal, nonpainful stimuli from causing pain; and antihyperalgesia — reducing heightened sensitivity to pain.”

Light therapy could help pain patients reduce their dose of opioids or even forgo the drugs altogether, Dr. Gulur said. “It is our hope this will become a useful adjuvant therapy to manage pain.”

In the University of Arizona studies, some patients on green-light therapy stopped their medications completely. Even if they didn’t, other benefits appeared. “They had improved quality of life, decreased depression and anxiety, and improved sleep,” Dr. Ibrahim said.

But not just any green light or green-tinted glasses will work, both researchers said. “We have found there are specific frequencies of green light that give this benefit,” Dr. Gulur said. “OTC products may not be helpful for that reason.”

While Dr. Ibrahim said it could be possible for healthcare practitioners and consumers to consult his studies and put together an inexpensive green-light device at home while carefully following the protocol participants used in the studies , it would first be a good idea for patients to talk with their family doctor or a pain specialist.

“A headache is not always just a headache,” Dr. Ibrahim said. “It could be some other abnormality that needs diagnosis and treatment. If you have long-lasting pain or pain that’s getting worse, it’s always better to discuss it with your physician.”
 

Helping Muscles Recover With Red Light

Intense exercise — whether it’s a sprint at the end of a morning run, an extra set of biceps curls, or a weekend of all-day DIY home improvement projects — can temporarily damage muscle, causing soreness, inflammation, and even swelling. Phototherapy with red and near-infrared light is widely used by sports trainers, physical therapists, and athletes to aid in recovery. It may even work better than a trendy plunge in an ice bath, according to a 2019 Texas State University review.

But how does it work? Jamie Ghigiarelli, PhD, professor of Allied Health & Kinesiology at Hofstra University in Hempstead, New York, looked closely at signs of inflammation and muscle damage in 12 athletes to find out.

Study participants overtaxed their muscles with rounds of chin-ups, high-speed sprints, and repeated bench presses. Afterward, they relaxed in a full-body red-light therapy bed or in a similar bed without lights.

The results, published in 2020, showed that blood levels of creatine kinase — an enzyme that’s elevated by muscle damage — were 18% lower 1-3 days after exercising for the light-bed group than for the control group.

“Photobiomodulation seems to help with muscle recovery,” Dr. Ghigiarelli said.

Red light at wavelengths from 650 to 820 nm can enter muscle cells, where it is absorbed by mitochondria and boosts their energy production, he said. At the time of his research, some exercise science researchers and athletes thought using light therapy before an event might also increase athletic performance, but according to Dr. Ghigiarelli, that use has not panned out.

Handheld red light and near-infrared light devices for muscle recovery are widely available, but it’s important to do your homework before buying one.

“You want to choose a device with the right energy production — the right wavelength of light, the right power — to be safe and effective,” he said.

For details, he recommends consulting a 2019 paper in The Brazilian Journal of Physical Therapy called “Clinical and scientific recommendations for the use of photobiomodulation therapy in exercise performance enhancement and post-exercise recovery: Current evidence and future directions.”

The paper, from the Laboratory of Phototherapy and Innovative Technologies in Health at the Universidade Nove de Julho in Sao Paulo, Brazil, recommends that for small muscle groups like the biceps or triceps, use red-light lasers or LED devices with a wavelength of 640 nm for red light or 950 nm for infrared light, at a power of 50-200 mW per diode for single-probe device types, at a dose of 20-60 J, given 5-10 minutes after exercise.

A version of this article appeared on Medscape.com.

A surprising therapy is showing promise for chronic pain, vision loss, and muscle recovery, among other conditions.

It’s not a pill, an injection, or surgery.

It’s light.

Yes, light. The thing that appears when you open the curtains, flip a switch, or strike a match.

Light illuminates our world and helps us see. Early human trials suggest it may help us heal in new ways as well.

“Phototherapy is still in its infancy,” said Mohab Ibrahim, MD, PhD, a professor of anesthesiology at the University of Arizona, Tucson, who studies the effects of light on chronic pain. “There are so many questions, a lot of things we do not understand yet. But that’s where it gets interesting. What we can conclude is that different colors of light can influence different biological functions.”

This growing field goes by several names. Light therapy. Phototherapy. Photobiomodulation.

It leverages known effects of light on human health — such as skin exposure to ultraviolet light producing vitamin D or blue light’s power to regulate human body clocks — to take light as medicine in surprising new directions.
 

New Science, Old Idea

The science is young, but the concept of using light to restore health is thousands of years old.

Hippocrates prescribed sunbathing to patients at his medical center on the Greek island of Kos in 400 BC. Florence Nightingale promoted sunshine, along with fresh air, as prerequisites for recovery in hospitals during the Civil War. A Danish doctor, Niels Finsen, won the Nobel Prize in 1903 for developing ultraviolet lamps to treat a tuberculosis-related skin condition. And worried parents of the 1930s sat their babies in front of mercury arc lamps, bought at the drugstore, to discourage rickets.

Today, light therapy is widely used in medicine for newborn jaundice, psoriasis, and seasonal affective disorder and in light-activated treatments for cancers of the esophagus and lungs, as well as for actinic keratosis, a skin condition that can lead to cancer.

But researchers are finding that light may be capable of far more, particularly in conditions with few treatment options or where available drugs have unwanted side effects.
 

How Red Light Could Restore Vision

When 100 midlife and older adults, aged 53-91, with the dry form of age-related macular degeneration (AMD) were treated with an experimental red-light therapy or a sham therapy, the light treatment group showed signs of improved vision, as measured on a standard eye chart.

Volunteers received the therapy three times a week for 3-5 weeks, every 4 months for 2 years. By the study’s end, 67% of those treated with light could read an additional five letters on the chart, and 20% could read 10 or more. About 7% developed geographic atrophy — the most advanced, vision-threatening stage of dry AMD — compared with 24% in the sham group.

The study, called LIGHTSITE III, was conducted at 10 ophthalmology centers across the United States. The device they used — the Valeda Light Delivery System from medical device company LumiThera — is available in Europe and now being reviewed by the Food and Drug Administration (FDA).

courtesy LumiThera

Exposure to red light at the wavelengths used in the study likely revitalizes failing mitochondria — the power plants inside cells — so they produce more energy, the researchers say.

“This is the first therapy for dry AMD that’s actually shown a benefit in improving vision,” said study coauthor Richard Rosen, MD, chair of ophthalmology at the Icahn School of Medicine at Mount Sinai and chief of Retinal Services at the New York Eye and Ear Infirmary in New York City. “Supplements called AREDS can reduce progression, and in wet AMD we can improve vision loss with injections. But in dry AMD, none of the treatments studied in the past have improved it.”

AMD develops when the eyes can’t break down natural by-products, which glom together as clumps of protein called drusen. Drusen can lodge under the retina, eventually damaging tissue.

“Retinal epithelial cells, a single layer of cells that cares for the photoreceptors in the eyes, are there for life,” Dr. Rosen said. “They have a tremendous capacity to repair themselves, but things [such as aging and smoking] get in the way.”

“I’m proposing,” Dr. Rosen said, “that by boosting energy levels in cells [with red light], we’re improving normal repair mechanisms.”

Lab studies support this idea.

In a 2017 mouse study from the University College London Institute of Ophthalmology in England, retinal function improved by 25% in old mice exposed to red light. And a 2019 study from the Ophthalmological Research Foundation, Oviedo, Spain, found that exposure to blue light harmed the mitochondria in retina cells, while red light somewhat counteracted the losses.

If cleared by the FDA — which the company anticipated could happen in 2024 — LumiThera’s light delivery device will likely be most useful in the beginning stages of dry AMD, Dr. Rosen said. “I think treatment of early dry AMD will be huge.”

Eventually, light therapy may also be valuable in treating or managing glaucoma and diabetic retinopathy.

For now, Dr. Rosen recommended that clinicians and consumers with AMD skip over-the-counter (OTC) red-light therapy devices currently on the market.

“We don’t know what kind of light the devices produce,” he said. “The wavelengths can vary. The eyes are delicate. Experimenting on your own may be hazardous to your vision.”
 

Green Light for Pain Relief

On his way to the pharmacy to pick up pain relievers for a headache, Dr. Ibrahim passed Gene C. Reid Park in Tucson. Recalling how his brother eased headaches by sitting in his backyard, Dr. Ibrahim pulled over.

“Reid Park is probably one of the greenest areas of Tucson,” said Dr. Ibrahim, who also serves as medical director of the Comprehensive Center for Pain & Addiction at Banner-University Medical Center Phoenix in Arizona. “I spent a half hour or 40 minutes there, and my headache felt better.”

Being outdoors in a green space may be soothing for lots of reasons, like the quiet or the fresh air. But there’s also sunlight reflected off and shining through greenery. The experience inspired Dr. Ibrahim to take a closer look at the effects of green light on chronic pain.

In his 2021 study of 29 people with migraines, participants reported that, after daily exposure to green light for 10 weeks, the number of days per month when they had headaches fell from 7.9 to 2.4 for those who had episodic migraines and from 22.3 to 9.4 for those with chronic migraines. In another 2021 study, 21 people with fibromyalgia who had green light therapy for 10 weeks said their average, self-reported pain intensity fell from 8.4 to 4.9 on a 10-point scale used at the University of Arizona’s pain clinic.

Volunteers in both studies got their light therapy at home, switching on green LED lights while they listened to music, read a book, relaxed, or exercised for 1 or 2 hours daily. The lights were within their field of vision, but they did not look directly at them.

Dr. Ibrahim now has funding from the Department of Defense and Department of Veterans Affairs to find out why green light alters pain perception.

“What we know is that the visual system is connected to certain areas of the brain that also modulate pain,” he said. “We are trying to understand the connection.”

Padma Gulur, MD, a professor of anesthesiology and population health and director of Pain Management Strategy and Opioid Surveillance at Duke University, Durham, North Carolina, saw similar results in a 2023 study of 45 people with fibromyalgia. But instead of using a light source, volunteers wore glasses with clear, green, or blue lenses for 4 hours a day.

After 2 weeks, 33% in the green lens group reduced their use of opioids by 10% or more, compared with 11% in the blue lens group and 8% who wore clear lenses. Previous studies have found green light affects levels of the feel-good brain chemical serotonin and stimulates the body’s own opioid system, the authors noted.

“Green light helps your body control and reduce pain,” Dr. Gulur said. It “seems to help with pain relief by affecting the body’s natural pain management system. This effect appears to play a crucial role in antinociception — reducing the sensation of pain; antiallodynia — preventing normal, nonpainful stimuli from causing pain; and antihyperalgesia — reducing heightened sensitivity to pain.”

Light therapy could help pain patients reduce their dose of opioids or even forgo the drugs altogether, Dr. Gulur said. “It is our hope this will become a useful adjuvant therapy to manage pain.”

In the University of Arizona studies, some patients on green-light therapy stopped their medications completely. Even if they didn’t, other benefits appeared. “They had improved quality of life, decreased depression and anxiety, and improved sleep,” Dr. Ibrahim said.

But not just any green light or green-tinted glasses will work, both researchers said. “We have found there are specific frequencies of green light that give this benefit,” Dr. Gulur said. “OTC products may not be helpful for that reason.”

While Dr. Ibrahim said it could be possible for healthcare practitioners and consumers to consult his studies and put together an inexpensive green-light device at home while carefully following the protocol participants used in the studies , it would first be a good idea for patients to talk with their family doctor or a pain specialist.

“A headache is not always just a headache,” Dr. Ibrahim said. “It could be some other abnormality that needs diagnosis and treatment. If you have long-lasting pain or pain that’s getting worse, it’s always better to discuss it with your physician.”
 

Helping Muscles Recover With Red Light

Intense exercise — whether it’s a sprint at the end of a morning run, an extra set of biceps curls, or a weekend of all-day DIY home improvement projects — can temporarily damage muscle, causing soreness, inflammation, and even swelling. Phototherapy with red and near-infrared light is widely used by sports trainers, physical therapists, and athletes to aid in recovery. It may even work better than a trendy plunge in an ice bath, according to a 2019 Texas State University review.

But how does it work? Jamie Ghigiarelli, PhD, professor of Allied Health & Kinesiology at Hofstra University in Hempstead, New York, looked closely at signs of inflammation and muscle damage in 12 athletes to find out.

Study participants overtaxed their muscles with rounds of chin-ups, high-speed sprints, and repeated bench presses. Afterward, they relaxed in a full-body red-light therapy bed or in a similar bed without lights.

The results, published in 2020, showed that blood levels of creatine kinase — an enzyme that’s elevated by muscle damage — were 18% lower 1-3 days after exercising for the light-bed group than for the control group.

“Photobiomodulation seems to help with muscle recovery,” Dr. Ghigiarelli said.

Red light at wavelengths from 650 to 820 nm can enter muscle cells, where it is absorbed by mitochondria and boosts their energy production, he said. At the time of his research, some exercise science researchers and athletes thought using light therapy before an event might also increase athletic performance, but according to Dr. Ghigiarelli, that use has not panned out.

Handheld red light and near-infrared light devices for muscle recovery are widely available, but it’s important to do your homework before buying one.

“You want to choose a device with the right energy production — the right wavelength of light, the right power — to be safe and effective,” he said.

For details, he recommends consulting a 2019 paper in The Brazilian Journal of Physical Therapy called “Clinical and scientific recommendations for the use of photobiomodulation therapy in exercise performance enhancement and post-exercise recovery: Current evidence and future directions.”

The paper, from the Laboratory of Phototherapy and Innovative Technologies in Health at the Universidade Nove de Julho in Sao Paulo, Brazil, recommends that for small muscle groups like the biceps or triceps, use red-light lasers or LED devices with a wavelength of 640 nm for red light or 950 nm for infrared light, at a power of 50-200 mW per diode for single-probe device types, at a dose of 20-60 J, given 5-10 minutes after exercise.

A version of this article appeared on Medscape.com.

A surprising therapy is showing promise for chronic pain, vision loss, and muscle recovery, among other conditions.

It’s not a pill, an injection, or surgery.

It’s light.

Yes, light. The thing that appears when you open the curtains, flip a switch, or strike a match.

Light illuminates our world and helps us see. Early human trials suggest it may help us heal in new ways as well.

“Phototherapy is still in its infancy,” said Mohab Ibrahim, MD, PhD, a professor of anesthesiology at the University of Arizona, Tucson, who studies the effects of light on chronic pain. “There are so many questions, a lot of things we do not understand yet. But that’s where it gets interesting. What we can conclude is that different colors of light can influence different biological functions.”

This growing field goes by several names. Light therapy. Phototherapy. Photobiomodulation.

It leverages known effects of light on human health — such as skin exposure to ultraviolet light producing vitamin D or blue light’s power to regulate human body clocks — to take light as medicine in surprising new directions.
 

New Science, Old Idea

The science is young, but the concept of using light to restore health is thousands of years old.

Hippocrates prescribed sunbathing to patients at his medical center on the Greek island of Kos in 400 BC. Florence Nightingale promoted sunshine, along with fresh air, as prerequisites for recovery in hospitals during the Civil War. A Danish doctor, Niels Finsen, won the Nobel Prize in 1903 for developing ultraviolet lamps to treat a tuberculosis-related skin condition. And worried parents of the 1930s sat their babies in front of mercury arc lamps, bought at the drugstore, to discourage rickets.

Today, light therapy is widely used in medicine for newborn jaundice, psoriasis, and seasonal affective disorder and in light-activated treatments for cancers of the esophagus and lungs, as well as for actinic keratosis, a skin condition that can lead to cancer.

But researchers are finding that light may be capable of far more, particularly in conditions with few treatment options or where available drugs have unwanted side effects.
 

How Red Light Could Restore Vision

When 100 midlife and older adults, aged 53-91, with the dry form of age-related macular degeneration (AMD) were treated with an experimental red-light therapy or a sham therapy, the light treatment group showed signs of improved vision, as measured on a standard eye chart.

Volunteers received the therapy three times a week for 3-5 weeks, every 4 months for 2 years. By the study’s end, 67% of those treated with light could read an additional five letters on the chart, and 20% could read 10 or more. About 7% developed geographic atrophy — the most advanced, vision-threatening stage of dry AMD — compared with 24% in the sham group.

The study, called LIGHTSITE III, was conducted at 10 ophthalmology centers across the United States. The device they used — the Valeda Light Delivery System from medical device company LumiThera — is available in Europe and now being reviewed by the Food and Drug Administration (FDA).

courtesy LumiThera

Exposure to red light at the wavelengths used in the study likely revitalizes failing mitochondria — the power plants inside cells — so they produce more energy, the researchers say.

“This is the first therapy for dry AMD that’s actually shown a benefit in improving vision,” said study coauthor Richard Rosen, MD, chair of ophthalmology at the Icahn School of Medicine at Mount Sinai and chief of Retinal Services at the New York Eye and Ear Infirmary in New York City. “Supplements called AREDS can reduce progression, and in wet AMD we can improve vision loss with injections. But in dry AMD, none of the treatments studied in the past have improved it.”

AMD develops when the eyes can’t break down natural by-products, which glom together as clumps of protein called drusen. Drusen can lodge under the retina, eventually damaging tissue.

“Retinal epithelial cells, a single layer of cells that cares for the photoreceptors in the eyes, are there for life,” Dr. Rosen said. “They have a tremendous capacity to repair themselves, but things [such as aging and smoking] get in the way.”

“I’m proposing,” Dr. Rosen said, “that by boosting energy levels in cells [with red light], we’re improving normal repair mechanisms.”

Lab studies support this idea.

In a 2017 mouse study from the University College London Institute of Ophthalmology in England, retinal function improved by 25% in old mice exposed to red light. And a 2019 study from the Ophthalmological Research Foundation, Oviedo, Spain, found that exposure to blue light harmed the mitochondria in retina cells, while red light somewhat counteracted the losses.

If cleared by the FDA — which the company anticipated could happen in 2024 — LumiThera’s light delivery device will likely be most useful in the beginning stages of dry AMD, Dr. Rosen said. “I think treatment of early dry AMD will be huge.”

Eventually, light therapy may also be valuable in treating or managing glaucoma and diabetic retinopathy.

For now, Dr. Rosen recommended that clinicians and consumers with AMD skip over-the-counter (OTC) red-light therapy devices currently on the market.

“We don’t know what kind of light the devices produce,” he said. “The wavelengths can vary. The eyes are delicate. Experimenting on your own may be hazardous to your vision.”
 

Green Light for Pain Relief

On his way to the pharmacy to pick up pain relievers for a headache, Dr. Ibrahim passed Gene C. Reid Park in Tucson. Recalling how his brother eased headaches by sitting in his backyard, Dr. Ibrahim pulled over.

“Reid Park is probably one of the greenest areas of Tucson,” said Dr. Ibrahim, who also serves as medical director of the Comprehensive Center for Pain & Addiction at Banner-University Medical Center Phoenix in Arizona. “I spent a half hour or 40 minutes there, and my headache felt better.”

Being outdoors in a green space may be soothing for lots of reasons, like the quiet or the fresh air. But there’s also sunlight reflected off and shining through greenery. The experience inspired Dr. Ibrahim to take a closer look at the effects of green light on chronic pain.

In his 2021 study of 29 people with migraines, participants reported that, after daily exposure to green light for 10 weeks, the number of days per month when they had headaches fell from 7.9 to 2.4 for those who had episodic migraines and from 22.3 to 9.4 for those with chronic migraines. In another 2021 study, 21 people with fibromyalgia who had green light therapy for 10 weeks said their average, self-reported pain intensity fell from 8.4 to 4.9 on a 10-point scale used at the University of Arizona’s pain clinic.

Volunteers in both studies got their light therapy at home, switching on green LED lights while they listened to music, read a book, relaxed, or exercised for 1 or 2 hours daily. The lights were within their field of vision, but they did not look directly at them.

Dr. Ibrahim now has funding from the Department of Defense and Department of Veterans Affairs to find out why green light alters pain perception.

“What we know is that the visual system is connected to certain areas of the brain that also modulate pain,” he said. “We are trying to understand the connection.”

Padma Gulur, MD, a professor of anesthesiology and population health and director of Pain Management Strategy and Opioid Surveillance at Duke University, Durham, North Carolina, saw similar results in a 2023 study of 45 people with fibromyalgia. But instead of using a light source, volunteers wore glasses with clear, green, or blue lenses for 4 hours a day.

After 2 weeks, 33% in the green lens group reduced their use of opioids by 10% or more, compared with 11% in the blue lens group and 8% who wore clear lenses. Previous studies have found green light affects levels of the feel-good brain chemical serotonin and stimulates the body’s own opioid system, the authors noted.

“Green light helps your body control and reduce pain,” Dr. Gulur said. It “seems to help with pain relief by affecting the body’s natural pain management system. This effect appears to play a crucial role in antinociception — reducing the sensation of pain; antiallodynia — preventing normal, nonpainful stimuli from causing pain; and antihyperalgesia — reducing heightened sensitivity to pain.”

Light therapy could help pain patients reduce their dose of opioids or even forgo the drugs altogether, Dr. Gulur said. “It is our hope this will become a useful adjuvant therapy to manage pain.”

In the University of Arizona studies, some patients on green-light therapy stopped their medications completely. Even if they didn’t, other benefits appeared. “They had improved quality of life, decreased depression and anxiety, and improved sleep,” Dr. Ibrahim said.

But not just any green light or green-tinted glasses will work, both researchers said. “We have found there are specific frequencies of green light that give this benefit,” Dr. Gulur said. “OTC products may not be helpful for that reason.”

While Dr. Ibrahim said it could be possible for healthcare practitioners and consumers to consult his studies and put together an inexpensive green-light device at home while carefully following the protocol participants used in the studies , it would first be a good idea for patients to talk with their family doctor or a pain specialist.

“A headache is not always just a headache,” Dr. Ibrahim said. “It could be some other abnormality that needs diagnosis and treatment. If you have long-lasting pain or pain that’s getting worse, it’s always better to discuss it with your physician.”
 

Helping Muscles Recover With Red Light

Intense exercise — whether it’s a sprint at the end of a morning run, an extra set of biceps curls, or a weekend of all-day DIY home improvement projects — can temporarily damage muscle, causing soreness, inflammation, and even swelling. Phototherapy with red and near-infrared light is widely used by sports trainers, physical therapists, and athletes to aid in recovery. It may even work better than a trendy plunge in an ice bath, according to a 2019 Texas State University review.

But how does it work? Jamie Ghigiarelli, PhD, professor of Allied Health & Kinesiology at Hofstra University in Hempstead, New York, looked closely at signs of inflammation and muscle damage in 12 athletes to find out.

Study participants overtaxed their muscles with rounds of chin-ups, high-speed sprints, and repeated bench presses. Afterward, they relaxed in a full-body red-light therapy bed or in a similar bed without lights.

The results, published in 2020, showed that blood levels of creatine kinase — an enzyme that’s elevated by muscle damage — were 18% lower 1-3 days after exercising for the light-bed group than for the control group.

“Photobiomodulation seems to help with muscle recovery,” Dr. Ghigiarelli said.

Red light at wavelengths from 650 to 820 nm can enter muscle cells, where it is absorbed by mitochondria and boosts their energy production, he said. At the time of his research, some exercise science researchers and athletes thought using light therapy before an event might also increase athletic performance, but according to Dr. Ghigiarelli, that use has not panned out.

Handheld red light and near-infrared light devices for muscle recovery are widely available, but it’s important to do your homework before buying one.

“You want to choose a device with the right energy production — the right wavelength of light, the right power — to be safe and effective,” he said.

For details, he recommends consulting a 2019 paper in The Brazilian Journal of Physical Therapy called “Clinical and scientific recommendations for the use of photobiomodulation therapy in exercise performance enhancement and post-exercise recovery: Current evidence and future directions.”

The paper, from the Laboratory of Phototherapy and Innovative Technologies in Health at the Universidade Nove de Julho in Sao Paulo, Brazil, recommends that for small muscle groups like the biceps or triceps, use red-light lasers or LED devices with a wavelength of 640 nm for red light or 950 nm for infrared light, at a power of 50-200 mW per diode for single-probe device types, at a dose of 20-60 J, given 5-10 minutes after exercise.

A version of this article appeared on Medscape.com.

Telemedicine interest, which was relatively quiescent prior to the COVID-19 pandemic, has surged in popularity in the past few years.¹ It can now be utilized seamlessly in dermatology practices to deliver exceptional patient care while reducing costs and travel time and offering dermatologists flexibility and improved work-life balance. Teledermatology applications include synchronous, asynchronous, and hybrid platforms.² For synchronous teledermatology, patient visits are carried out in real time with audio and video technology.³ For asynchronous teledermatology—also known as the store-and-forward model—the dermatologist receives the patient’s history and photographs and then renders an assessment and treatment plan.² Hybrid teledermatology uses real-time audio and video conferencing for history taking, assessment and treatment plan, and patient education, with photographs sent asynchronously.³ Telemedicine may not be initially intuitive or easy to integrate into clinical practice, but with time and effort, it will complement your dermatology practice, making it run more efficiently.

Patient Satisfaction With Teledermatology

Studies generally have shown very high patient satisfaction rates and shorter wait times with teledermatology vs in-person visits; for example, in a systematic review of 15 teledermatology studies including 7781 patients, more than 80% of participants reported high satisfaction with their telemedicine visit, with up to 92% reporting that they would choose to do a televisit again.⁴ In a retrospective analysis of 615 Zocdoc physicians, 65% of whom were dermatologists, mean wait times were 2.4 days for virtual appointments compared with 11.7 days for in-person appointments.⁵ Similarly, in a retrospective single-institution study, mean wait times for televisits were 14.3 days compared with 34.7 days for in-person referrals.⁶

Follow-Up Visits for Nail Disorders Via Teledermatology

Teledermatology may be particularly well suited for treating patients with nail disorders. In a prospective observational study, Onyeka et al⁷ accessed 813 images from 63 dermatology patients via teledermatology over a 6-month period to assess distance, focus, brightness, background, and image quality; of them, 83% were rated as high quality. Notably, images of nail disorders, skin growths, or pigmentation disorders were rated as having better image quality than images of inflammatory skin conditions (odds ratio [OR], 4.2-12.9 [P<.005]).⁷ In a retrospective study of 107 telemedicine visits for nail disorders during the COVID-19 pandemic, patients with longitudinal melanonychia were recommended for in-person visits for physical examination and dermoscopy, as were patients with suspected onychomycosis, who required nail plate sampling for diagnostic confirmation; however, approximately half of visits did not require in-person follow-up, including those patients with confirmed onychomycosis.⁸ Onychomycosis patients could be examined for clinical improvement and counseled on medication compliance via telemedicine. Other patients who did not require in-person follow-ups were those with traumatic nail disorders such as subungual hematoma and retronychia as well as those with body‐focused repetitive behaviors, including habit-tic nail deformity, onychophagia, and onychotillomania.⁸

Patients undergoing nail biopsies to rule out malignancies or to diagnose inflammatory nail disorders also may be managed via telemedicine. Patients for whom nail biopsies are recommended often are anxious about the procedure, which may be due to portrayal of nail trauma in the media⁹ or lack of accurate information on nail biopsies online.¹⁰ Therefore, counseling via telemedicine about the details of the procedure in a patient-friendly way (eg, showing an animated video and narrating it¹¹) can allay anxiety without the inconvenience, cost, and time missed from work associated with traveling to an in-person visit. In addition, postoperative counseling ideally is performed via telemedicine because complications following nail procedures are uncommon. In a retrospective study of 502 patients who underwent a nail biopsy at a single academic center, only 14 developed surgical site infections within 8 days on average (range, 5–13 days), with a higher infection risk in patients with type 2 ­diabetes mellitus (P<.0003).¹²

Advantages and Limitations

There are many benefits to incorporating telemedicine into dermatology practices, including reduced overhead costs, convenience and time saved for patients, and flexibility and improved work-life balance for dermatologists. In addition, because the number of in-person visits seen generally is fixed due to space constraints and work-hour restrictions, delegating follow-up visits to telemedicine can free up in-person slots for new patients and those needing procedures. However, there also are some inherent limitations to telemedicine: technology access, vision or hearing difficulties or low digital health literacy, or language barriers. In the prospective observational study by Onyeka et al⁷ analyzing 813 teledermatology images, patients aged 65 to 74 years sent in more clinically useful images (OR, 7.9) and images that were more often in focus (OR, 2.6) compared with patients older than 85 years.

Final Thoughts

Incorporation of telemedicine into dermatologic practice is a valuable tool for triaging patients with acute issues, improving patient care and health care access, making practices more efficient, and improving dermatologist flexibility and work-life balance. Further development of teledermatology to provide access to underserved populations prioritizing dermatologist reimbursement and progress on technologic innovations will make teledermatology even more useful in the coming years.

Telemedicine interest, which was relatively quiescent prior to the COVID-19 pandemic, has surged in popularity in the past few years.¹ It can now be utilized seamlessly in dermatology practices to deliver exceptional patient care while reducing costs and travel time and offering dermatologists flexibility and improved work-life balance. Teledermatology applications include synchronous, asynchronous, and hybrid platforms.² For synchronous teledermatology, patient visits are carried out in real time with audio and video technology.³ For asynchronous teledermatology—also known as the store-and-forward model—the dermatologist receives the patient’s history and photographs and then renders an assessment and treatment plan.² Hybrid teledermatology uses real-time audio and video conferencing for history taking, assessment and treatment plan, and patient education, with photographs sent asynchronously.³ Telemedicine may not be initially intuitive or easy to integrate into clinical practice, but with time and effort, it will complement your dermatology practice, making it run more efficiently.

Patient Satisfaction With Teledermatology

Studies generally have shown very high patient satisfaction rates and shorter wait times with teledermatology vs in-person visits; for example, in a systematic review of 15 teledermatology studies including 7781 patients, more than 80% of participants reported high satisfaction with their telemedicine visit, with up to 92% reporting that they would choose to do a televisit again.⁴ In a retrospective analysis of 615 Zocdoc physicians, 65% of whom were dermatologists, mean wait times were 2.4 days for virtual appointments compared with 11.7 days for in-person appointments.⁵ Similarly, in a retrospective single-institution study, mean wait times for televisits were 14.3 days compared with 34.7 days for in-person referrals.⁶

Follow-Up Visits for Nail Disorders Via Teledermatology

Teledermatology may be particularly well suited for treating patients with nail disorders. In a prospective observational study, Onyeka et al⁷ accessed 813 images from 63 dermatology patients via teledermatology over a 6-month period to assess distance, focus, brightness, background, and image quality; of them, 83% were rated as high quality. Notably, images of nail disorders, skin growths, or pigmentation disorders were rated as having better image quality than images of inflammatory skin conditions (odds ratio [OR], 4.2-12.9 [P<.005]).⁷ In a retrospective study of 107 telemedicine visits for nail disorders during the COVID-19 pandemic, patients with longitudinal melanonychia were recommended for in-person visits for physical examination and dermoscopy, as were patients with suspected onychomycosis, who required nail plate sampling for diagnostic confirmation; however, approximately half of visits did not require in-person follow-up, including those patients with confirmed onychomycosis.⁸ Onychomycosis patients could be examined for clinical improvement and counseled on medication compliance via telemedicine. Other patients who did not require in-person follow-ups were those with traumatic nail disorders such as subungual hematoma and retronychia as well as those with body‐focused repetitive behaviors, including habit-tic nail deformity, onychophagia, and onychotillomania.⁸

Patients undergoing nail biopsies to rule out malignancies or to diagnose inflammatory nail disorders also may be managed via telemedicine. Patients for whom nail biopsies are recommended often are anxious about the procedure, which may be due to portrayal of nail trauma in the media⁹ or lack of accurate information on nail biopsies online.¹⁰ Therefore, counseling via telemedicine about the details of the procedure in a patient-friendly way (eg, showing an animated video and narrating it¹¹) can allay anxiety without the inconvenience, cost, and time missed from work associated with traveling to an in-person visit. In addition, postoperative counseling ideally is performed via telemedicine because complications following nail procedures are uncommon. In a retrospective study of 502 patients who underwent a nail biopsy at a single academic center, only 14 developed surgical site infections within 8 days on average (range, 5–13 days), with a higher infection risk in patients with type 2 ­diabetes mellitus (P<.0003).¹²

Advantages and Limitations

There are many benefits to incorporating telemedicine into dermatology practices, including reduced overhead costs, convenience and time saved for patients, and flexibility and improved work-life balance for dermatologists. In addition, because the number of in-person visits seen generally is fixed due to space constraints and work-hour restrictions, delegating follow-up visits to telemedicine can free up in-person slots for new patients and those needing procedures. However, there also are some inherent limitations to telemedicine: technology access, vision or hearing difficulties or low digital health literacy, or language barriers. In the prospective observational study by Onyeka et al⁷ analyzing 813 teledermatology images, patients aged 65 to 74 years sent in more clinically useful images (OR, 7.9) and images that were more often in focus (OR, 2.6) compared with patients older than 85 years.

Final Thoughts

Incorporation of telemedicine into dermatologic practice is a valuable tool for triaging patients with acute issues, improving patient care and health care access, making practices more efficient, and improving dermatologist flexibility and work-life balance. Further development of teledermatology to provide access to underserved populations prioritizing dermatologist reimbursement and progress on technologic innovations will make teledermatology even more useful in the coming years.

Telemedicine interest, which was relatively quiescent prior to the COVID-19 pandemic, has surged in popularity in the past few years.¹ It can now be utilized seamlessly in dermatology practices to deliver exceptional patient care while reducing costs and travel time and offering dermatologists flexibility and improved work-life balance. Teledermatology applications include synchronous, asynchronous, and hybrid platforms.² For synchronous teledermatology, patient visits are carried out in real time with audio and video technology.³ For asynchronous teledermatology—also known as the store-and-forward model—the dermatologist receives the patient’s history and photographs and then renders an assessment and treatment plan.² Hybrid teledermatology uses real-time audio and video conferencing for history taking, assessment and treatment plan, and patient education, with photographs sent asynchronously.³ Telemedicine may not be initially intuitive or easy to integrate into clinical practice, but with time and effort, it will complement your dermatology practice, making it run more efficiently.

Patient Satisfaction With Teledermatology

Studies generally have shown very high patient satisfaction rates and shorter wait times with teledermatology vs in-person visits; for example, in a systematic review of 15 teledermatology studies including 7781 patients, more than 80% of participants reported high satisfaction with their telemedicine visit, with up to 92% reporting that they would choose to do a televisit again.⁴ In a retrospective analysis of 615 Zocdoc physicians, 65% of whom were dermatologists, mean wait times were 2.4 days for virtual appointments compared with 11.7 days for in-person appointments.⁵ Similarly, in a retrospective single-institution study, mean wait times for televisits were 14.3 days compared with 34.7 days for in-person referrals.⁶

Follow-Up Visits for Nail Disorders Via Teledermatology

Teledermatology may be particularly well suited for treating patients with nail disorders. In a prospective observational study, Onyeka et al⁷ accessed 813 images from 63 dermatology patients via teledermatology over a 6-month period to assess distance, focus, brightness, background, and image quality; of them, 83% were rated as high quality. Notably, images of nail disorders, skin growths, or pigmentation disorders were rated as having better image quality than images of inflammatory skin conditions (odds ratio [OR], 4.2-12.9 [P<.005]).⁷ In a retrospective study of 107 telemedicine visits for nail disorders during the COVID-19 pandemic, patients with longitudinal melanonychia were recommended for in-person visits for physical examination and dermoscopy, as were patients with suspected onychomycosis, who required nail plate sampling for diagnostic confirmation; however, approximately half of visits did not require in-person follow-up, including those patients with confirmed onychomycosis.⁸ Onychomycosis patients could be examined for clinical improvement and counseled on medication compliance via telemedicine. Other patients who did not require in-person follow-ups were those with traumatic nail disorders such as subungual hematoma and retronychia as well as those with body‐focused repetitive behaviors, including habit-tic nail deformity, onychophagia, and onychotillomania.⁸

Patients undergoing nail biopsies to rule out malignancies or to diagnose inflammatory nail disorders also may be managed via telemedicine. Patients for whom nail biopsies are recommended often are anxious about the procedure, which may be due to portrayal of nail trauma in the media⁹ or lack of accurate information on nail biopsies online.¹⁰ Therefore, counseling via telemedicine about the details of the procedure in a patient-friendly way (eg, showing an animated video and narrating it¹¹) can allay anxiety without the inconvenience, cost, and time missed from work associated with traveling to an in-person visit. In addition, postoperative counseling ideally is performed via telemedicine because complications following nail procedures are uncommon. In a retrospective study of 502 patients who underwent a nail biopsy at a single academic center, only 14 developed surgical site infections within 8 days on average (range, 5–13 days), with a higher infection risk in patients with type 2 ­diabetes mellitus (P<.0003).¹²

Advantages and Limitations

There are many benefits to incorporating telemedicine into dermatology practices, including reduced overhead costs, convenience and time saved for patients, and flexibility and improved work-life balance for dermatologists. In addition, because the number of in-person visits seen generally is fixed due to space constraints and work-hour restrictions, delegating follow-up visits to telemedicine can free up in-person slots for new patients and those needing procedures. However, there also are some inherent limitations to telemedicine: technology access, vision or hearing difficulties or low digital health literacy, or language barriers. In the prospective observational study by Onyeka et al⁷ analyzing 813 teledermatology images, patients aged 65 to 74 years sent in more clinically useful images (OR, 7.9) and images that were more often in focus (OR, 2.6) compared with patients older than 85 years.

Final Thoughts

Incorporation of telemedicine into dermatologic practice is a valuable tool for triaging patients with acute issues, improving patient care and health care access, making practices more efficient, and improving dermatologist flexibility and work-life balance. Further development of teledermatology to provide access to underserved populations prioritizing dermatologist reimbursement and progress on technologic innovations will make teledermatology even more useful in the coming years.

Practice Gap

Longitudinal melanonychia (LM) is characterized by the presence of a dark brown, longitudinal, pigmented band on the nail unit, often caused by melanocytic activation or melanocytic hyperplasia in the nail matrix. Distinguishing between benign and early malignant LM is crucial due to their similar clinical presentations.¹ Hence, surgical excision of the pigmented nail matrix followed by histopathologic examination is a common procedure aimed at managing LM and reducing the risk for delayed diagnosis of subungual melanoma.

Tangential matrix excision combined with the nail window technique has emerged as a common and favored surgical strategy for managing LM.² This method is highly valued for its ability to minimize the risk for severe permanent nail dystrophy and effectively reduce postsurgical pigmentation recurrence.

The procedure begins with the creation of a matrix window along the lateral edge of the pigmented band followed by 1 lateral incision carefully made on each side of the nail fold. This meticulous approach allows for the complete exposure of the pigmented lesion. Subsequently, the nail fold is separated from the dorsal surface of the nail plate to facilitate access to the pigmented nail matrix. Finally, the target pigmented area is excised using a scalpel.

Despite the recognized efficacy of this procedure, challenges do arise, particularly when the width of the pigmented matrix lesion is narrow. Holding the scalpel horizontally to ensure precise excision can prove to be demanding, leading to difficulty achieving complete lesion removal and obtaining the desired cosmetic outcomes. As such, there is a clear need to explore alternative tools that can effectively address these challenges while ensuring optimal surgical outcomes for patients with LM. We propose the use of the customized dermal curette.

The Technique

An improved curette tool is a practical solution for complete removal of the pigmented nail matrix. This enhanced instrument is crafted from a sterile disposable dermal curette with its top flattened using a needle holder(Figure 1). Termed the customized dermal curette, this device is a simple yet accurate tool for the precise excision of pigmented lesions within the nail matrix. Importantly, it offers versatility by accommodating different widths of pigmented lesions through the availability of various sizes of dermal curettes (Figure 2).

Histopathologically, we have found that the scalpel technique may lead to variable tissue removal, resulting in differences in tissue thickness, fragility, and completeness (Figure 3A). Conversely, the customized dermal curette consistently provides more accurate tissue excision, resulting in uniform tissue thickness and integrity (Figure 3B).

Practice Implications

Compared to the traditional scalpel, this modified tool offers distinct advantages. Specifically, the customized dermal curette provides enhanced maneuverability and control during the procedure, thereby improving the overall efficacy of the excision process. It also offers a more accurate approach to completely remove pigmented bands, which reduces the risk for postoperative recurrence. The simplicity, affordability, and ease of operation associated with customized dermal curettes holds promise as an effective alternative for tissue shaving, especially in cases involving narrow pigmented matrix lesions, thereby addressing a notable practice gap and enhancing patient care.

Practice Gap

Longitudinal melanonychia (LM) is characterized by the presence of a dark brown, longitudinal, pigmented band on the nail unit, often caused by melanocytic activation or melanocytic hyperplasia in the nail matrix. Distinguishing between benign and early malignant LM is crucial due to their similar clinical presentations.¹ Hence, surgical excision of the pigmented nail matrix followed by histopathologic examination is a common procedure aimed at managing LM and reducing the risk for delayed diagnosis of subungual melanoma.

Tangential matrix excision combined with the nail window technique has emerged as a common and favored surgical strategy for managing LM.² This method is highly valued for its ability to minimize the risk for severe permanent nail dystrophy and effectively reduce postsurgical pigmentation recurrence.

The procedure begins with the creation of a matrix window along the lateral edge of the pigmented band followed by 1 lateral incision carefully made on each side of the nail fold. This meticulous approach allows for the complete exposure of the pigmented lesion. Subsequently, the nail fold is separated from the dorsal surface of the nail plate to facilitate access to the pigmented nail matrix. Finally, the target pigmented area is excised using a scalpel.

Despite the recognized efficacy of this procedure, challenges do arise, particularly when the width of the pigmented matrix lesion is narrow. Holding the scalpel horizontally to ensure precise excision can prove to be demanding, leading to difficulty achieving complete lesion removal and obtaining the desired cosmetic outcomes. As such, there is a clear need to explore alternative tools that can effectively address these challenges while ensuring optimal surgical outcomes for patients with LM. We propose the use of the customized dermal curette.

The Technique

An improved curette tool is a practical solution for complete removal of the pigmented nail matrix. This enhanced instrument is crafted from a sterile disposable dermal curette with its top flattened using a needle holder(Figure 1). Termed the customized dermal curette, this device is a simple yet accurate tool for the precise excision of pigmented lesions within the nail matrix. Importantly, it offers versatility by accommodating different widths of pigmented lesions through the availability of various sizes of dermal curettes (Figure 2).

Histopathologically, we have found that the scalpel technique may lead to variable tissue removal, resulting in differences in tissue thickness, fragility, and completeness (Figure 3A). Conversely, the customized dermal curette consistently provides more accurate tissue excision, resulting in uniform tissue thickness and integrity (Figure 3B).

Practice Implications

Compared to the traditional scalpel, this modified tool offers distinct advantages. Specifically, the customized dermal curette provides enhanced maneuverability and control during the procedure, thereby improving the overall efficacy of the excision process. It also offers a more accurate approach to completely remove pigmented bands, which reduces the risk for postoperative recurrence. The simplicity, affordability, and ease of operation associated with customized dermal curettes holds promise as an effective alternative for tissue shaving, especially in cases involving narrow pigmented matrix lesions, thereby addressing a notable practice gap and enhancing patient care.

Practice Gap

Longitudinal melanonychia (LM) is characterized by the presence of a dark brown, longitudinal, pigmented band on the nail unit, often caused by melanocytic activation or melanocytic hyperplasia in the nail matrix. Distinguishing between benign and early malignant LM is crucial due to their similar clinical presentations.¹ Hence, surgical excision of the pigmented nail matrix followed by histopathologic examination is a common procedure aimed at managing LM and reducing the risk for delayed diagnosis of subungual melanoma.

Tangential matrix excision combined with the nail window technique has emerged as a common and favored surgical strategy for managing LM.² This method is highly valued for its ability to minimize the risk for severe permanent nail dystrophy and effectively reduce postsurgical pigmentation recurrence.

The procedure begins with the creation of a matrix window along the lateral edge of the pigmented band followed by 1 lateral incision carefully made on each side of the nail fold. This meticulous approach allows for the complete exposure of the pigmented lesion. Subsequently, the nail fold is separated from the dorsal surface of the nail plate to facilitate access to the pigmented nail matrix. Finally, the target pigmented area is excised using a scalpel.

Despite the recognized efficacy of this procedure, challenges do arise, particularly when the width of the pigmented matrix lesion is narrow. Holding the scalpel horizontally to ensure precise excision can prove to be demanding, leading to difficulty achieving complete lesion removal and obtaining the desired cosmetic outcomes. As such, there is a clear need to explore alternative tools that can effectively address these challenges while ensuring optimal surgical outcomes for patients with LM. We propose the use of the customized dermal curette.

The Technique

An improved curette tool is a practical solution for complete removal of the pigmented nail matrix. This enhanced instrument is crafted from a sterile disposable dermal curette with its top flattened using a needle holder(Figure 1). Termed the customized dermal curette, this device is a simple yet accurate tool for the precise excision of pigmented lesions within the nail matrix. Importantly, it offers versatility by accommodating different widths of pigmented lesions through the availability of various sizes of dermal curettes (Figure 2).

Histopathologically, we have found that the scalpel technique may lead to variable tissue removal, resulting in differences in tissue thickness, fragility, and completeness (Figure 3A). Conversely, the customized dermal curette consistently provides more accurate tissue excision, resulting in uniform tissue thickness and integrity (Figure 3B).

Practice Implications

Compared to the traditional scalpel, this modified tool offers distinct advantages. Specifically, the customized dermal curette provides enhanced maneuverability and control during the procedure, thereby improving the overall efficacy of the excision process. It also offers a more accurate approach to completely remove pigmented bands, which reduces the risk for postoperative recurrence. The simplicity, affordability, and ease of operation associated with customized dermal curettes holds promise as an effective alternative for tissue shaving, especially in cases involving narrow pigmented matrix lesions, thereby addressing a notable practice gap and enhancing patient care.

The Food and Drug Administration has approved denileukin diftitox-cxdl (Lymphir, Citius Pharmaceuticals) for adults with relapsed or refractory stage 1-3 cutaneous T-cell lymphoma after at least one prior systemic therapy.

The immunotherapy is a reformulation of denileukin diftitox (Ontak), initially approved in 1999 for certain patients with persistent or recurrent cutaneous T-cell lymphoma. In 2014, the original formulation was voluntarily withdrawn from the US market. Citius acquired rights to market a reformulated product outside of Asia in 2021. 

This is the first indication for Lymphir, which targets interleukin-2 receptors on malignant T cells.

This approval marks “a significant milestone” for patients with cutaneous T-cell lymphoma, a rare cancer, company CEO Leonard Mazur said in a press release announcing the approval. “The introduction of Lymphir, with its potential to rapidly reduce skin disease and control symptomatic itching without cumulative toxicity, is expected to expand the [cutaneous T-cell lymphoma] treatment landscape and grow the overall market, currently estimated to be $300-$400 million.” 

Approval was based on the single-arm, open-label 302 study in 69 patients who had a median of four prior anticancer therapies. Patients received 9 mcg/kg daily from day 1 to day 5 of 21-day cycles until disease progression or unacceptable toxicity.

The objective response rate was 36.2%, including complete responses in 8.7% of patients. Responses lasted 6 months or longer in 52% of patients. Over 80% of subjects had a decrease in skin tumor burden, and almost a third had clinically significant improvements in pruritus. 

Adverse events occurring in 20% or more of patients include increased transaminases, decreased albumin, decreased hemoglobin, nausea, edema, fatigue, musculoskeletal pain, rash, chills, constipation, pyrexia, and capillary leak syndrome.

Labeling carries a boxed warning of capillary leak syndrome. Other warnings include visual impairment, infusion reactions, hepatotoxicity, and embryo-fetal toxicity. Citius is under a postmarketing requirement to characterize the risk for visual impairment.

The company expects to launch the agent within 5 months.

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

The Food and Drug Administration has approved denileukin diftitox-cxdl (Lymphir, Citius Pharmaceuticals) for adults with relapsed or refractory stage 1-3 cutaneous T-cell lymphoma after at least one prior systemic therapy.

The immunotherapy is a reformulation of denileukin diftitox (Ontak), initially approved in 1999 for certain patients with persistent or recurrent cutaneous T-cell lymphoma. In 2014, the original formulation was voluntarily withdrawn from the US market. Citius acquired rights to market a reformulated product outside of Asia in 2021. 

This is the first indication for Lymphir, which targets interleukin-2 receptors on malignant T cells.

This approval marks “a significant milestone” for patients with cutaneous T-cell lymphoma, a rare cancer, company CEO Leonard Mazur said in a press release announcing the approval. “The introduction of Lymphir, with its potential to rapidly reduce skin disease and control symptomatic itching without cumulative toxicity, is expected to expand the [cutaneous T-cell lymphoma] treatment landscape and grow the overall market, currently estimated to be $300-$400 million.” 

Approval was based on the single-arm, open-label 302 study in 69 patients who had a median of four prior anticancer therapies. Patients received 9 mcg/kg daily from day 1 to day 5 of 21-day cycles until disease progression or unacceptable toxicity.

The objective response rate was 36.2%, including complete responses in 8.7% of patients. Responses lasted 6 months or longer in 52% of patients. Over 80% of subjects had a decrease in skin tumor burden, and almost a third had clinically significant improvements in pruritus. 

Adverse events occurring in 20% or more of patients include increased transaminases, decreased albumin, decreased hemoglobin, nausea, edema, fatigue, musculoskeletal pain, rash, chills, constipation, pyrexia, and capillary leak syndrome.

Labeling carries a boxed warning of capillary leak syndrome. Other warnings include visual impairment, infusion reactions, hepatotoxicity, and embryo-fetal toxicity. Citius is under a postmarketing requirement to characterize the risk for visual impairment.

The company expects to launch the agent within 5 months.

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

The Food and Drug Administration has approved denileukin diftitox-cxdl (Lymphir, Citius Pharmaceuticals) for adults with relapsed or refractory stage 1-3 cutaneous T-cell lymphoma after at least one prior systemic therapy.

The immunotherapy is a reformulation of denileukin diftitox (Ontak), initially approved in 1999 for certain patients with persistent or recurrent cutaneous T-cell lymphoma. In 2014, the original formulation was voluntarily withdrawn from the US market. Citius acquired rights to market a reformulated product outside of Asia in 2021. 

This is the first indication for Lymphir, which targets interleukin-2 receptors on malignant T cells.

This approval marks “a significant milestone” for patients with cutaneous T-cell lymphoma, a rare cancer, company CEO Leonard Mazur said in a press release announcing the approval. “The introduction of Lymphir, with its potential to rapidly reduce skin disease and control symptomatic itching without cumulative toxicity, is expected to expand the [cutaneous T-cell lymphoma] treatment landscape and grow the overall market, currently estimated to be $300-$400 million.” 

Approval was based on the single-arm, open-label 302 study in 69 patients who had a median of four prior anticancer therapies. Patients received 9 mcg/kg daily from day 1 to day 5 of 21-day cycles until disease progression or unacceptable toxicity.

The objective response rate was 36.2%, including complete responses in 8.7% of patients. Responses lasted 6 months or longer in 52% of patients. Over 80% of subjects had a decrease in skin tumor burden, and almost a third had clinically significant improvements in pruritus. 

Adverse events occurring in 20% or more of patients include increased transaminases, decreased albumin, decreased hemoglobin, nausea, edema, fatigue, musculoskeletal pain, rash, chills, constipation, pyrexia, and capillary leak syndrome.

Labeling carries a boxed warning of capillary leak syndrome. Other warnings include visual impairment, infusion reactions, hepatotoxicity, and embryo-fetal toxicity. Citius is under a postmarketing requirement to characterize the risk for visual impairment.

The company expects to launch the agent within 5 months.

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

The Diagnosis: Microsecretory Adenocarcinoma

Microscopically, the tumor was relatively well circumscribed but had irregular borders. It consisted of microcysts and tubules lined by flattened to plump eosinophilic cells with mildly enlarged nuclei and intraluminal basophilic secretions. Peripheral lymphocytic aggregates also were seen in the mid and deep reticular dermis. Tumor necrosis, lymphovascular invasion, and notable mitotic activity were absent. Immunohistochemistry was diffusely positive for cytokeratin (CK) 7 and CK5/6. Occasional tumor cells showed variable expression of alpha smooth muscle actin, S-100 protein, and p40 and p63 antibodies. Immunohistochemistry was negative for CK20; GATA binding protein 3; MYB proto-oncogene, transcription factor; and insulinoma-associated protein ¹. A dual-color, break-apart fluorescence in situ hybridization probe identified a rearrangement of the SS18 (SYT) gene locus on chromosome 18. The nodule was excised with clear surgical margins, and the patient had no evidence of recurrent disease or metastasis at 2-year follow-up.

In recent years, there has been a growing recognition of the pivotal role played by gene fusions in driving oncogenesis, encompassing a diverse range of benign and malignant cutaneous neoplasms. These investigations have shed light on previously unknown mechanisms and pathways contributing to the pathogenesis of these neoplastic conditions, offering invaluable insights into their underlying biology. As a result, our ability to classify and diagnose these cutaneous tumors has improved. A notable example of how our current understanding has evolved is the discovery of the new cutaneous adnexal tumor microsecretory adenocarcinoma (MSA). Initially described by Bishop et al¹ in 2019 as predominantly occurring in the intraoral minor salivary glands, rare instances of primary cutaneous MSA involving the head and neck regions also have been reported.² Microsecretory adenocarcinoma represents an important addition to the group of fusion-driven tumors with both salivary gland and cutaneous adnexal analogues, characterized by a MEF2C::SS18 gene fusion. This entity is now recognized as a group of cutaneous adnexal tumors with distinct gene fusions, including both relatively recently discovered entities (eg, secretory carcinoma with NTRK fusions) and previously known entities with newly identified gene fusions (eg, poroid neoplasms with NUTM1, YAP1, or WWTR1 fusions; hidradenomatous neoplasms with CRTC1::MAML2 fusions; and adenoid cystic carcinoma with MYB, MYBL1, and/or NFIB rearrangements).³

Microsecretory adenocarcinoma exhibits a high degree of morphologic consistency, characterized by a microcystic-predominant growth pattern, uniform intercalated ductlike tumor cells with attenuated eosinophilic to clear cytoplasm, monotonous oval hyperchromatic nuclei with indistinct nucleoli, abundant basophilic luminal secretions, and a variably cellular fibromyxoid stroma. It also shows rounded borders with subtle infiltrative growth. Occasionally, pseudoepitheliomatous hyperplasia, tumor-associated lymphoid proliferation, or metaplastic bone formation may accompany MSA. Perineural invasion is rare, necrosis is absent, and mitotic rates generally are low, contributing to its distinctive histopathologic features that aid in accurate diagnosis and differentiation from other entities. Immunohistochemistry reveals diffuse positivity for CK7 and patchy to diffuse expression of S-100 in tumor cells as well as variable expression of p40 and p63. Highly specific SS18 gene translocations at chromosome 18q are useful for diagnosing MSA when found alongside its characteristic appearance, and SS18 break-apart fluorescence in situ hybridization can serve reliably as an accurate diagnostic method (Figure 1).⁴ Our case illustrates how molecular analysis assists in distinguishing MSA from other cutaneous adnexal tumors, exemplifying the power of our evolving understanding in refining diagnostic accuracy and guiding targeted therapies in clinical practice.

The differential diagnosis of MSA includes tubular adenoma, secretory carcinoma, cribriform tumor (previously carcinoma), and metastatic adenocarcinoma. Tubular adenoma is a rare benign neoplasm that predominantly affects females and can manifest at any age in adulthood. It typically manifests as a slow-growing, occasionally pedunculated nodule, often measuring less than 2 cm. Although it most commonly manifests on the scalp, tubular adenoma also may arise in diverse sites such as the face, axillae, lower extremities, or genitalia.

Notably, scalp lesions often are associated with nevus sebaceus of Jadassohn or syringocystadenoma papilliferum. Microscopically, tubular adenoma is well circumscribed within the dermis and may extend into the subcutis in some cases. Its distinctive appearance consists of variably sized tubules lined by a double or multilayered cuboidal to columnar epithelium, frequently displaying apocrine decapitation secretion (Figure 2). Cystic changes and intraluminal papillae devoid of true fibrovascular cores frequently are observed. Immunohistochemically, luminal epithelial cells express epithelial membrane antigen and carcinoembryonic antigen, while the myoepithelial layer expresses smooth muscle markers, p40, and S-100 protein. BRAF V600E mutation can be detected using immunohistochemistry, with excellent sensitivity and specificity using the anti-BRAF V600E antibody (clone VE1).⁵ Distinguishing tubular adenoma from MSA is achievable by observing its larger, more variable tubules, along with the consistent presence of a peripheral myoepithelial layer.

Secretory carcinoma is recognized as a low-grade gene fusion–driven carcinoma that primarily arises in salivary glands (both major and minor), with occasional occurrences in the breast and extremely rare instances in other locations such as the skin, thyroid gland, and lung.⁶ Although the axilla is the most common cutaneous site, diverse locations such as the neck, eyelids, extremities, and nipples also have been documented. Secretory carcinoma affects individuals across a wide age range (13–71 years).⁶ The hallmark tumors exhibit densely packed, sievelike microcystic glands and tubular spaces filled with abundant eosinophilic intraluminal secretions (Figure 3). Additionally, morphologic variants, such as predominantly papillary, papillary-cystic, macrocystic, solid, partially mucinous, and mixed-pattern neoplasms, have been described. Secretory carcinoma shares certain features with MSA; however, it is distinguished by the presence of pronounced eosinophilic secretions, plump and vacuolated cytoplasm, and a less conspicuous fibromyxoid stroma. Immunohistochemistry reveals tumor cells that are positive for CK7, SOX-10, S-100, mammaglobin, MUC4, and variably GATA-3. Genetically, secretory carcinoma exhibits distinct characteristics, commonly showing the ETV6::NTRK3 fusion, detectable through molecular techniques or pan-TRK immunohistochemistry, while RET fusions and other rare variants are less frequent.⁷

In 1998, Requena et al⁸ introduced the concept of primary cutaneous cribriform carcinoma. Despite initially being classified as a carcinoma, the malignant potential of this tumor remains uncertain. Consequently, the term cribriform tumor now has become the preferred terminology for denoting this rare entity.⁹ Primary cutaneous cribriform tumors are observed more commonly in women and typically affect individuals aged 20 to 55 years (mean, 44 years). Predominant locations include the upper and lower extremities, especially the thighs, knees, and legs, with additional cases occurring on the head and trunk. Microscopically, cribriform tumor is characterized by a partially circumscribed, unencapsulated dermal nodule composed of round or oval nuclei displaying hyperchromatism and mild pleomorphism. The defining aspect of its morphology revolves around interspersed small round cavities that give rise to the hallmark cribriform pattern (Figure 4). Although MSA occasionally may exhibit a cribriform architectural pattern, it typically lacks the distinctive feature of thin, threadlike, intraluminal bridging strands observed in cribriform tumors. Similarly, luminal cells within the cribriform tumor express CK7 and exhibit variable S-100 expression. It is recognized as an indolent neoplasm with uncertain malignant potential.

The histopathologic features of metastatic carcinomas can overlap with those of primary cutaneous tumors, particularly adnexal neoplasms.¹⁰ However, several key features can aid in the differentiation of cutaneous metastases, including a dermal-based growth pattern with or without subcutaneous involvement, the presence of multiple lesions, and the occurrence of lymphovascular invasion (Figure 5). Conversely, features that suggest a primary cutaneous adnexal neoplasm include the presence of superimposed in situ disease, carcinoma developing within a benign adnexal neoplasm, and notable stromal and/or vascular hyalinization within benign-appearing areas. In some cases, it can be difficult to determine the primary site of origin of a metastatic carcinoma to the skin based on morphologic features alone. In these cases, immunohistochemistry can be helpful. The most cost-effective and time-efficient approach to accurate diagnosis is to obtain a comprehensive clinical history. If there is a known history of cancer, a small panel of organ-specific immunohistochemical studies can be performed to confirm the diagnosis. If there is no known history, an algorithmic approach can be used to identify the primary site of origin. In all circumstances, it cannot be stressed enough that acquiring a thorough clinical history before conducting any diagnostic examinations is paramount.

The Diagnosis: Microsecretory Adenocarcinoma

Microscopically, the tumor was relatively well circumscribed but had irregular borders. It consisted of microcysts and tubules lined by flattened to plump eosinophilic cells with mildly enlarged nuclei and intraluminal basophilic secretions. Peripheral lymphocytic aggregates also were seen in the mid and deep reticular dermis. Tumor necrosis, lymphovascular invasion, and notable mitotic activity were absent. Immunohistochemistry was diffusely positive for cytokeratin (CK) 7 and CK5/6. Occasional tumor cells showed variable expression of alpha smooth muscle actin, S-100 protein, and p40 and p63 antibodies. Immunohistochemistry was negative for CK20; GATA binding protein 3; MYB proto-oncogene, transcription factor; and insulinoma-associated protein ¹. A dual-color, break-apart fluorescence in situ hybridization probe identified a rearrangement of the SS18 (SYT) gene locus on chromosome 18. The nodule was excised with clear surgical margins, and the patient had no evidence of recurrent disease or metastasis at 2-year follow-up.

In recent years, there has been a growing recognition of the pivotal role played by gene fusions in driving oncogenesis, encompassing a diverse range of benign and malignant cutaneous neoplasms. These investigations have shed light on previously unknown mechanisms and pathways contributing to the pathogenesis of these neoplastic conditions, offering invaluable insights into their underlying biology. As a result, our ability to classify and diagnose these cutaneous tumors has improved. A notable example of how our current understanding has evolved is the discovery of the new cutaneous adnexal tumor microsecretory adenocarcinoma (MSA). Initially described by Bishop et al¹ in 2019 as predominantly occurring in the intraoral minor salivary glands, rare instances of primary cutaneous MSA involving the head and neck regions also have been reported.² Microsecretory adenocarcinoma represents an important addition to the group of fusion-driven tumors with both salivary gland and cutaneous adnexal analogues, characterized by a MEF2C::SS18 gene fusion. This entity is now recognized as a group of cutaneous adnexal tumors with distinct gene fusions, including both relatively recently discovered entities (eg, secretory carcinoma with NTRK fusions) and previously known entities with newly identified gene fusions (eg, poroid neoplasms with NUTM1, YAP1, or WWTR1 fusions; hidradenomatous neoplasms with CRTC1::MAML2 fusions; and adenoid cystic carcinoma with MYB, MYBL1, and/or NFIB rearrangements).³

Microsecretory adenocarcinoma exhibits a high degree of morphologic consistency, characterized by a microcystic-predominant growth pattern, uniform intercalated ductlike tumor cells with attenuated eosinophilic to clear cytoplasm, monotonous oval hyperchromatic nuclei with indistinct nucleoli, abundant basophilic luminal secretions, and a variably cellular fibromyxoid stroma. It also shows rounded borders with subtle infiltrative growth. Occasionally, pseudoepitheliomatous hyperplasia, tumor-associated lymphoid proliferation, or metaplastic bone formation may accompany MSA. Perineural invasion is rare, necrosis is absent, and mitotic rates generally are low, contributing to its distinctive histopathologic features that aid in accurate diagnosis and differentiation from other entities. Immunohistochemistry reveals diffuse positivity for CK7 and patchy to diffuse expression of S-100 in tumor cells as well as variable expression of p40 and p63. Highly specific SS18 gene translocations at chromosome 18q are useful for diagnosing MSA when found alongside its characteristic appearance, and SS18 break-apart fluorescence in situ hybridization can serve reliably as an accurate diagnostic method (Figure 1).⁴ Our case illustrates how molecular analysis assists in distinguishing MSA from other cutaneous adnexal tumors, exemplifying the power of our evolving understanding in refining diagnostic accuracy and guiding targeted therapies in clinical practice.

The differential diagnosis of MSA includes tubular adenoma, secretory carcinoma, cribriform tumor (previously carcinoma), and metastatic adenocarcinoma. Tubular adenoma is a rare benign neoplasm that predominantly affects females and can manifest at any age in adulthood. It typically manifests as a slow-growing, occasionally pedunculated nodule, often measuring less than 2 cm. Although it most commonly manifests on the scalp, tubular adenoma also may arise in diverse sites such as the face, axillae, lower extremities, or genitalia.

Notably, scalp lesions often are associated with nevus sebaceus of Jadassohn or syringocystadenoma papilliferum. Microscopically, tubular adenoma is well circumscribed within the dermis and may extend into the subcutis in some cases. Its distinctive appearance consists of variably sized tubules lined by a double or multilayered cuboidal to columnar epithelium, frequently displaying apocrine decapitation secretion (Figure 2). Cystic changes and intraluminal papillae devoid of true fibrovascular cores frequently are observed. Immunohistochemically, luminal epithelial cells express epithelial membrane antigen and carcinoembryonic antigen, while the myoepithelial layer expresses smooth muscle markers, p40, and S-100 protein. BRAF V600E mutation can be detected using immunohistochemistry, with excellent sensitivity and specificity using the anti-BRAF V600E antibody (clone VE1).⁵ Distinguishing tubular adenoma from MSA is achievable by observing its larger, more variable tubules, along with the consistent presence of a peripheral myoepithelial layer.

Secretory carcinoma is recognized as a low-grade gene fusion–driven carcinoma that primarily arises in salivary glands (both major and minor), with occasional occurrences in the breast and extremely rare instances in other locations such as the skin, thyroid gland, and lung.⁶ Although the axilla is the most common cutaneous site, diverse locations such as the neck, eyelids, extremities, and nipples also have been documented. Secretory carcinoma affects individuals across a wide age range (13–71 years).⁶ The hallmark tumors exhibit densely packed, sievelike microcystic glands and tubular spaces filled with abundant eosinophilic intraluminal secretions (Figure 3). Additionally, morphologic variants, such as predominantly papillary, papillary-cystic, macrocystic, solid, partially mucinous, and mixed-pattern neoplasms, have been described. Secretory carcinoma shares certain features with MSA; however, it is distinguished by the presence of pronounced eosinophilic secretions, plump and vacuolated cytoplasm, and a less conspicuous fibromyxoid stroma. Immunohistochemistry reveals tumor cells that are positive for CK7, SOX-10, S-100, mammaglobin, MUC4, and variably GATA-3. Genetically, secretory carcinoma exhibits distinct characteristics, commonly showing the ETV6::NTRK3 fusion, detectable through molecular techniques or pan-TRK immunohistochemistry, while RET fusions and other rare variants are less frequent.⁷

In 1998, Requena et al⁸ introduced the concept of primary cutaneous cribriform carcinoma. Despite initially being classified as a carcinoma, the malignant potential of this tumor remains uncertain. Consequently, the term cribriform tumor now has become the preferred terminology for denoting this rare entity.⁹ Primary cutaneous cribriform tumors are observed more commonly in women and typically affect individuals aged 20 to 55 years (mean, 44 years). Predominant locations include the upper and lower extremities, especially the thighs, knees, and legs, with additional cases occurring on the head and trunk. Microscopically, cribriform tumor is characterized by a partially circumscribed, unencapsulated dermal nodule composed of round or oval nuclei displaying hyperchromatism and mild pleomorphism. The defining aspect of its morphology revolves around interspersed small round cavities that give rise to the hallmark cribriform pattern (Figure 4). Although MSA occasionally may exhibit a cribriform architectural pattern, it typically lacks the distinctive feature of thin, threadlike, intraluminal bridging strands observed in cribriform tumors. Similarly, luminal cells within the cribriform tumor express CK7 and exhibit variable S-100 expression. It is recognized as an indolent neoplasm with uncertain malignant potential.

The histopathologic features of metastatic carcinomas can overlap with those of primary cutaneous tumors, particularly adnexal neoplasms.¹⁰ However, several key features can aid in the differentiation of cutaneous metastases, including a dermal-based growth pattern with or without subcutaneous involvement, the presence of multiple lesions, and the occurrence of lymphovascular invasion (Figure 5). Conversely, features that suggest a primary cutaneous adnexal neoplasm include the presence of superimposed in situ disease, carcinoma developing within a benign adnexal neoplasm, and notable stromal and/or vascular hyalinization within benign-appearing areas. In some cases, it can be difficult to determine the primary site of origin of a metastatic carcinoma to the skin based on morphologic features alone. In these cases, immunohistochemistry can be helpful. The most cost-effective and time-efficient approach to accurate diagnosis is to obtain a comprehensive clinical history. If there is a known history of cancer, a small panel of organ-specific immunohistochemical studies can be performed to confirm the diagnosis. If there is no known history, an algorithmic approach can be used to identify the primary site of origin. In all circumstances, it cannot be stressed enough that acquiring a thorough clinical history before conducting any diagnostic examinations is paramount.

The Diagnosis: Microsecretory Adenocarcinoma

Microscopically, the tumor was relatively well circumscribed but had irregular borders. It consisted of microcysts and tubules lined by flattened to plump eosinophilic cells with mildly enlarged nuclei and intraluminal basophilic secretions. Peripheral lymphocytic aggregates also were seen in the mid and deep reticular dermis. Tumor necrosis, lymphovascular invasion, and notable mitotic activity were absent. Immunohistochemistry was diffusely positive for cytokeratin (CK) 7 and CK5/6. Occasional tumor cells showed variable expression of alpha smooth muscle actin, S-100 protein, and p40 and p63 antibodies. Immunohistochemistry was negative for CK20; GATA binding protein 3; MYB proto-oncogene, transcription factor; and insulinoma-associated protein ¹. A dual-color, break-apart fluorescence in situ hybridization probe identified a rearrangement of the SS18 (SYT) gene locus on chromosome 18. The nodule was excised with clear surgical margins, and the patient had no evidence of recurrent disease or metastasis at 2-year follow-up.

In recent years, there has been a growing recognition of the pivotal role played by gene fusions in driving oncogenesis, encompassing a diverse range of benign and malignant cutaneous neoplasms. These investigations have shed light on previously unknown mechanisms and pathways contributing to the pathogenesis of these neoplastic conditions, offering invaluable insights into their underlying biology. As a result, our ability to classify and diagnose these cutaneous tumors has improved. A notable example of how our current understanding has evolved is the discovery of the new cutaneous adnexal tumor microsecretory adenocarcinoma (MSA). Initially described by Bishop et al¹ in 2019 as predominantly occurring in the intraoral minor salivary glands, rare instances of primary cutaneous MSA involving the head and neck regions also have been reported.² Microsecretory adenocarcinoma represents an important addition to the group of fusion-driven tumors with both salivary gland and cutaneous adnexal analogues, characterized by a MEF2C::SS18 gene fusion. This entity is now recognized as a group of cutaneous adnexal tumors with distinct gene fusions, including both relatively recently discovered entities (eg, secretory carcinoma with NTRK fusions) and previously known entities with newly identified gene fusions (eg, poroid neoplasms with NUTM1, YAP1, or WWTR1 fusions; hidradenomatous neoplasms with CRTC1::MAML2 fusions; and adenoid cystic carcinoma with MYB, MYBL1, and/or NFIB rearrangements).³

Microsecretory adenocarcinoma exhibits a high degree of morphologic consistency, characterized by a microcystic-predominant growth pattern, uniform intercalated ductlike tumor cells with attenuated eosinophilic to clear cytoplasm, monotonous oval hyperchromatic nuclei with indistinct nucleoli, abundant basophilic luminal secretions, and a variably cellular fibromyxoid stroma. It also shows rounded borders with subtle infiltrative growth. Occasionally, pseudoepitheliomatous hyperplasia, tumor-associated lymphoid proliferation, or metaplastic bone formation may accompany MSA. Perineural invasion is rare, necrosis is absent, and mitotic rates generally are low, contributing to its distinctive histopathologic features that aid in accurate diagnosis and differentiation from other entities. Immunohistochemistry reveals diffuse positivity for CK7 and patchy to diffuse expression of S-100 in tumor cells as well as variable expression of p40 and p63. Highly specific SS18 gene translocations at chromosome 18q are useful for diagnosing MSA when found alongside its characteristic appearance, and SS18 break-apart fluorescence in situ hybridization can serve reliably as an accurate diagnostic method (Figure 1).⁴ Our case illustrates how molecular analysis assists in distinguishing MSA from other cutaneous adnexal tumors, exemplifying the power of our evolving understanding in refining diagnostic accuracy and guiding targeted therapies in clinical practice.

The differential diagnosis of MSA includes tubular adenoma, secretory carcinoma, cribriform tumor (previously carcinoma), and metastatic adenocarcinoma. Tubular adenoma is a rare benign neoplasm that predominantly affects females and can manifest at any age in adulthood. It typically manifests as a slow-growing, occasionally pedunculated nodule, often measuring less than 2 cm. Although it most commonly manifests on the scalp, tubular adenoma also may arise in diverse sites such as the face, axillae, lower extremities, or genitalia.

Notably, scalp lesions often are associated with nevus sebaceus of Jadassohn or syringocystadenoma papilliferum. Microscopically, tubular adenoma is well circumscribed within the dermis and may extend into the subcutis in some cases. Its distinctive appearance consists of variably sized tubules lined by a double or multilayered cuboidal to columnar epithelium, frequently displaying apocrine decapitation secretion (Figure 2). Cystic changes and intraluminal papillae devoid of true fibrovascular cores frequently are observed. Immunohistochemically, luminal epithelial cells express epithelial membrane antigen and carcinoembryonic antigen, while the myoepithelial layer expresses smooth muscle markers, p40, and S-100 protein. BRAF V600E mutation can be detected using immunohistochemistry, with excellent sensitivity and specificity using the anti-BRAF V600E antibody (clone VE1).⁵ Distinguishing tubular adenoma from MSA is achievable by observing its larger, more variable tubules, along with the consistent presence of a peripheral myoepithelial layer.

Secretory carcinoma is recognized as a low-grade gene fusion–driven carcinoma that primarily arises in salivary glands (both major and minor), with occasional occurrences in the breast and extremely rare instances in other locations such as the skin, thyroid gland, and lung.⁶ Although the axilla is the most common cutaneous site, diverse locations such as the neck, eyelids, extremities, and nipples also have been documented. Secretory carcinoma affects individuals across a wide age range (13–71 years).⁶ The hallmark tumors exhibit densely packed, sievelike microcystic glands and tubular spaces filled with abundant eosinophilic intraluminal secretions (Figure 3). Additionally, morphologic variants, such as predominantly papillary, papillary-cystic, macrocystic, solid, partially mucinous, and mixed-pattern neoplasms, have been described. Secretory carcinoma shares certain features with MSA; however, it is distinguished by the presence of pronounced eosinophilic secretions, plump and vacuolated cytoplasm, and a less conspicuous fibromyxoid stroma. Immunohistochemistry reveals tumor cells that are positive for CK7, SOX-10, S-100, mammaglobin, MUC4, and variably GATA-3. Genetically, secretory carcinoma exhibits distinct characteristics, commonly showing the ETV6::NTRK3 fusion, detectable through molecular techniques or pan-TRK immunohistochemistry, while RET fusions and other rare variants are less frequent.⁷

In 1998, Requena et al⁸ introduced the concept of primary cutaneous cribriform carcinoma. Despite initially being classified as a carcinoma, the malignant potential of this tumor remains uncertain. Consequently, the term cribriform tumor now has become the preferred terminology for denoting this rare entity.⁹ Primary cutaneous cribriform tumors are observed more commonly in women and typically affect individuals aged 20 to 55 years (mean, 44 years). Predominant locations include the upper and lower extremities, especially the thighs, knees, and legs, with additional cases occurring on the head and trunk. Microscopically, cribriform tumor is characterized by a partially circumscribed, unencapsulated dermal nodule composed of round or oval nuclei displaying hyperchromatism and mild pleomorphism. The defining aspect of its morphology revolves around interspersed small round cavities that give rise to the hallmark cribriform pattern (Figure 4). Although MSA occasionally may exhibit a cribriform architectural pattern, it typically lacks the distinctive feature of thin, threadlike, intraluminal bridging strands observed in cribriform tumors. Similarly, luminal cells within the cribriform tumor express CK7 and exhibit variable S-100 expression. It is recognized as an indolent neoplasm with uncertain malignant potential.

The histopathologic features of metastatic carcinomas can overlap with those of primary cutaneous tumors, particularly adnexal neoplasms.¹⁰ However, several key features can aid in the differentiation of cutaneous metastases, including a dermal-based growth pattern with or without subcutaneous involvement, the presence of multiple lesions, and the occurrence of lymphovascular invasion (Figure 5). Conversely, features that suggest a primary cutaneous adnexal neoplasm include the presence of superimposed in situ disease, carcinoma developing within a benign adnexal neoplasm, and notable stromal and/or vascular hyalinization within benign-appearing areas. In some cases, it can be difficult to determine the primary site of origin of a metastatic carcinoma to the skin based on morphologic features alone. In these cases, immunohistochemistry can be helpful. The most cost-effective and time-efficient approach to accurate diagnosis is to obtain a comprehensive clinical history. If there is a known history of cancer, a small panel of organ-specific immunohistochemical studies can be performed to confirm the diagnosis. If there is no known history, an algorithmic approach can be used to identify the primary site of origin. In all circumstances, it cannot be stressed enough that acquiring a thorough clinical history before conducting any diagnostic examinations is paramount.

TOPLINE:

The maternal and neonatal outcomes in pregnant women treated with anti–interleukin (IL)-6 therapy for COVID-19 are largely favorable, with transient neonatal cytopenia observed in around one third of the babies being the only possible adverse outcome that could be related to anti–IL-6 therapy.

METHODOLOGY:

• Despite guidance, very few pregnant women with COVID-19 are offered evidence-based therapies such as anti–IL-6 due to concerns regarding fetal safety in later pregnancy.
• In this retrospective study, researchers evaluated maternal and neonatal outcomes in 25 pregnant women with COVID-19 (mean age at admission, 33 years) treated with anti–IL-6 (tocilizumab or sarilumab) at two tertiary hospitals in London.
• Most women (n = 16) received anti–IL-6 in the third trimester of pregnancy, whereas nine received it during the second trimester.
• Maternal and neonatal outcomes were assessed through medical record reviews and maternal medicine networks, with follow-up for 12 months.
• The women included in the study constituted a high-risk population with severe COVID-19; 24 required level two or three critical care. All women were receiving at least three concomitant medications due to their critical illness.

TAKEAWAY:

• Overall, 24 of 25 women treated with IL-6 receptor antibodies survived until hospital discharge.
• The sole death occurred in a woman with severe COVID-19 pneumonitis who later developed myocarditis and cardiac arrest. The physicians believed that these complications were more likely due to severe COVID-19 rather than anti–IL-6 therapy.
• All pregnancies resulted in live births; however, 16 babies had to be delivered preterm due to COVID-19 complications.
• Transient cytopenia was observed in 6 of 19 babies in whom a full blood count was performed. All the six babies were premature, with cytopenia resolving within 7 days in four babies; one baby died from complications associated with extreme prematurity.

IN PRACTICE:

“Although the authors found mild, transitory cytopenia in some (6 of 19) exposed infants, most had been delivered prematurely due to progressive COVID-19–related morbidity, and distinguishing drug effects from similar prematurity-related effects is difficult,” wrote Steven L. Clark, MD, from the Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, in an accompanying editorial.

SOURCE:

The study was led by Melanie Nana, MRCP, from the Department of Obstetric Medicine, St Thomas’ Hospital, London, England. It was published online in The Lancet Rheumatology.

LIMITATIONS:

The study was retrospective in design, which may have introduced bias. The small sample size of 25 women may have limited the generalizability of the findings. Additionally, the study did not include a control group, which made it difficult to attribute outcomes solely to anti–IL-6 therapy. The lack of long-term follow-up data on the neonates also limited the understanding of potential long-term effects.

DISCLOSURES:

This study did not receive any funding. Some authors, including the lead author, received speaker fees, grants, or consultancy fees from academic institutions or pharmaceutical companies or had other ties with various sources.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The maternal and neonatal outcomes in pregnant women treated with anti–interleukin (IL)-6 therapy for COVID-19 are largely favorable, with transient neonatal cytopenia observed in around one third of the babies being the only possible adverse outcome that could be related to anti–IL-6 therapy.

METHODOLOGY:

• Despite guidance, very few pregnant women with COVID-19 are offered evidence-based therapies such as anti–IL-6 due to concerns regarding fetal safety in later pregnancy.
• In this retrospective study, researchers evaluated maternal and neonatal outcomes in 25 pregnant women with COVID-19 (mean age at admission, 33 years) treated with anti–IL-6 (tocilizumab or sarilumab) at two tertiary hospitals in London.
• Most women (n = 16) received anti–IL-6 in the third trimester of pregnancy, whereas nine received it during the second trimester.
• Maternal and neonatal outcomes were assessed through medical record reviews and maternal medicine networks, with follow-up for 12 months.
• The women included in the study constituted a high-risk population with severe COVID-19; 24 required level two or three critical care. All women were receiving at least three concomitant medications due to their critical illness.

TAKEAWAY:

• Overall, 24 of 25 women treated with IL-6 receptor antibodies survived until hospital discharge.
• The sole death occurred in a woman with severe COVID-19 pneumonitis who later developed myocarditis and cardiac arrest. The physicians believed that these complications were more likely due to severe COVID-19 rather than anti–IL-6 therapy.
• All pregnancies resulted in live births; however, 16 babies had to be delivered preterm due to COVID-19 complications.
• Transient cytopenia was observed in 6 of 19 babies in whom a full blood count was performed. All the six babies were premature, with cytopenia resolving within 7 days in four babies; one baby died from complications associated with extreme prematurity.

IN PRACTICE:

“Although the authors found mild, transitory cytopenia in some (6 of 19) exposed infants, most had been delivered prematurely due to progressive COVID-19–related morbidity, and distinguishing drug effects from similar prematurity-related effects is difficult,” wrote Steven L. Clark, MD, from the Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, in an accompanying editorial.

SOURCE:

The study was led by Melanie Nana, MRCP, from the Department of Obstetric Medicine, St Thomas’ Hospital, London, England. It was published online in The Lancet Rheumatology.

LIMITATIONS:

The study was retrospective in design, which may have introduced bias. The small sample size of 25 women may have limited the generalizability of the findings. Additionally, the study did not include a control group, which made it difficult to attribute outcomes solely to anti–IL-6 therapy. The lack of long-term follow-up data on the neonates also limited the understanding of potential long-term effects.

DISCLOSURES:

This study did not receive any funding. Some authors, including the lead author, received speaker fees, grants, or consultancy fees from academic institutions or pharmaceutical companies or had other ties with various sources.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The maternal and neonatal outcomes in pregnant women treated with anti–interleukin (IL)-6 therapy for COVID-19 are largely favorable, with transient neonatal cytopenia observed in around one third of the babies being the only possible adverse outcome that could be related to anti–IL-6 therapy.

METHODOLOGY:

• Despite guidance, very few pregnant women with COVID-19 are offered evidence-based therapies such as anti–IL-6 due to concerns regarding fetal safety in later pregnancy.
• In this retrospective study, researchers evaluated maternal and neonatal outcomes in 25 pregnant women with COVID-19 (mean age at admission, 33 years) treated with anti–IL-6 (tocilizumab or sarilumab) at two tertiary hospitals in London.
• Most women (n = 16) received anti–IL-6 in the third trimester of pregnancy, whereas nine received it during the second trimester.
• Maternal and neonatal outcomes were assessed through medical record reviews and maternal medicine networks, with follow-up for 12 months.
• The women included in the study constituted a high-risk population with severe COVID-19; 24 required level two or three critical care. All women were receiving at least three concomitant medications due to their critical illness.

TAKEAWAY:

• Overall, 24 of 25 women treated with IL-6 receptor antibodies survived until hospital discharge.
• The sole death occurred in a woman with severe COVID-19 pneumonitis who later developed myocarditis and cardiac arrest. The physicians believed that these complications were more likely due to severe COVID-19 rather than anti–IL-6 therapy.
• All pregnancies resulted in live births; however, 16 babies had to be delivered preterm due to COVID-19 complications.
• Transient cytopenia was observed in 6 of 19 babies in whom a full blood count was performed. All the six babies were premature, with cytopenia resolving within 7 days in four babies; one baby died from complications associated with extreme prematurity.

IN PRACTICE:

“Although the authors found mild, transitory cytopenia in some (6 of 19) exposed infants, most had been delivered prematurely due to progressive COVID-19–related morbidity, and distinguishing drug effects from similar prematurity-related effects is difficult,” wrote Steven L. Clark, MD, from the Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, in an accompanying editorial.

SOURCE:

The study was led by Melanie Nana, MRCP, from the Department of Obstetric Medicine, St Thomas’ Hospital, London, England. It was published online in The Lancet Rheumatology.

LIMITATIONS:

The study was retrospective in design, which may have introduced bias. The small sample size of 25 women may have limited the generalizability of the findings. Additionally, the study did not include a control group, which made it difficult to attribute outcomes solely to anti–IL-6 therapy. The lack of long-term follow-up data on the neonates also limited the understanding of potential long-term effects.

DISCLOSURES:

This study did not receive any funding. Some authors, including the lead author, received speaker fees, grants, or consultancy fees from academic institutions or pharmaceutical companies or had other ties with various sources.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Chemotherapy has fallen out of favor for treating cancer toward the end of life. The toxicity is too high, and the benefit, if any, is often too low.

Immunotherapy, however, has been taking its place. Checkpoint inhibitors are increasingly being initiated to treat metastatic cancer in patients approaching the end of life and have become the leading driver of end-of-life cancer spending.

This means “there are patients who are getting immunotherapy who shouldn’t,” said Yale University, New Haven, Connecticut, surgical oncologist Sajid Khan, MD, senior investigator on a recent study that highlighted the growing use of these agents in patients’ last month of life.

What’s driving this trend, and how can oncologists avoid overtreatment with immunotherapy at the end of life?
 

The N-of-1 Patient

With immunotherapy at the end of life, “each of us has had our N-of-1” where a patient bounces back with a remarkable and durable response, said Don Dizon, MD, a gynecologic oncologist at Brown University, Providence, Rhode Island.

He recalled a patient with sarcoma who did not respond to chemotherapy. But after Dr. Dizon started her on immunotherapy, everything turned around. She has now been in remission for 8 years and counting.

The possibility of an unexpected or remarkable responder is seductive. And the improved safety of immunotherapy over chemotherapy adds to the allure.

Meanwhile, patients are often desperate. It’s rare for someone to be ready to stop treatment, Dr. Dizon said. Everybody “hopes that they’re going to be the exceptional responder.”

At the end of the day, the question often becomes: “Why not try immunotherapy? What’s there to lose?”

This thinking may be prompting broader use of immunotherapy in late-stage disease, even in instances with no Food and Drug Administration indication and virtually no supportive data, such as for metastatic ovarian cancer, Dr. Dizon said.
 

Back to Earth

The problem with the hopeful approach is that end-of-life turnarounds with immunotherapy are rare, and there’s no way at the moment to predict who will have one, said Laura Petrillo, MD, a palliative care physician at Massachusetts General Hospital, Boston.

Even though immunotherapy generally comes with fewer adverse events than chemotherapy, catastrophic side effects are still possible.

Dr. Petrillo recalled a 95-year-old woman with metastatic cancer who was largely asymptomatic.

She had a qualifying mutation for a checkpoint inhibitor, so her oncologist started her on one. The patient never bounced back from the severe colitis the agent caused, and she died of complications in the hospital.

Although such reactions with immunotherapy are uncommon, less serious problems caused by the agents can still have a major impact on a person’s quality of life. Low-grade diarrhea, for instance, may not sound too bad, but in a patient’s daily life, it can translate to six or more episodes a day.

Even with no side effects, prescribing immunotherapy can mean that patients with limited time left spend a good portion of it at an infusion clinic instead of at home. These patients are also less likely to be referred to hospice and more likely to be admitted to and die in the hospital.

And with treatments that can cost $20,000 per dose, financial toxicity becomes a big concern.

In short, some of the reasons why chemotherapy is not recommended at the end of life also apply to immunotherapy, Dr. Petrillo said.
 

Prescribing Decisions

Recent research highlights the growing use of immunotherapy at the end of life.

Dr. Khan’s retrospective study found, for instance, that the percentage of patients starting immunotherapy in the last 30 days of life increased by about fourfold to fivefold over the study period for the three cancers analyzed — stage IV melanoma, lung, and kidney cancers.

Among the population that died within 30 days, the percentage receiving immunotherapy increased over the study periods — 0.8%-4.3% for melanoma, 0.9%-3.2% for NSCLC, and 0.5%-2.6% for kidney cell carcinoma — prompting the conclusion that immunotherapy prescriptions in the last month of life are on the rise.

Prescribing immunotherapy in patients who ultimately died within 1 month occurred more frequently at low-volume, nonacademic centers than at academic or high-volume centers, and outcomes varied by practice setting.

Patients had better survival outcomes overall when receiving immunotherapy at academic or high-volume centers — a finding Dr. Khan said is worth investigating further. Possible explanations include better management of severe immune-related side effects at larger centers and more caution when prescribing immunotherapy to “borderline” candidates, such as those with several comorbidities.

Importantly, given the retrospective design, Dr. Khan and colleagues already knew which patients prescribed immunotherapy died within 30 days of initiating treatment.

More specifically, 5192 of 71,204 patients who received immunotherapy (7.3%) died within a month of initiating therapy, while 66,012 (92.7%) lived beyond that point.

The study, however, did not assess how the remaining 92.7% who lived beyond 30 days fared on immunotherapy and the differences between those who lived less than 30 days and those who survived longer.

Knowing the outcome of patients at the outset of the analysis still leaves open the question of when immunotherapy can extend life and when it can’t for the patient in front of you.

To avoid overtreating at the end of life, it’s important to have “the same standard that you have for giving chemotherapy. You have to treat it with the same respect,” said Moshe Chasky, MD, a community medical oncologist with Alliance Cancer Specialists in Philadelphia, Pennsylvania. “You can’t just be throwing” immunotherapy around “at the end of life.”

While there are no clear predictors of risk and benefit, there are some factors to help guide decisions.

As with chemotherapy, Dr. Petrillo said performance status is key. Dr. Petrillo and colleagues found that median overall survival with immune checkpoint inhibitors for advanced non–small cell lung cancer was 14.3 months in patients with an Eastern Cooperative Oncology Group performance score of 0-1 but only 4.5 months with scores of ≥ 2.

Dr. Khan also found that immunotherapy survival is, unsurprisingly, worse in patients with high metastatic burdens and more comorbidities.

“You should still consider immunotherapy for metastatic melanoma, non–small cell lung cancer, and renal cell carcinoma,” Dr. Khan said. The message here is to “think twice before using” it, especially in comorbid patients with widespread metastases.

“Just because something can be done doesn’t always mean it should be done,” he said.

At Yale, when Dr. Khan works, immunotherapy decisions are considered by a multidisciplinary tumor board. At Mass General, immunotherapy has generally moved to the frontline setting, and the hospital no longer prescribes checkpoint inhibitors to hospitalized patients because the cost is too high relative to the potential benefit, Dr. Petrillo explained.

Still, with all the uncertainties about risk and benefit, counseling patients is a challenge. Dr. Dizon called it “the epitome of shared decision-making.”

Dr. Petrillo noted that it’s critical not to counsel patients based solely on the anecdotal patients who do surprisingly well.

“It’s hard to mention that and not have that be what somebody anchors on,” she said. But that speaks to “how desperate people can feel, how hopeful they can be.”

Dr. Khan, Dr. Petrillo, and Dr. Chasky all reported no relevant conflicts of interest.

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

Chemotherapy has fallen out of favor for treating cancer toward the end of life. The toxicity is too high, and the benefit, if any, is often too low.

Immunotherapy, however, has been taking its place. Checkpoint inhibitors are increasingly being initiated to treat metastatic cancer in patients approaching the end of life and have become the leading driver of end-of-life cancer spending.

This means “there are patients who are getting immunotherapy who shouldn’t,” said Yale University, New Haven, Connecticut, surgical oncologist Sajid Khan, MD, senior investigator on a recent study that highlighted the growing use of these agents in patients’ last month of life.

What’s driving this trend, and how can oncologists avoid overtreatment with immunotherapy at the end of life?
 

The N-of-1 Patient

With immunotherapy at the end of life, “each of us has had our N-of-1” where a patient bounces back with a remarkable and durable response, said Don Dizon, MD, a gynecologic oncologist at Brown University, Providence, Rhode Island.

He recalled a patient with sarcoma who did not respond to chemotherapy. But after Dr. Dizon started her on immunotherapy, everything turned around. She has now been in remission for 8 years and counting.

The possibility of an unexpected or remarkable responder is seductive. And the improved safety of immunotherapy over chemotherapy adds to the allure.

Meanwhile, patients are often desperate. It’s rare for someone to be ready to stop treatment, Dr. Dizon said. Everybody “hopes that they’re going to be the exceptional responder.”

At the end of the day, the question often becomes: “Why not try immunotherapy? What’s there to lose?”

This thinking may be prompting broader use of immunotherapy in late-stage disease, even in instances with no Food and Drug Administration indication and virtually no supportive data, such as for metastatic ovarian cancer, Dr. Dizon said.
 

Back to Earth

The problem with the hopeful approach is that end-of-life turnarounds with immunotherapy are rare, and there’s no way at the moment to predict who will have one, said Laura Petrillo, MD, a palliative care physician at Massachusetts General Hospital, Boston.

Even though immunotherapy generally comes with fewer adverse events than chemotherapy, catastrophic side effects are still possible.

Dr. Petrillo recalled a 95-year-old woman with metastatic cancer who was largely asymptomatic.

She had a qualifying mutation for a checkpoint inhibitor, so her oncologist started her on one. The patient never bounced back from the severe colitis the agent caused, and she died of complications in the hospital.

Although such reactions with immunotherapy are uncommon, less serious problems caused by the agents can still have a major impact on a person’s quality of life. Low-grade diarrhea, for instance, may not sound too bad, but in a patient’s daily life, it can translate to six or more episodes a day.

Even with no side effects, prescribing immunotherapy can mean that patients with limited time left spend a good portion of it at an infusion clinic instead of at home. These patients are also less likely to be referred to hospice and more likely to be admitted to and die in the hospital.

And with treatments that can cost $20,000 per dose, financial toxicity becomes a big concern.

In short, some of the reasons why chemotherapy is not recommended at the end of life also apply to immunotherapy, Dr. Petrillo said.
 

Prescribing Decisions

Recent research highlights the growing use of immunotherapy at the end of life.

Dr. Khan’s retrospective study found, for instance, that the percentage of patients starting immunotherapy in the last 30 days of life increased by about fourfold to fivefold over the study period for the three cancers analyzed — stage IV melanoma, lung, and kidney cancers.

Among the population that died within 30 days, the percentage receiving immunotherapy increased over the study periods — 0.8%-4.3% for melanoma, 0.9%-3.2% for NSCLC, and 0.5%-2.6% for kidney cell carcinoma — prompting the conclusion that immunotherapy prescriptions in the last month of life are on the rise.

Prescribing immunotherapy in patients who ultimately died within 1 month occurred more frequently at low-volume, nonacademic centers than at academic or high-volume centers, and outcomes varied by practice setting.

Patients had better survival outcomes overall when receiving immunotherapy at academic or high-volume centers — a finding Dr. Khan said is worth investigating further. Possible explanations include better management of severe immune-related side effects at larger centers and more caution when prescribing immunotherapy to “borderline” candidates, such as those with several comorbidities.

Importantly, given the retrospective design, Dr. Khan and colleagues already knew which patients prescribed immunotherapy died within 30 days of initiating treatment.

More specifically, 5192 of 71,204 patients who received immunotherapy (7.3%) died within a month of initiating therapy, while 66,012 (92.7%) lived beyond that point.

The study, however, did not assess how the remaining 92.7% who lived beyond 30 days fared on immunotherapy and the differences between those who lived less than 30 days and those who survived longer.

Knowing the outcome of patients at the outset of the analysis still leaves open the question of when immunotherapy can extend life and when it can’t for the patient in front of you.

To avoid overtreating at the end of life, it’s important to have “the same standard that you have for giving chemotherapy. You have to treat it with the same respect,” said Moshe Chasky, MD, a community medical oncologist with Alliance Cancer Specialists in Philadelphia, Pennsylvania. “You can’t just be throwing” immunotherapy around “at the end of life.”

While there are no clear predictors of risk and benefit, there are some factors to help guide decisions.

As with chemotherapy, Dr. Petrillo said performance status is key. Dr. Petrillo and colleagues found that median overall survival with immune checkpoint inhibitors for advanced non–small cell lung cancer was 14.3 months in patients with an Eastern Cooperative Oncology Group performance score of 0-1 but only 4.5 months with scores of ≥ 2.

Dr. Khan also found that immunotherapy survival is, unsurprisingly, worse in patients with high metastatic burdens and more comorbidities.

“You should still consider immunotherapy for metastatic melanoma, non–small cell lung cancer, and renal cell carcinoma,” Dr. Khan said. The message here is to “think twice before using” it, especially in comorbid patients with widespread metastases.

“Just because something can be done doesn’t always mean it should be done,” he said.

At Yale, when Dr. Khan works, immunotherapy decisions are considered by a multidisciplinary tumor board. At Mass General, immunotherapy has generally moved to the frontline setting, and the hospital no longer prescribes checkpoint inhibitors to hospitalized patients because the cost is too high relative to the potential benefit, Dr. Petrillo explained.

Still, with all the uncertainties about risk and benefit, counseling patients is a challenge. Dr. Dizon called it “the epitome of shared decision-making.”

Dr. Petrillo noted that it’s critical not to counsel patients based solely on the anecdotal patients who do surprisingly well.

“It’s hard to mention that and not have that be what somebody anchors on,” she said. But that speaks to “how desperate people can feel, how hopeful they can be.”

Dr. Khan, Dr. Petrillo, and Dr. Chasky all reported no relevant conflicts of interest.

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

Chemotherapy has fallen out of favor for treating cancer toward the end of life. The toxicity is too high, and the benefit, if any, is often too low.

Immunotherapy, however, has been taking its place. Checkpoint inhibitors are increasingly being initiated to treat metastatic cancer in patients approaching the end of life and have become the leading driver of end-of-life cancer spending.

This means “there are patients who are getting immunotherapy who shouldn’t,” said Yale University, New Haven, Connecticut, surgical oncologist Sajid Khan, MD, senior investigator on a recent study that highlighted the growing use of these agents in patients’ last month of life.

What’s driving this trend, and how can oncologists avoid overtreatment with immunotherapy at the end of life?
 

The N-of-1 Patient

With immunotherapy at the end of life, “each of us has had our N-of-1” where a patient bounces back with a remarkable and durable response, said Don Dizon, MD, a gynecologic oncologist at Brown University, Providence, Rhode Island.

He recalled a patient with sarcoma who did not respond to chemotherapy. But after Dr. Dizon started her on immunotherapy, everything turned around. She has now been in remission for 8 years and counting.

The possibility of an unexpected or remarkable responder is seductive. And the improved safety of immunotherapy over chemotherapy adds to the allure.

Meanwhile, patients are often desperate. It’s rare for someone to be ready to stop treatment, Dr. Dizon said. Everybody “hopes that they’re going to be the exceptional responder.”

At the end of the day, the question often becomes: “Why not try immunotherapy? What’s there to lose?”

This thinking may be prompting broader use of immunotherapy in late-stage disease, even in instances with no Food and Drug Administration indication and virtually no supportive data, such as for metastatic ovarian cancer, Dr. Dizon said.
 

Back to Earth

The problem with the hopeful approach is that end-of-life turnarounds with immunotherapy are rare, and there’s no way at the moment to predict who will have one, said Laura Petrillo, MD, a palliative care physician at Massachusetts General Hospital, Boston.

Even though immunotherapy generally comes with fewer adverse events than chemotherapy, catastrophic side effects are still possible.

Dr. Petrillo recalled a 95-year-old woman with metastatic cancer who was largely asymptomatic.

She had a qualifying mutation for a checkpoint inhibitor, so her oncologist started her on one. The patient never bounced back from the severe colitis the agent caused, and she died of complications in the hospital.

Although such reactions with immunotherapy are uncommon, less serious problems caused by the agents can still have a major impact on a person’s quality of life. Low-grade diarrhea, for instance, may not sound too bad, but in a patient’s daily life, it can translate to six or more episodes a day.

Even with no side effects, prescribing immunotherapy can mean that patients with limited time left spend a good portion of it at an infusion clinic instead of at home. These patients are also less likely to be referred to hospice and more likely to be admitted to and die in the hospital.

And with treatments that can cost $20,000 per dose, financial toxicity becomes a big concern.

In short, some of the reasons why chemotherapy is not recommended at the end of life also apply to immunotherapy, Dr. Petrillo said.
 

Prescribing Decisions

Recent research highlights the growing use of immunotherapy at the end of life.

Dr. Khan’s retrospective study found, for instance, that the percentage of patients starting immunotherapy in the last 30 days of life increased by about fourfold to fivefold over the study period for the three cancers analyzed — stage IV melanoma, lung, and kidney cancers.

Among the population that died within 30 days, the percentage receiving immunotherapy increased over the study periods — 0.8%-4.3% for melanoma, 0.9%-3.2% for NSCLC, and 0.5%-2.6% for kidney cell carcinoma — prompting the conclusion that immunotherapy prescriptions in the last month of life are on the rise.

Prescribing immunotherapy in patients who ultimately died within 1 month occurred more frequently at low-volume, nonacademic centers than at academic or high-volume centers, and outcomes varied by practice setting.

Patients had better survival outcomes overall when receiving immunotherapy at academic or high-volume centers — a finding Dr. Khan said is worth investigating further. Possible explanations include better management of severe immune-related side effects at larger centers and more caution when prescribing immunotherapy to “borderline” candidates, such as those with several comorbidities.

Importantly, given the retrospective design, Dr. Khan and colleagues already knew which patients prescribed immunotherapy died within 30 days of initiating treatment.

More specifically, 5192 of 71,204 patients who received immunotherapy (7.3%) died within a month of initiating therapy, while 66,012 (92.7%) lived beyond that point.

The study, however, did not assess how the remaining 92.7% who lived beyond 30 days fared on immunotherapy and the differences between those who lived less than 30 days and those who survived longer.

Knowing the outcome of patients at the outset of the analysis still leaves open the question of when immunotherapy can extend life and when it can’t for the patient in front of you.

To avoid overtreating at the end of life, it’s important to have “the same standard that you have for giving chemotherapy. You have to treat it with the same respect,” said Moshe Chasky, MD, a community medical oncologist with Alliance Cancer Specialists in Philadelphia, Pennsylvania. “You can’t just be throwing” immunotherapy around “at the end of life.”

While there are no clear predictors of risk and benefit, there are some factors to help guide decisions.

As with chemotherapy, Dr. Petrillo said performance status is key. Dr. Petrillo and colleagues found that median overall survival with immune checkpoint inhibitors for advanced non–small cell lung cancer was 14.3 months in patients with an Eastern Cooperative Oncology Group performance score of 0-1 but only 4.5 months with scores of ≥ 2.

Dr. Khan also found that immunotherapy survival is, unsurprisingly, worse in patients with high metastatic burdens and more comorbidities.

“You should still consider immunotherapy for metastatic melanoma, non–small cell lung cancer, and renal cell carcinoma,” Dr. Khan said. The message here is to “think twice before using” it, especially in comorbid patients with widespread metastases.

“Just because something can be done doesn’t always mean it should be done,” he said.

At Yale, when Dr. Khan works, immunotherapy decisions are considered by a multidisciplinary tumor board. At Mass General, immunotherapy has generally moved to the frontline setting, and the hospital no longer prescribes checkpoint inhibitors to hospitalized patients because the cost is too high relative to the potential benefit, Dr. Petrillo explained.

Still, with all the uncertainties about risk and benefit, counseling patients is a challenge. Dr. Dizon called it “the epitome of shared decision-making.”

Dr. Petrillo noted that it’s critical not to counsel patients based solely on the anecdotal patients who do surprisingly well.

“It’s hard to mention that and not have that be what somebody anchors on,” she said. But that speaks to “how desperate people can feel, how hopeful they can be.”

Dr. Khan, Dr. Petrillo, and Dr. Chasky all reported no relevant conflicts of interest.

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

TOPLINE:

Elevated depression symptoms are linked to an increased risk for severe chemotherapy toxicity in older adults with cancer. This risk is mitigated by geriatric assessment (GA)-driven interventions.

METHODOLOGY:

• Researchers conducted a secondary analysis of a randomized controlled trial to evaluate whether greater reductions in grade 3 chemotherapy-related toxicities occurred with geriatric assessment-driven interventions vs standard care.
• A total of 605 patients aged 65 years and older with any stage of solid malignancy were included, with 402 randomized to the intervention arm and 203 to the standard-of-care arm.
• Mental health was assessed using the Mental Health Inventory 13, and chemotherapy toxicity was graded by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.
• Patients in the intervention arm received recommendations from a multidisciplinary team based on their baseline GA, while those in the standard-of-care arm received only the baseline assessment results.
• The study was conducted at City of Hope National Medical Center in Duarte, California, and patients were followed throughout treatment or for up to 6 months from starting chemotherapy.

TAKEAWAY:

• According to the authors, patients with depression had increased chemotherapy toxicity in the standard-of-care arm (70.7% vs 54.3%; P = .02) but not in the GA-driven intervention arm (54.3% vs 48.5%; P = .27).
• The association between depression and chemotherapy toxicity was also seen after adjustment for the Cancer and Aging Research Group toxicity score (odds ratio, [OR], 1.98; 95% CI, 1.07-3.65) and for demographic, disease, and treatment factors (OR, 2.00; 95% CI, 1.03-3.85).
• No significant association was found between anxiety and chemotherapy toxicity in either the standard-of-care arm (univariate OR, 1.07; 95% CI, 0.61-1.88) or the GA-driven intervention arm (univariate OR, 1.15; 95% CI, 0.78-1.71).
• The authors stated that depression was associated with increased odds of hematologic-only toxicities (OR, 2.50; 95% CI, 1.13-5.56) in the standard-of-care arm.
• An analysis of a small subgroup found associations between elevated anxiety symptoms and increased risk for hematologic and nonhematologic chemotherapy toxicities.

IN PRACTICE:

“The current study showed that elevated depression symptoms are associated with increased risk of severe chemotherapy toxicities in older adults with cancer. This risk was mitigated in those in the GA intervention arm, which suggests that addressing elevated depression symptoms may lower the risk of toxicities,” the authors wrote. “Overall, elevated anxiety symptoms were not associated with risk for severe chemotherapy toxicity.”

SOURCE:

Reena V. Jayani, MD, MSCI, of Vanderbilt University Medical Center in Nashville, Tennessee, was the first and corresponding author for this paper. This study was published online August 4, 2024, in Cancer. 

LIMITATIONS:

The thresholds for depression and anxiety used in the Mental Health Inventory 13 were based on an English-speaking population, which may not be fully applicable to Chinese- and Spanish-speaking patients included in the study. Depression and anxiety were not evaluated by a mental health professional or with a structured interview to assess formal diagnostic criteria. Psychiatric medication used at the time of baseline GA was not included in the analysis. The study is a secondary analysis of a randomized controlled trial, and it is not known which components of the interventions affected mental health.

DISCLOSURES:

This research project was supported by the UniHealth Foundation, the City of Hope Center for Cancer and Aging, and the National Institutes of Health. One coauthor disclosed receiving institutional research funding from AstraZeneca and Brooklyn ImmunoTherapeutics and consulting for multiple pharmaceutical companies, including AbbVie, Adagene, and Bayer HealthCare Pharmaceuticals. William Dale, MD, PhD, of City of Hope National Medical Center, served as senior author and a principal investigator. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Elevated depression symptoms are linked to an increased risk for severe chemotherapy toxicity in older adults with cancer. This risk is mitigated by geriatric assessment (GA)-driven interventions.

METHODOLOGY:

• Researchers conducted a secondary analysis of a randomized controlled trial to evaluate whether greater reductions in grade 3 chemotherapy-related toxicities occurred with geriatric assessment-driven interventions vs standard care.
• A total of 605 patients aged 65 years and older with any stage of solid malignancy were included, with 402 randomized to the intervention arm and 203 to the standard-of-care arm.
• Mental health was assessed using the Mental Health Inventory 13, and chemotherapy toxicity was graded by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.
• Patients in the intervention arm received recommendations from a multidisciplinary team based on their baseline GA, while those in the standard-of-care arm received only the baseline assessment results.
• The study was conducted at City of Hope National Medical Center in Duarte, California, and patients were followed throughout treatment or for up to 6 months from starting chemotherapy.

TAKEAWAY:

• According to the authors, patients with depression had increased chemotherapy toxicity in the standard-of-care arm (70.7% vs 54.3%; P = .02) but not in the GA-driven intervention arm (54.3% vs 48.5%; P = .27).
• The association between depression and chemotherapy toxicity was also seen after adjustment for the Cancer and Aging Research Group toxicity score (odds ratio, [OR], 1.98; 95% CI, 1.07-3.65) and for demographic, disease, and treatment factors (OR, 2.00; 95% CI, 1.03-3.85).
• No significant association was found between anxiety and chemotherapy toxicity in either the standard-of-care arm (univariate OR, 1.07; 95% CI, 0.61-1.88) or the GA-driven intervention arm (univariate OR, 1.15; 95% CI, 0.78-1.71).
• The authors stated that depression was associated with increased odds of hematologic-only toxicities (OR, 2.50; 95% CI, 1.13-5.56) in the standard-of-care arm.
• An analysis of a small subgroup found associations between elevated anxiety symptoms and increased risk for hematologic and nonhematologic chemotherapy toxicities.

IN PRACTICE:

“The current study showed that elevated depression symptoms are associated with increased risk of severe chemotherapy toxicities in older adults with cancer. This risk was mitigated in those in the GA intervention arm, which suggests that addressing elevated depression symptoms may lower the risk of toxicities,” the authors wrote. “Overall, elevated anxiety symptoms were not associated with risk for severe chemotherapy toxicity.”

SOURCE:

Reena V. Jayani, MD, MSCI, of Vanderbilt University Medical Center in Nashville, Tennessee, was the first and corresponding author for this paper. This study was published online August 4, 2024, in Cancer. 

LIMITATIONS:

The thresholds for depression and anxiety used in the Mental Health Inventory 13 were based on an English-speaking population, which may not be fully applicable to Chinese- and Spanish-speaking patients included in the study. Depression and anxiety were not evaluated by a mental health professional or with a structured interview to assess formal diagnostic criteria. Psychiatric medication used at the time of baseline GA was not included in the analysis. The study is a secondary analysis of a randomized controlled trial, and it is not known which components of the interventions affected mental health.

DISCLOSURES:

This research project was supported by the UniHealth Foundation, the City of Hope Center for Cancer and Aging, and the National Institutes of Health. One coauthor disclosed receiving institutional research funding from AstraZeneca and Brooklyn ImmunoTherapeutics and consulting for multiple pharmaceutical companies, including AbbVie, Adagene, and Bayer HealthCare Pharmaceuticals. William Dale, MD, PhD, of City of Hope National Medical Center, served as senior author and a principal investigator. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Elevated depression symptoms are linked to an increased risk for severe chemotherapy toxicity in older adults with cancer. This risk is mitigated by geriatric assessment (GA)-driven interventions.

METHODOLOGY:

• Researchers conducted a secondary analysis of a randomized controlled trial to evaluate whether greater reductions in grade 3 chemotherapy-related toxicities occurred with geriatric assessment-driven interventions vs standard care.
• A total of 605 patients aged 65 years and older with any stage of solid malignancy were included, with 402 randomized to the intervention arm and 203 to the standard-of-care arm.
• Mental health was assessed using the Mental Health Inventory 13, and chemotherapy toxicity was graded by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.
• Patients in the intervention arm received recommendations from a multidisciplinary team based on their baseline GA, while those in the standard-of-care arm received only the baseline assessment results.
• The study was conducted at City of Hope National Medical Center in Duarte, California, and patients were followed throughout treatment or for up to 6 months from starting chemotherapy.

TAKEAWAY:

• According to the authors, patients with depression had increased chemotherapy toxicity in the standard-of-care arm (70.7% vs 54.3%; P = .02) but not in the GA-driven intervention arm (54.3% vs 48.5%; P = .27).
• The association between depression and chemotherapy toxicity was also seen after adjustment for the Cancer and Aging Research Group toxicity score (odds ratio, [OR], 1.98; 95% CI, 1.07-3.65) and for demographic, disease, and treatment factors (OR, 2.00; 95% CI, 1.03-3.85).
• No significant association was found between anxiety and chemotherapy toxicity in either the standard-of-care arm (univariate OR, 1.07; 95% CI, 0.61-1.88) or the GA-driven intervention arm (univariate OR, 1.15; 95% CI, 0.78-1.71).
• The authors stated that depression was associated with increased odds of hematologic-only toxicities (OR, 2.50; 95% CI, 1.13-5.56) in the standard-of-care arm.
• An analysis of a small subgroup found associations between elevated anxiety symptoms and increased risk for hematologic and nonhematologic chemotherapy toxicities.

IN PRACTICE:

“The current study showed that elevated depression symptoms are associated with increased risk of severe chemotherapy toxicities in older adults with cancer. This risk was mitigated in those in the GA intervention arm, which suggests that addressing elevated depression symptoms may lower the risk of toxicities,” the authors wrote. “Overall, elevated anxiety symptoms were not associated with risk for severe chemotherapy toxicity.”

SOURCE:

Reena V. Jayani, MD, MSCI, of Vanderbilt University Medical Center in Nashville, Tennessee, was the first and corresponding author for this paper. This study was published online August 4, 2024, in Cancer. 

LIMITATIONS:

The thresholds for depression and anxiety used in the Mental Health Inventory 13 were based on an English-speaking population, which may not be fully applicable to Chinese- and Spanish-speaking patients included in the study. Depression and anxiety were not evaluated by a mental health professional or with a structured interview to assess formal diagnostic criteria. Psychiatric medication used at the time of baseline GA was not included in the analysis. The study is a secondary analysis of a randomized controlled trial, and it is not known which components of the interventions affected mental health.

DISCLOSURES:

This research project was supported by the UniHealth Foundation, the City of Hope Center for Cancer and Aging, and the National Institutes of Health. One coauthor disclosed receiving institutional research funding from AstraZeneca and Brooklyn ImmunoTherapeutics and consulting for multiple pharmaceutical companies, including AbbVie, Adagene, and Bayer HealthCare Pharmaceuticals. William Dale, MD, PhD, of City of Hope National Medical Center, served as senior author and a principal investigator. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.