Cutis

Practice Gap

Onychocryptosis, or ingrown toenail, is a highly prevalent nail condition characterized by penetration of the periungual skin by the nail plate (Figure, A). Patients may report pain either while at rest or walking, which may be debilitating in severe cases and may adversely affect daily living. Treatment may be approached using conservative or surgical therapies. Conservative methods are noninvasive and appropriate for mild cases but require excellent compliance. Although nail trimming is the simplest method, it may necessitate cutting soft tissue, particularly when the nail is anchored deep within the periungual skin. Another conservative method is taping, which aims to separate the nail fold from the offending nail edge by using an adhesive. In common practice, the adhesive often detaches within a few hours, which is further exacerbated by moisture from sweating or bathing.¹ Therefore, for effective treatment of onychocryptosis, the tape typically must be reapplied multiple times per day, limiting compliance.

Tools

We propose using kinesiology tape to treat onychocryptosis. Kinesiology tape is a highly elastic adhesive that was originally employed by athletes to relieve pain while supporting muscles, tendons, and ligaments during strenuous activity. We hypothesized that its stronger adherent properties and greater elasticity would be advantageous for treatment of onychocryptosis compared to standard tape.

The Technique

A strip of tape is cut to approximately 10 to 15 mm×5 cm and is applied once daily to the lateral nail fold, pulling it away from the nail plate in oblique and proximal directions and then wrapping it around the plantar surface dorsally (Figure, B). Kinesiology tape properties allow for less frequent application and greater tension to be applied to the nail fold while reducing the risk for vasoconstriction, as the tape does not need to be fully wrapped around the digit for reliable adherence.

Practice Implications

Kinesiology tape adheres more firmly than other tapes and requires less frequent applications. Use of kinesiology tape for onychocryptosis therapy often is effective and may negate the need for more invasive procedures and improve quality of life during and after treatment.

Practice Gap

Onychocryptosis, or ingrown toenail, is a highly prevalent nail condition characterized by penetration of the periungual skin by the nail plate (Figure, A). Patients may report pain either while at rest or walking, which may be debilitating in severe cases and may adversely affect daily living. Treatment may be approached using conservative or surgical therapies. Conservative methods are noninvasive and appropriate for mild cases but require excellent compliance. Although nail trimming is the simplest method, it may necessitate cutting soft tissue, particularly when the nail is anchored deep within the periungual skin. Another conservative method is taping, which aims to separate the nail fold from the offending nail edge by using an adhesive. In common practice, the adhesive often detaches within a few hours, which is further exacerbated by moisture from sweating or bathing.¹ Therefore, for effective treatment of onychocryptosis, the tape typically must be reapplied multiple times per day, limiting compliance.

Tools

We propose using kinesiology tape to treat onychocryptosis. Kinesiology tape is a highly elastic adhesive that was originally employed by athletes to relieve pain while supporting muscles, tendons, and ligaments during strenuous activity. We hypothesized that its stronger adherent properties and greater elasticity would be advantageous for treatment of onychocryptosis compared to standard tape.

The Technique

A strip of tape is cut to approximately 10 to 15 mm×5 cm and is applied once daily to the lateral nail fold, pulling it away from the nail plate in oblique and proximal directions and then wrapping it around the plantar surface dorsally (Figure, B). Kinesiology tape properties allow for less frequent application and greater tension to be applied to the nail fold while reducing the risk for vasoconstriction, as the tape does not need to be fully wrapped around the digit for reliable adherence.

Practice Implications

Kinesiology tape adheres more firmly than other tapes and requires less frequent applications. Use of kinesiology tape for onychocryptosis therapy often is effective and may negate the need for more invasive procedures and improve quality of life during and after treatment.

Practice Gap

Onychocryptosis, or ingrown toenail, is a highly prevalent nail condition characterized by penetration of the periungual skin by the nail plate (Figure, A). Patients may report pain either while at rest or walking, which may be debilitating in severe cases and may adversely affect daily living. Treatment may be approached using conservative or surgical therapies. Conservative methods are noninvasive and appropriate for mild cases but require excellent compliance. Although nail trimming is the simplest method, it may necessitate cutting soft tissue, particularly when the nail is anchored deep within the periungual skin. Another conservative method is taping, which aims to separate the nail fold from the offending nail edge by using an adhesive. In common practice, the adhesive often detaches within a few hours, which is further exacerbated by moisture from sweating or bathing.¹ Therefore, for effective treatment of onychocryptosis, the tape typically must be reapplied multiple times per day, limiting compliance.

Tools

We propose using kinesiology tape to treat onychocryptosis. Kinesiology tape is a highly elastic adhesive that was originally employed by athletes to relieve pain while supporting muscles, tendons, and ligaments during strenuous activity. We hypothesized that its stronger adherent properties and greater elasticity would be advantageous for treatment of onychocryptosis compared to standard tape.

The Technique

A strip of tape is cut to approximately 10 to 15 mm×5 cm and is applied once daily to the lateral nail fold, pulling it away from the nail plate in oblique and proximal directions and then wrapping it around the plantar surface dorsally (Figure, B). Kinesiology tape properties allow for less frequent application and greater tension to be applied to the nail fold while reducing the risk for vasoconstriction, as the tape does not need to be fully wrapped around the digit for reliable adherence.

Practice Implications

Kinesiology tape adheres more firmly than other tapes and requires less frequent applications. Use of kinesiology tape for onychocryptosis therapy often is effective and may negate the need for more invasive procedures and improve quality of life during and after treatment.

Clinical Presentation

Millipedes secrete a noxious toxin implicated in millipede burns. The toxic substance is benzoquinone, a strong irritant secreted from the repugnatorial glands contained in each segment of the arthropod (Figure 1). This compound serves as a natural insect repellant, acting as the millipede’s defense mechanism from potential predators.¹ On human skin, benzoquinone causes localized pigmentary changes most commonly presenting on the feet and toes. Local lesions may be associated with pain or burning, but there are no known reports of adverse systemic effects.² Affected patients experience cutaneous pigmentary changes, which may be dark red, blue, or black, and spontaneously resolve over time.² The degree of pigment change may be associated with duration of skin contact with the toxin. The affected areas may resemble burns, dermatitis, or skin necrosis. More distal lesions may present similarly to blue toe syndrome or acute arterial occlusion but can be differentiated by the presence of intact peripheral pulses and lack of temperature discrepancy between the feet.^3,4 Histologic evaluation of the lesions generally reveals nonspecific full-thickness epidermal necrosis, making clinical suspicion and physical examination paramount to the diagnosis of millipede burns.⁵

Diagnostic Difficulties

Accurate diagnosis of millipede burns is more difficult when the burn involves an unusual site. The most common site of involvement is the foot (Figure 2), followed by other commonly exposed areas such as the arms, face, and eyes.^2,3,6,7 Covered parts of the body are much less commonly affected, requiring the arthropod to gain access via infiltration of clothing, often when hanging on a clothesline. In these cases, burns may be mistaken for child abuse, especially if certain areas of the body are involved, such as the groin and genitals.² The well-defined arcuate lesions of the burns may resemble injuries from a wire or belt to the unsuspecting observer.

Conclusion

Although millipedes often are regarded as harmless, they are capable of causing adverse reactions through the secretion of toxic chemicals. Millipede burns cause localized pigmentary changes that may be associated with pain or burning in some patients. Because these burns may resemble child abuse in pediatric patients, physicians should be aware of this diagnosis when unusual parts of the body are involved.

Clinical Presentation

Millipedes secrete a noxious toxin implicated in millipede burns. The toxic substance is benzoquinone, a strong irritant secreted from the repugnatorial glands contained in each segment of the arthropod (Figure 1). This compound serves as a natural insect repellant, acting as the millipede’s defense mechanism from potential predators.¹ On human skin, benzoquinone causes localized pigmentary changes most commonly presenting on the feet and toes. Local lesions may be associated with pain or burning, but there are no known reports of adverse systemic effects.² Affected patients experience cutaneous pigmentary changes, which may be dark red, blue, or black, and spontaneously resolve over time.² The degree of pigment change may be associated with duration of skin contact with the toxin. The affected areas may resemble burns, dermatitis, or skin necrosis. More distal lesions may present similarly to blue toe syndrome or acute arterial occlusion but can be differentiated by the presence of intact peripheral pulses and lack of temperature discrepancy between the feet.^3,4 Histologic evaluation of the lesions generally reveals nonspecific full-thickness epidermal necrosis, making clinical suspicion and physical examination paramount to the diagnosis of millipede burns.⁵

Diagnostic Difficulties

Accurate diagnosis of millipede burns is more difficult when the burn involves an unusual site. The most common site of involvement is the foot (Figure 2), followed by other commonly exposed areas such as the arms, face, and eyes.^2,3,6,7 Covered parts of the body are much less commonly affected, requiring the arthropod to gain access via infiltration of clothing, often when hanging on a clothesline. In these cases, burns may be mistaken for child abuse, especially if certain areas of the body are involved, such as the groin and genitals.² The well-defined arcuate lesions of the burns may resemble injuries from a wire or belt to the unsuspecting observer.

Conclusion

Although millipedes often are regarded as harmless, they are capable of causing adverse reactions through the secretion of toxic chemicals. Millipede burns cause localized pigmentary changes that may be associated with pain or burning in some patients. Because these burns may resemble child abuse in pediatric patients, physicians should be aware of this diagnosis when unusual parts of the body are involved.

Clinical Presentation

Millipedes secrete a noxious toxin implicated in millipede burns. The toxic substance is benzoquinone, a strong irritant secreted from the repugnatorial glands contained in each segment of the arthropod (Figure 1). This compound serves as a natural insect repellant, acting as the millipede’s defense mechanism from potential predators.¹ On human skin, benzoquinone causes localized pigmentary changes most commonly presenting on the feet and toes. Local lesions may be associated with pain or burning, but there are no known reports of adverse systemic effects.² Affected patients experience cutaneous pigmentary changes, which may be dark red, blue, or black, and spontaneously resolve over time.² The degree of pigment change may be associated with duration of skin contact with the toxin. The affected areas may resemble burns, dermatitis, or skin necrosis. More distal lesions may present similarly to blue toe syndrome or acute arterial occlusion but can be differentiated by the presence of intact peripheral pulses and lack of temperature discrepancy between the feet.^3,4 Histologic evaluation of the lesions generally reveals nonspecific full-thickness epidermal necrosis, making clinical suspicion and physical examination paramount to the diagnosis of millipede burns.⁵

Diagnostic Difficulties

Accurate diagnosis of millipede burns is more difficult when the burn involves an unusual site. The most common site of involvement is the foot (Figure 2), followed by other commonly exposed areas such as the arms, face, and eyes.^2,3,6,7 Covered parts of the body are much less commonly affected, requiring the arthropod to gain access via infiltration of clothing, often when hanging on a clothesline. In these cases, burns may be mistaken for child abuse, especially if certain areas of the body are involved, such as the groin and genitals.² The well-defined arcuate lesions of the burns may resemble injuries from a wire or belt to the unsuspecting observer.

Conclusion

Although millipedes often are regarded as harmless, they are capable of causing adverse reactions through the secretion of toxic chemicals. Millipede burns cause localized pigmentary changes that may be associated with pain or burning in some patients. Because these burns may resemble child abuse in pediatric patients, physicians should be aware of this diagnosis when unusual parts of the body are involved.

Each year, the American Contact Dermatitis Society (ACDS) names an allergen of the year with the purpose of promoting greater awareness of a key allergen and its impact on patients. Often, the allergen of the year is an emerging allergen that may represent an underrecognized or novel cause of allergic contact dermatitis (ACD). In 2019, the ACDS chose parabens as the “nonallergen” of the year to draw attention to their low rate of associated ACD despite high public interest in limiting exposure to parabens.¹

What types of products contain parabens?

Parabens are preservatives commonly found in many different categories of personal care products. Preservatives inhibit microbial growth and are necessary ingredients in water-based products. The 4 most common parabens used in personal care products are methylparaben, ethylparaben, propylparaben, and butylparaben.¹ Parabens are metabolized to 4-hydroxybenzoic acid and are excreted in urine. When parabens are applied topically, there is minimal penetration through intact human skin.² In the United States, parabens are allowed as preservatives in cosmetics at concentrations up to 0.4% when used alone or up to 0.8% when used in combination with other parabens.³

Consumers are exposed to parabens in a wide variety of personal care products. The Contact Allergen Management Program (CAMP) is a system owned and managed by the ACDS that typically is used to generate lists of safe personal care products for patients and also can be queried for the presence of individual chemicals in products. According to a 2018 query of the CAMP, parabens were found in 19% of all products.¹ A more recent query of CAMP (http://www.contactderm.org/resources/acds-camp) in March 2019 showed parabens were present in 39.3% of makeup products, especially in eye products, foundations, and concealers; parabens also were found in 34% of moisturizers, 11.5% of soaps, and 19% of sunscreens. Notably, 14.8% of prescription topical steroids listed in the CAMP contained a paraben. Another method for evaluating chemical contents of personal care products is a review of the Voluntary Cosmetic Registration Program, a US Food and Drug Administration–based registry for cosmetic products. Survey data from the Voluntary Cosmetic Registration Program in 2018 documented methylparaben in 11,626 formulations.⁴ Other parabens included propylparaben (8885 products), butylparaben (3915 products), and ethylparaben (3860 products). Parabens were reported more frequently in leave-on rather than rinse-off products.⁴

In medications, parabens are recommended at concentrations of no more than 0.1%.¹ Fransway et al¹ compiled a list of medications that contain parabens, including commonly prescribed dermatologic topical medications such as corticosteroids, several acne preparations, eflornithine, fluorouracil, hydroquinone, imiquimod, urea, and sertaconazole. Oral and parenteral medications including local anesthetics and corticosteroids also may contain parabens.

Consumers also may be exposed to parabens through foodstuffs. Methylparaben and propylparaben have been classified as generally recognized as safe in foods by the US Food and Drug Administration.⁵ The acceptable daily intake of parabens in food is 0 to 10 mg/kg of body weight,¹ and the estimated dietary intake for a typical adult is 307 mg/kg of body weight daily.⁶ Several studies on paraben content in foodstuffs have confirmed their presence in both natural and processed foods.^1,6 Systemic contact dermatitis caused by ingestion of parabens is rare. In general, individuals with positive patch test reactions to parabens should not routinely avoid them in foods or oral medications,¹ but they should, of course, be avoided in topical medications.

What is the rate of ACD with parabens?

One of the main reasons that parabens were designated as the ACDS nonallergen of the year is the very low rate of ACD associated with parabens. The North American Contact Dermatitis Group, a research group with members in the United States and Canada, reported a 0.6% positive reaction rate when patch testing with paraben mix 12%,⁷ which closely compares with a 0.8% positive reaction rate when patch testing with paraben mix 16% using the Mayo Clinic standard series.⁸ From the standpoint of ACD, this very low patch test reaction rate makes parabens one of the safest preservative options for use in cosmetic products.

Are there health risks associated with parabens?

The paraben controversy in the scientific literature and in the lay press centers around potential health risks and endocrine disruption. We will focus on the conversation regarding parabens and the risk for endocrine disruption and association with breast cancer.

Parabens have been reported to have estrogenic effects; however, the bulk of the data is limited to in vitro and animal studies, with less evidence of endocrine disruption in humans.² In vitro studies have demonstrated that the estrogenic potency of parabens is much less than that of estrogen. In one study, parabens were shown to be 10,000-fold less potent than 17β-estradiol⁹; in a separate study, they had a maximum potency of only 1/4000 that of estrogen.¹⁰ Additionally, an in vitro study showed varying ability for parabens to bind estrogen receptors, with a greater ability to bind with longer alkyl side chains.¹¹ The result is decreased or increased estrogen activity, dependent on side chain length and type of receptor.² Finally, some studies add conflicting results that parabens may actually create an antiestrogenic effect in human breast cancer cells.¹² From the standpoint of estrogen mimicry, there are no known studies in humans confirming harmful effects associated with paraben exposure.

The reported association between parabens and breast cancer is closely related to their theoretical estrogenic effects. The conversation regarding parabens and breast cancer has been fueled by the identification of parabens in human breast tumors and their presence in concentrations similar to what is needed to stimulate in vitro breast cancer cells.² The existing data do not confirm causation. An association with parabens in topical axillary personal care products has been theorized but not confirmed; for example, it was shown that paraben levels were highest in the axillary region of breast cancer tissue, including women who had never used deodorant. It was concluded that the presence of axillary parabens was due to sources other than topical axillary personal care products.¹³ Another study confirmed there was not an increased risk for breast cancer in patients who applied personal care products to the axillary area within an hour of shaving.¹⁴ The existing data do not support topical paraben exposure as a risk for breast cancer.

Final Thoughts

Parabens are preservatives frequently found in personal care products and exhibit a very low rate of associated ACD. Consumers may be exposed to parabens through foods, cosmetics, and medications. Although there have been consumer concerns regarding endocrine disruption or carcinogenicity associated with parabens, definite evidence of their harm is lacking in the scientific literature, and many studies confirm their safety.² With their high prevalence in personal care products and low rates of associated contact allergy, parabens remain ideal preservative agents.

Ultimately, contact dermatitis is a common yet often underrecognized dermatologic condition. To address this knowledge gap in clinical practice, we are proud to launch Final Interpretation, a new column in Cutis covering emerging trends in contact dermatitis. We will address pearls, pitfalls, and updates in contact dermatitis. Although our primary focus will be ACD, other important causes of contact dermatitis will be highlighted. Look for the inaugural column in the June 2019 issue of Cutis.

Each year, the American Contact Dermatitis Society (ACDS) names an allergen of the year with the purpose of promoting greater awareness of a key allergen and its impact on patients. Often, the allergen of the year is an emerging allergen that may represent an underrecognized or novel cause of allergic contact dermatitis (ACD). In 2019, the ACDS chose parabens as the “nonallergen” of the year to draw attention to their low rate of associated ACD despite high public interest in limiting exposure to parabens.¹

What types of products contain parabens?

Parabens are preservatives commonly found in many different categories of personal care products. Preservatives inhibit microbial growth and are necessary ingredients in water-based products. The 4 most common parabens used in personal care products are methylparaben, ethylparaben, propylparaben, and butylparaben.¹ Parabens are metabolized to 4-hydroxybenzoic acid and are excreted in urine. When parabens are applied topically, there is minimal penetration through intact human skin.² In the United States, parabens are allowed as preservatives in cosmetics at concentrations up to 0.4% when used alone or up to 0.8% when used in combination with other parabens.³

Consumers are exposed to parabens in a wide variety of personal care products. The Contact Allergen Management Program (CAMP) is a system owned and managed by the ACDS that typically is used to generate lists of safe personal care products for patients and also can be queried for the presence of individual chemicals in products. According to a 2018 query of the CAMP, parabens were found in 19% of all products.¹ A more recent query of CAMP (http://www.contactderm.org/resources/acds-camp) in March 2019 showed parabens were present in 39.3% of makeup products, especially in eye products, foundations, and concealers; parabens also were found in 34% of moisturizers, 11.5% of soaps, and 19% of sunscreens. Notably, 14.8% of prescription topical steroids listed in the CAMP contained a paraben. Another method for evaluating chemical contents of personal care products is a review of the Voluntary Cosmetic Registration Program, a US Food and Drug Administration–based registry for cosmetic products. Survey data from the Voluntary Cosmetic Registration Program in 2018 documented methylparaben in 11,626 formulations.⁴ Other parabens included propylparaben (8885 products), butylparaben (3915 products), and ethylparaben (3860 products). Parabens were reported more frequently in leave-on rather than rinse-off products.⁴

In medications, parabens are recommended at concentrations of no more than 0.1%.¹ Fransway et al¹ compiled a list of medications that contain parabens, including commonly prescribed dermatologic topical medications such as corticosteroids, several acne preparations, eflornithine, fluorouracil, hydroquinone, imiquimod, urea, and sertaconazole. Oral and parenteral medications including local anesthetics and corticosteroids also may contain parabens.

Consumers also may be exposed to parabens through foodstuffs. Methylparaben and propylparaben have been classified as generally recognized as safe in foods by the US Food and Drug Administration.⁵ The acceptable daily intake of parabens in food is 0 to 10 mg/kg of body weight,¹ and the estimated dietary intake for a typical adult is 307 mg/kg of body weight daily.⁶ Several studies on paraben content in foodstuffs have confirmed their presence in both natural and processed foods.^1,6 Systemic contact dermatitis caused by ingestion of parabens is rare. In general, individuals with positive patch test reactions to parabens should not routinely avoid them in foods or oral medications,¹ but they should, of course, be avoided in topical medications.

What is the rate of ACD with parabens?

One of the main reasons that parabens were designated as the ACDS nonallergen of the year is the very low rate of ACD associated with parabens. The North American Contact Dermatitis Group, a research group with members in the United States and Canada, reported a 0.6% positive reaction rate when patch testing with paraben mix 12%,⁷ which closely compares with a 0.8% positive reaction rate when patch testing with paraben mix 16% using the Mayo Clinic standard series.⁸ From the standpoint of ACD, this very low patch test reaction rate makes parabens one of the safest preservative options for use in cosmetic products.

Are there health risks associated with parabens?

The paraben controversy in the scientific literature and in the lay press centers around potential health risks and endocrine disruption. We will focus on the conversation regarding parabens and the risk for endocrine disruption and association with breast cancer.

Parabens have been reported to have estrogenic effects; however, the bulk of the data is limited to in vitro and animal studies, with less evidence of endocrine disruption in humans.² In vitro studies have demonstrated that the estrogenic potency of parabens is much less than that of estrogen. In one study, parabens were shown to be 10,000-fold less potent than 17β-estradiol⁹; in a separate study, they had a maximum potency of only 1/4000 that of estrogen.¹⁰ Additionally, an in vitro study showed varying ability for parabens to bind estrogen receptors, with a greater ability to bind with longer alkyl side chains.¹¹ The result is decreased or increased estrogen activity, dependent on side chain length and type of receptor.² Finally, some studies add conflicting results that parabens may actually create an antiestrogenic effect in human breast cancer cells.¹² From the standpoint of estrogen mimicry, there are no known studies in humans confirming harmful effects associated with paraben exposure.

The reported association between parabens and breast cancer is closely related to their theoretical estrogenic effects. The conversation regarding parabens and breast cancer has been fueled by the identification of parabens in human breast tumors and their presence in concentrations similar to what is needed to stimulate in vitro breast cancer cells.² The existing data do not confirm causation. An association with parabens in topical axillary personal care products has been theorized but not confirmed; for example, it was shown that paraben levels were highest in the axillary region of breast cancer tissue, including women who had never used deodorant. It was concluded that the presence of axillary parabens was due to sources other than topical axillary personal care products.¹³ Another study confirmed there was not an increased risk for breast cancer in patients who applied personal care products to the axillary area within an hour of shaving.¹⁴ The existing data do not support topical paraben exposure as a risk for breast cancer.

Final Thoughts

Parabens are preservatives frequently found in personal care products and exhibit a very low rate of associated ACD. Consumers may be exposed to parabens through foods, cosmetics, and medications. Although there have been consumer concerns regarding endocrine disruption or carcinogenicity associated with parabens, definite evidence of their harm is lacking in the scientific literature, and many studies confirm their safety.² With their high prevalence in personal care products and low rates of associated contact allergy, parabens remain ideal preservative agents.

Ultimately, contact dermatitis is a common yet often underrecognized dermatologic condition. To address this knowledge gap in clinical practice, we are proud to launch Final Interpretation, a new column in Cutis covering emerging trends in contact dermatitis. We will address pearls, pitfalls, and updates in contact dermatitis. Although our primary focus will be ACD, other important causes of contact dermatitis will be highlighted. Look for the inaugural column in the June 2019 issue of Cutis.

Each year, the American Contact Dermatitis Society (ACDS) names an allergen of the year with the purpose of promoting greater awareness of a key allergen and its impact on patients. Often, the allergen of the year is an emerging allergen that may represent an underrecognized or novel cause of allergic contact dermatitis (ACD). In 2019, the ACDS chose parabens as the “nonallergen” of the year to draw attention to their low rate of associated ACD despite high public interest in limiting exposure to parabens.¹

What types of products contain parabens?

Parabens are preservatives commonly found in many different categories of personal care products. Preservatives inhibit microbial growth and are necessary ingredients in water-based products. The 4 most common parabens used in personal care products are methylparaben, ethylparaben, propylparaben, and butylparaben.¹ Parabens are metabolized to 4-hydroxybenzoic acid and are excreted in urine. When parabens are applied topically, there is minimal penetration through intact human skin.² In the United States, parabens are allowed as preservatives in cosmetics at concentrations up to 0.4% when used alone or up to 0.8% when used in combination with other parabens.³

Consumers are exposed to parabens in a wide variety of personal care products. The Contact Allergen Management Program (CAMP) is a system owned and managed by the ACDS that typically is used to generate lists of safe personal care products for patients and also can be queried for the presence of individual chemicals in products. According to a 2018 query of the CAMP, parabens were found in 19% of all products.¹ A more recent query of CAMP (http://www.contactderm.org/resources/acds-camp) in March 2019 showed parabens were present in 39.3% of makeup products, especially in eye products, foundations, and concealers; parabens also were found in 34% of moisturizers, 11.5% of soaps, and 19% of sunscreens. Notably, 14.8% of prescription topical steroids listed in the CAMP contained a paraben. Another method for evaluating chemical contents of personal care products is a review of the Voluntary Cosmetic Registration Program, a US Food and Drug Administration–based registry for cosmetic products. Survey data from the Voluntary Cosmetic Registration Program in 2018 documented methylparaben in 11,626 formulations.⁴ Other parabens included propylparaben (8885 products), butylparaben (3915 products), and ethylparaben (3860 products). Parabens were reported more frequently in leave-on rather than rinse-off products.⁴

In medications, parabens are recommended at concentrations of no more than 0.1%.¹ Fransway et al¹ compiled a list of medications that contain parabens, including commonly prescribed dermatologic topical medications such as corticosteroids, several acne preparations, eflornithine, fluorouracil, hydroquinone, imiquimod, urea, and sertaconazole. Oral and parenteral medications including local anesthetics and corticosteroids also may contain parabens.

Consumers also may be exposed to parabens through foodstuffs. Methylparaben and propylparaben have been classified as generally recognized as safe in foods by the US Food and Drug Administration.⁵ The acceptable daily intake of parabens in food is 0 to 10 mg/kg of body weight,¹ and the estimated dietary intake for a typical adult is 307 mg/kg of body weight daily.⁶ Several studies on paraben content in foodstuffs have confirmed their presence in both natural and processed foods.^1,6 Systemic contact dermatitis caused by ingestion of parabens is rare. In general, individuals with positive patch test reactions to parabens should not routinely avoid them in foods or oral medications,¹ but they should, of course, be avoided in topical medications.

What is the rate of ACD with parabens?

One of the main reasons that parabens were designated as the ACDS nonallergen of the year is the very low rate of ACD associated with parabens. The North American Contact Dermatitis Group, a research group with members in the United States and Canada, reported a 0.6% positive reaction rate when patch testing with paraben mix 12%,⁷ which closely compares with a 0.8% positive reaction rate when patch testing with paraben mix 16% using the Mayo Clinic standard series.⁸ From the standpoint of ACD, this very low patch test reaction rate makes parabens one of the safest preservative options for use in cosmetic products.

Are there health risks associated with parabens?

The paraben controversy in the scientific literature and in the lay press centers around potential health risks and endocrine disruption. We will focus on the conversation regarding parabens and the risk for endocrine disruption and association with breast cancer.

Parabens have been reported to have estrogenic effects; however, the bulk of the data is limited to in vitro and animal studies, with less evidence of endocrine disruption in humans.² In vitro studies have demonstrated that the estrogenic potency of parabens is much less than that of estrogen. In one study, parabens were shown to be 10,000-fold less potent than 17β-estradiol⁹; in a separate study, they had a maximum potency of only 1/4000 that of estrogen.¹⁰ Additionally, an in vitro study showed varying ability for parabens to bind estrogen receptors, with a greater ability to bind with longer alkyl side chains.¹¹ The result is decreased or increased estrogen activity, dependent on side chain length and type of receptor.² Finally, some studies add conflicting results that parabens may actually create an antiestrogenic effect in human breast cancer cells.¹² From the standpoint of estrogen mimicry, there are no known studies in humans confirming harmful effects associated with paraben exposure.

The reported association between parabens and breast cancer is closely related to their theoretical estrogenic effects. The conversation regarding parabens and breast cancer has been fueled by the identification of parabens in human breast tumors and their presence in concentrations similar to what is needed to stimulate in vitro breast cancer cells.² The existing data do not confirm causation. An association with parabens in topical axillary personal care products has been theorized but not confirmed; for example, it was shown that paraben levels were highest in the axillary region of breast cancer tissue, including women who had never used deodorant. It was concluded that the presence of axillary parabens was due to sources other than topical axillary personal care products.¹³ Another study confirmed there was not an increased risk for breast cancer in patients who applied personal care products to the axillary area within an hour of shaving.¹⁴ The existing data do not support topical paraben exposure as a risk for breast cancer.

Final Thoughts

Parabens are preservatives frequently found in personal care products and exhibit a very low rate of associated ACD. Consumers may be exposed to parabens through foods, cosmetics, and medications. Although there have been consumer concerns regarding endocrine disruption or carcinogenicity associated with parabens, definite evidence of their harm is lacking in the scientific literature, and many studies confirm their safety.² With their high prevalence in personal care products and low rates of associated contact allergy, parabens remain ideal preservative agents.

Ultimately, contact dermatitis is a common yet often underrecognized dermatologic condition. To address this knowledge gap in clinical practice, we are proud to launch Final Interpretation, a new column in Cutis covering emerging trends in contact dermatitis. We will address pearls, pitfalls, and updates in contact dermatitis. Although our primary focus will be ACD, other important causes of contact dermatitis will be highlighted. Look for the inaugural column in the June 2019 issue of Cutis.

To the Editor:

A 28-year-old recently homeless white man with a history of heroin abuse was admitted with a worsening rash and left ankle pain of 1 week’s duration, as well as subjective fever after 3 weeks of a productive cough, sore throat, hoarse voice, and general malaise. Six days prior to presentation, he developed redness and swelling of the dorsal aspects of both hands with accompanying rash, and 2 days prior to presentation he developed a similar rash on the legs with associated left ankle pain, redness, and swelling. He also reported eye redness, pain, photophobia, crusty eye discharge, and a pins and needles sensation on the soles of both feet. Additionally, he had noted difficulty with urination over several days. He had been homeless for less than 1 month prior to admission.

On physical examination, the patient appeared to be well nourished. Skin examination was notable for scattered perifollicular hemorrhagic and hyperkeratotic papules ranging in size from 3 to 6 mm with associated nummular alopecia of the bilateral medial thighs (Figure); well-demarcated desquamated patches on the weight-bearing aspects of the plantar feet; and a 2.0-cm, well-demarcated, thinly raised erythematous patch of the inferolateral penile shaft. Oral examination was notable for multiple discrete areas of ulceration on the lateral aspects of the tongue. Ophthalmic examination revealed conjunctival injection and photophobia. The ankles were edematous and tender (the left ankle more than the right), and range of passive motion was limited by pain.

Vitamin C (ascorbic acid) plays a crucial role in human biochemistry. Although many plants and animals can synthesize ascorbic acid, humans and other animals such as guinea pigs lack the required enzyme, making vitamin C an essential nutrient required in dietary intake.^­2-4 Hypovitaminosis C leads to scurvy when collagen production becomes impaired due to lack of ascorbic acid as a required cofactor for its synthesis, which leads to tissue and capillary fragility, causing hemorrhage and perivascular edema.⁴ The diagnosis of scurvy is clinical and typically is based on signs such as perivascular hemorrhage, bleeding gums, anemia, impaired wound healing, and ecchymoses in the setting of vitamin C deficiency (<11 μmol/L or <0.2 mg/dL) with rapid resolution upon vitamin C supplementation.⁵

Important sources of vitamin C include citrus fruits, strawberries, broccoli, spinach, and potatoes. Recommended daily intake is 75 to 90 mg, with smokers requiring 110 to 125 mg daily because of increased oxidative stress.^6-9 Although access to these foods in the modern United States is high, as many as 10% of males and 6.9% of females are vitamin C deficient, and in the subset of generally healthy middle-class Americans, as many as 6% are deficient.^8,10 The highest risk groups tend to be smokers and individuals with low incomes.⁸ Although vitamin C deficiency does not automatically equate to scurvy, early studies on experimentally induced scurvy in prisoners showed that signs of scurvy may begin to develop in as few as 29 days of complete vitamin C deprivation, with overt scurvy developing after approximately 40 to 90 days.^11,12

Patients with scurvy often pose a diagnostic dilemma for physicians because their presenting symptoms, such as fatigue, anemia, and rash, are nonspecific and can lead physicians down a laborious and costly road of unnecessary tests including vasculitic, infectious, and rheumatologic workups to determine the cause of the symptoms. Increased awareness of the current prevalence of hypovitaminosis C may help to decrease these unnecessary costs by putting scurvy higher on the differential for patients with this spectrum of symptoms.

Scurvy has been called the eternal masquerader because its nonspecific signs and symptoms have often led to misdiagnosis.¹³ Cases of scurvy mimicking diseases ranging from bone tumors¹⁴ to spondyloarthritis¹⁵ and vasculitis¹⁶ have been reported. The typical patient at risk for scurvy tends to fall in one of the following categories: psychiatric illness, gastrointestinal disorders, malnourishment, chronic alcoholism, drug use, elderly age, infants, restrictive dietary habits or food allergies, or those in developing countries.^17-20 Our patient did not fit particularly well into any of the aforementioned high-risk categories; he had only recently become homeless and had a history of intravenous drug use but had not been using drugs in the months prior to the development of scurvy. Additionally, his salient symptoms were more consistent with reactive arthritis than with classic scurvy.

Although he had many symptoms consistent with scurvy such as generalized malaise, perifollicular hemorrhage and hyperkeratosis, spongy edema of the joints, and mild anemia on laboratory testing, he was missing several classic scurvy symptoms. Unlike many patients with scurvy, our patient did not describe any history of bruising easily or dental concerns, and examination was notably absent of ecchymoses as well as spongy or bleeding gums. He did, however, present with eye irritation and photophobia. These symptoms, consistent with keratoconjunctivitis sicca, are lesser known because ocular findings are rarely found in scurvy.²¹ Patients with scurvy can report eye burning and irritation, redness, blurry vision, and sensitivity to bright light secondary to increased dryness of the corneal surfaces. Horrobin et al²² postulated that this symptom may be mediated by regulation of prostaglandin E1 by vitamin C.

Another less common sign of scurvy found in our patient was patchy alopecia. Alopecia most often is seen in association with concomitant Sjögren syndrome.^11,23 The etiology of the hair loss stems from the role of ascorbic acid in disulfide bonding during hair formation. The hair may fracture, coil into a corkscrew hair, or bend in several places, leading to a swan-neck deformity. Although a skin biopsy was not performed in our patient, results typically demonstrate a coiled hair in its follicle.^24,25

We present the case of an otherwise generally healthy patient who developed vitamin C deficiency due to a diet consisting mostly of soda and energy drinks. His case presented a diagnostic dilemma, as his symptoms at first seemed most consistent with reactive arthritis and he was missing several of the risk factors and symptoms that would have led to an early diagnosis of scurvy. Vitamin C deficiency is not as uncommon as expected in the developed world; practitioners must be aware of the common as well as the unusual signs of scurvy.

To the Editor:

A 28-year-old recently homeless white man with a history of heroin abuse was admitted with a worsening rash and left ankle pain of 1 week’s duration, as well as subjective fever after 3 weeks of a productive cough, sore throat, hoarse voice, and general malaise. Six days prior to presentation, he developed redness and swelling of the dorsal aspects of both hands with accompanying rash, and 2 days prior to presentation he developed a similar rash on the legs with associated left ankle pain, redness, and swelling. He also reported eye redness, pain, photophobia, crusty eye discharge, and a pins and needles sensation on the soles of both feet. Additionally, he had noted difficulty with urination over several days. He had been homeless for less than 1 month prior to admission.

On physical examination, the patient appeared to be well nourished. Skin examination was notable for scattered perifollicular hemorrhagic and hyperkeratotic papules ranging in size from 3 to 6 mm with associated nummular alopecia of the bilateral medial thighs (Figure); well-demarcated desquamated patches on the weight-bearing aspects of the plantar feet; and a 2.0-cm, well-demarcated, thinly raised erythematous patch of the inferolateral penile shaft. Oral examination was notable for multiple discrete areas of ulceration on the lateral aspects of the tongue. Ophthalmic examination revealed conjunctival injection and photophobia. The ankles were edematous and tender (the left ankle more than the right), and range of passive motion was limited by pain.

Vitamin C (ascorbic acid) plays a crucial role in human biochemistry. Although many plants and animals can synthesize ascorbic acid, humans and other animals such as guinea pigs lack the required enzyme, making vitamin C an essential nutrient required in dietary intake.^­2-4 Hypovitaminosis C leads to scurvy when collagen production becomes impaired due to lack of ascorbic acid as a required cofactor for its synthesis, which leads to tissue and capillary fragility, causing hemorrhage and perivascular edema.⁴ The diagnosis of scurvy is clinical and typically is based on signs such as perivascular hemorrhage, bleeding gums, anemia, impaired wound healing, and ecchymoses in the setting of vitamin C deficiency (<11 μmol/L or <0.2 mg/dL) with rapid resolution upon vitamin C supplementation.⁵

Important sources of vitamin C include citrus fruits, strawberries, broccoli, spinach, and potatoes. Recommended daily intake is 75 to 90 mg, with smokers requiring 110 to 125 mg daily because of increased oxidative stress.^6-9 Although access to these foods in the modern United States is high, as many as 10% of males and 6.9% of females are vitamin C deficient, and in the subset of generally healthy middle-class Americans, as many as 6% are deficient.^8,10 The highest risk groups tend to be smokers and individuals with low incomes.⁸ Although vitamin C deficiency does not automatically equate to scurvy, early studies on experimentally induced scurvy in prisoners showed that signs of scurvy may begin to develop in as few as 29 days of complete vitamin C deprivation, with overt scurvy developing after approximately 40 to 90 days.^11,12

Patients with scurvy often pose a diagnostic dilemma for physicians because their presenting symptoms, such as fatigue, anemia, and rash, are nonspecific and can lead physicians down a laborious and costly road of unnecessary tests including vasculitic, infectious, and rheumatologic workups to determine the cause of the symptoms. Increased awareness of the current prevalence of hypovitaminosis C may help to decrease these unnecessary costs by putting scurvy higher on the differential for patients with this spectrum of symptoms.

Scurvy has been called the eternal masquerader because its nonspecific signs and symptoms have often led to misdiagnosis.¹³ Cases of scurvy mimicking diseases ranging from bone tumors¹⁴ to spondyloarthritis¹⁵ and vasculitis¹⁶ have been reported. The typical patient at risk for scurvy tends to fall in one of the following categories: psychiatric illness, gastrointestinal disorders, malnourishment, chronic alcoholism, drug use, elderly age, infants, restrictive dietary habits or food allergies, or those in developing countries.^17-20 Our patient did not fit particularly well into any of the aforementioned high-risk categories; he had only recently become homeless and had a history of intravenous drug use but had not been using drugs in the months prior to the development of scurvy. Additionally, his salient symptoms were more consistent with reactive arthritis than with classic scurvy.

Although he had many symptoms consistent with scurvy such as generalized malaise, perifollicular hemorrhage and hyperkeratosis, spongy edema of the joints, and mild anemia on laboratory testing, he was missing several classic scurvy symptoms. Unlike many patients with scurvy, our patient did not describe any history of bruising easily or dental concerns, and examination was notably absent of ecchymoses as well as spongy or bleeding gums. He did, however, present with eye irritation and photophobia. These symptoms, consistent with keratoconjunctivitis sicca, are lesser known because ocular findings are rarely found in scurvy.²¹ Patients with scurvy can report eye burning and irritation, redness, blurry vision, and sensitivity to bright light secondary to increased dryness of the corneal surfaces. Horrobin et al²² postulated that this symptom may be mediated by regulation of prostaglandin E1 by vitamin C.

Another less common sign of scurvy found in our patient was patchy alopecia. Alopecia most often is seen in association with concomitant Sjögren syndrome.^11,23 The etiology of the hair loss stems from the role of ascorbic acid in disulfide bonding during hair formation. The hair may fracture, coil into a corkscrew hair, or bend in several places, leading to a swan-neck deformity. Although a skin biopsy was not performed in our patient, results typically demonstrate a coiled hair in its follicle.^24,25

We present the case of an otherwise generally healthy patient who developed vitamin C deficiency due to a diet consisting mostly of soda and energy drinks. His case presented a diagnostic dilemma, as his symptoms at first seemed most consistent with reactive arthritis and he was missing several of the risk factors and symptoms that would have led to an early diagnosis of scurvy. Vitamin C deficiency is not as uncommon as expected in the developed world; practitioners must be aware of the common as well as the unusual signs of scurvy.

To the Editor:

A 28-year-old recently homeless white man with a history of heroin abuse was admitted with a worsening rash and left ankle pain of 1 week’s duration, as well as subjective fever after 3 weeks of a productive cough, sore throat, hoarse voice, and general malaise. Six days prior to presentation, he developed redness and swelling of the dorsal aspects of both hands with accompanying rash, and 2 days prior to presentation he developed a similar rash on the legs with associated left ankle pain, redness, and swelling. He also reported eye redness, pain, photophobia, crusty eye discharge, and a pins and needles sensation on the soles of both feet. Additionally, he had noted difficulty with urination over several days. He had been homeless for less than 1 month prior to admission.

On physical examination, the patient appeared to be well nourished. Skin examination was notable for scattered perifollicular hemorrhagic and hyperkeratotic papules ranging in size from 3 to 6 mm with associated nummular alopecia of the bilateral medial thighs (Figure); well-demarcated desquamated patches on the weight-bearing aspects of the plantar feet; and a 2.0-cm, well-demarcated, thinly raised erythematous patch of the inferolateral penile shaft. Oral examination was notable for multiple discrete areas of ulceration on the lateral aspects of the tongue. Ophthalmic examination revealed conjunctival injection and photophobia. The ankles were edematous and tender (the left ankle more than the right), and range of passive motion was limited by pain.

Vitamin C (ascorbic acid) plays a crucial role in human biochemistry. Although many plants and animals can synthesize ascorbic acid, humans and other animals such as guinea pigs lack the required enzyme, making vitamin C an essential nutrient required in dietary intake.^­2-4 Hypovitaminosis C leads to scurvy when collagen production becomes impaired due to lack of ascorbic acid as a required cofactor for its synthesis, which leads to tissue and capillary fragility, causing hemorrhage and perivascular edema.⁴ The diagnosis of scurvy is clinical and typically is based on signs such as perivascular hemorrhage, bleeding gums, anemia, impaired wound healing, and ecchymoses in the setting of vitamin C deficiency (<11 μmol/L or <0.2 mg/dL) with rapid resolution upon vitamin C supplementation.⁵

Important sources of vitamin C include citrus fruits, strawberries, broccoli, spinach, and potatoes. Recommended daily intake is 75 to 90 mg, with smokers requiring 110 to 125 mg daily because of increased oxidative stress.^6-9 Although access to these foods in the modern United States is high, as many as 10% of males and 6.9% of females are vitamin C deficient, and in the subset of generally healthy middle-class Americans, as many as 6% are deficient.^8,10 The highest risk groups tend to be smokers and individuals with low incomes.⁸ Although vitamin C deficiency does not automatically equate to scurvy, early studies on experimentally induced scurvy in prisoners showed that signs of scurvy may begin to develop in as few as 29 days of complete vitamin C deprivation, with overt scurvy developing after approximately 40 to 90 days.^11,12

Patients with scurvy often pose a diagnostic dilemma for physicians because their presenting symptoms, such as fatigue, anemia, and rash, are nonspecific and can lead physicians down a laborious and costly road of unnecessary tests including vasculitic, infectious, and rheumatologic workups to determine the cause of the symptoms. Increased awareness of the current prevalence of hypovitaminosis C may help to decrease these unnecessary costs by putting scurvy higher on the differential for patients with this spectrum of symptoms.

Scurvy has been called the eternal masquerader because its nonspecific signs and symptoms have often led to misdiagnosis.¹³ Cases of scurvy mimicking diseases ranging from bone tumors¹⁴ to spondyloarthritis¹⁵ and vasculitis¹⁶ have been reported. The typical patient at risk for scurvy tends to fall in one of the following categories: psychiatric illness, gastrointestinal disorders, malnourishment, chronic alcoholism, drug use, elderly age, infants, restrictive dietary habits or food allergies, or those in developing countries.^17-20 Our patient did not fit particularly well into any of the aforementioned high-risk categories; he had only recently become homeless and had a history of intravenous drug use but had not been using drugs in the months prior to the development of scurvy. Additionally, his salient symptoms were more consistent with reactive arthritis than with classic scurvy.

Although he had many symptoms consistent with scurvy such as generalized malaise, perifollicular hemorrhage and hyperkeratosis, spongy edema of the joints, and mild anemia on laboratory testing, he was missing several classic scurvy symptoms. Unlike many patients with scurvy, our patient did not describe any history of bruising easily or dental concerns, and examination was notably absent of ecchymoses as well as spongy or bleeding gums. He did, however, present with eye irritation and photophobia. These symptoms, consistent with keratoconjunctivitis sicca, are lesser known because ocular findings are rarely found in scurvy.²¹ Patients with scurvy can report eye burning and irritation, redness, blurry vision, and sensitivity to bright light secondary to increased dryness of the corneal surfaces. Horrobin et al²² postulated that this symptom may be mediated by regulation of prostaglandin E1 by vitamin C.

Another less common sign of scurvy found in our patient was patchy alopecia. Alopecia most often is seen in association with concomitant Sjögren syndrome.^11,23 The etiology of the hair loss stems from the role of ascorbic acid in disulfide bonding during hair formation. The hair may fracture, coil into a corkscrew hair, or bend in several places, leading to a swan-neck deformity. Although a skin biopsy was not performed in our patient, results typically demonstrate a coiled hair in its follicle.^24,25

We present the case of an otherwise generally healthy patient who developed vitamin C deficiency due to a diet consisting mostly of soda and energy drinks. His case presented a diagnostic dilemma, as his symptoms at first seemed most consistent with reactive arthritis and he was missing several of the risk factors and symptoms that would have led to an early diagnosis of scurvy. Vitamin C deficiency is not as uncommon as expected in the developed world; practitioners must be aware of the common as well as the unusual signs of scurvy.

The Diagnosis:  Primary Cutaneous Perivascular Epithelioid Cell Tumor  

Perivascular epithelioid cell tumors (PEComas) were first described in 1996.¹ They comprise a family of rare mesenchymal neoplasms that have a unique characteristic of staining positive for melanocytic and smooth muscle markers on immunohistochemistry.² These neoplasms have been described in many areas of the body including the uterus, bladder, heart, pancreas, and prostate. The majority of PEComas are extracutaneous, with only 8% of reported cases originating on the skin.³ A case of primary cutaneous PEComa (pcPEComa) was described in 2003.⁴ The primary cutaneous form is extremely rare.^3,5-7  

A broad deep shave biopsy was performed in our patient in an attempt to sample the entire lesion. Histopathologic examination of the nodule demonstrated a dermal neoplasm comprised of a diffuse proliferation of large polygonal cells with abundant clear cytoplasm, fine chromatin, and prominent nucleoli (Figure 1A). Higher-power magnification showed moderate nuclear pleomorphism and only rare mitotic figures (Figure 1B).

Immunohistochemical staining revealed positivity for myomelanocytic markers with positivity for human melanoma black 45 (HMB-45)(Figure 2) and desmin (not shown). Additionally, the tumor was positive for CD163 and negative for smooth muscle actin, cytokeratin, and S-100 protein.  

Perivascular epithelioid cell tumors are characterized histologically as mesenchymal neoplasms containing large epithelioid to spindled cells with a slightly granular, vacuolated cytoplasm. These cells often are found in close proximity to vascular structures.^3,5,8 The hallmark of PEComas is the expression of both melanocytic and muscle markers.^3,8 A review of staining patterns of pcPEComas emphasized that immunophenotypes between visceral and primary cutaneous forms may vary considerably.^3,5,8 The most consistent and sensitive melanocytic marker is HMB-45 (88%-92% positive).^3,8 Positive Melan-A staining varies in the literature from 0% to 50% of cases.³ Our patient's neoplasm expressed the characteristic myomelanocytic immunophenotype with both HMB-45 and desmin positivity. 

Given the histologic characteristics, these lesions can be mistaken for melanocytic and other nonmelanocytic tumors with a clear cell morphology such as balloon cell nevus, hypomelanotic blue nevus, and melanoma.^2,3 A pigmented case of pcPEComa was reported in 2015 and was originally diagnosed as metastatic melanoma.⁶ Unlike pcPEComa, melanoma usually stains positive with S-100 protein in up to 99% of cases⁸ and is negative for muscle markers; however, a case series reported S-100 protein positivity in 38% of pcPEComas.³ Nonmelanocytic neoplasms in the histologic differential diagnosis include clear cell sarcoma and clear cell renal cell carcinoma, both of which show immunoreactivity for cytokeratin.⁹  

Histologic criteria exist for establishing malignancy potential for visceral PEComas but not for pcPEComas, though it has been suggested that the same malignancy criteria should be applied to pcPEComas.^3,9 Features associated with malignancy include size greater than 8 cm, mitotic activity greater than 1 mitosis per 50 high-power fields, infiltrative growth pattern, high nuclear grade, necrosis, and vascular invasion. Based on these criteria, fulfilling 2 or more features technically classifies the lesion as malignant, 1 feature classifies it as uncertain malignant potential, and a lack of these features renders the lesion benign.⁹  

The overwhelming majority of pcPEComas are considered benign. One case of pcPEComa was considered malignant with a high mitotic rate (5 mitoses per 10 high-power fields) and nuclear atypia.¹⁰ Further workup with thoracic computed tomography and positron emission tomography-computed tomography was negative for metastasis. Treatment with wide excision and radiotherapy was performed with no sign of recurrence at 24-month follow-up.¹⁰  

Although pcPEComas arising from the dermis seem to be benign overall, PEComas originating from the subcutaneous tissue may have greater malignancy potential. Two cases of subcutaneous PEComas presenting as nodules resulted in metastasis; one case had local nodal metastasis and another developed metastasis to the lungs months later.^10,11 

The Diagnosis:  Primary Cutaneous Perivascular Epithelioid Cell Tumor  

Perivascular epithelioid cell tumors (PEComas) were first described in 1996.¹ They comprise a family of rare mesenchymal neoplasms that have a unique characteristic of staining positive for melanocytic and smooth muscle markers on immunohistochemistry.² These neoplasms have been described in many areas of the body including the uterus, bladder, heart, pancreas, and prostate. The majority of PEComas are extracutaneous, with only 8% of reported cases originating on the skin.³ A case of primary cutaneous PEComa (pcPEComa) was described in 2003.⁴ The primary cutaneous form is extremely rare.^3,5-7  

A broad deep shave biopsy was performed in our patient in an attempt to sample the entire lesion. Histopathologic examination of the nodule demonstrated a dermal neoplasm comprised of a diffuse proliferation of large polygonal cells with abundant clear cytoplasm, fine chromatin, and prominent nucleoli (Figure 1A). Higher-power magnification showed moderate nuclear pleomorphism and only rare mitotic figures (Figure 1B).

Immunohistochemical staining revealed positivity for myomelanocytic markers with positivity for human melanoma black 45 (HMB-45)(Figure 2) and desmin (not shown). Additionally, the tumor was positive for CD163 and negative for smooth muscle actin, cytokeratin, and S-100 protein.  

Perivascular epithelioid cell tumors are characterized histologically as mesenchymal neoplasms containing large epithelioid to spindled cells with a slightly granular, vacuolated cytoplasm. These cells often are found in close proximity to vascular structures.^3,5,8 The hallmark of PEComas is the expression of both melanocytic and muscle markers.^3,8 A review of staining patterns of pcPEComas emphasized that immunophenotypes between visceral and primary cutaneous forms may vary considerably.^3,5,8 The most consistent and sensitive melanocytic marker is HMB-45 (88%-92% positive).^3,8 Positive Melan-A staining varies in the literature from 0% to 50% of cases.³ Our patient's neoplasm expressed the characteristic myomelanocytic immunophenotype with both HMB-45 and desmin positivity. 

Given the histologic characteristics, these lesions can be mistaken for melanocytic and other nonmelanocytic tumors with a clear cell morphology such as balloon cell nevus, hypomelanotic blue nevus, and melanoma.^2,3 A pigmented case of pcPEComa was reported in 2015 and was originally diagnosed as metastatic melanoma.⁶ Unlike pcPEComa, melanoma usually stains positive with S-100 protein in up to 99% of cases⁸ and is negative for muscle markers; however, a case series reported S-100 protein positivity in 38% of pcPEComas.³ Nonmelanocytic neoplasms in the histologic differential diagnosis include clear cell sarcoma and clear cell renal cell carcinoma, both of which show immunoreactivity for cytokeratin.⁹  

Histologic criteria exist for establishing malignancy potential for visceral PEComas but not for pcPEComas, though it has been suggested that the same malignancy criteria should be applied to pcPEComas.^3,9 Features associated with malignancy include size greater than 8 cm, mitotic activity greater than 1 mitosis per 50 high-power fields, infiltrative growth pattern, high nuclear grade, necrosis, and vascular invasion. Based on these criteria, fulfilling 2 or more features technically classifies the lesion as malignant, 1 feature classifies it as uncertain malignant potential, and a lack of these features renders the lesion benign.⁹  

The overwhelming majority of pcPEComas are considered benign. One case of pcPEComa was considered malignant with a high mitotic rate (5 mitoses per 10 high-power fields) and nuclear atypia.¹⁰ Further workup with thoracic computed tomography and positron emission tomography-computed tomography was negative for metastasis. Treatment with wide excision and radiotherapy was performed with no sign of recurrence at 24-month follow-up.¹⁰  

Although pcPEComas arising from the dermis seem to be benign overall, PEComas originating from the subcutaneous tissue may have greater malignancy potential. Two cases of subcutaneous PEComas presenting as nodules resulted in metastasis; one case had local nodal metastasis and another developed metastasis to the lungs months later.^10,11 

The Diagnosis:  Primary Cutaneous Perivascular Epithelioid Cell Tumor  

Perivascular epithelioid cell tumors (PEComas) were first described in 1996.¹ They comprise a family of rare mesenchymal neoplasms that have a unique characteristic of staining positive for melanocytic and smooth muscle markers on immunohistochemistry.² These neoplasms have been described in many areas of the body including the uterus, bladder, heart, pancreas, and prostate. The majority of PEComas are extracutaneous, with only 8% of reported cases originating on the skin.³ A case of primary cutaneous PEComa (pcPEComa) was described in 2003.⁴ The primary cutaneous form is extremely rare.^3,5-7  

A broad deep shave biopsy was performed in our patient in an attempt to sample the entire lesion. Histopathologic examination of the nodule demonstrated a dermal neoplasm comprised of a diffuse proliferation of large polygonal cells with abundant clear cytoplasm, fine chromatin, and prominent nucleoli (Figure 1A). Higher-power magnification showed moderate nuclear pleomorphism and only rare mitotic figures (Figure 1B).

Immunohistochemical staining revealed positivity for myomelanocytic markers with positivity for human melanoma black 45 (HMB-45)(Figure 2) and desmin (not shown). Additionally, the tumor was positive for CD163 and negative for smooth muscle actin, cytokeratin, and S-100 protein.  

Perivascular epithelioid cell tumors are characterized histologically as mesenchymal neoplasms containing large epithelioid to spindled cells with a slightly granular, vacuolated cytoplasm. These cells often are found in close proximity to vascular structures.^3,5,8 The hallmark of PEComas is the expression of both melanocytic and muscle markers.^3,8 A review of staining patterns of pcPEComas emphasized that immunophenotypes between visceral and primary cutaneous forms may vary considerably.^3,5,8 The most consistent and sensitive melanocytic marker is HMB-45 (88%-92% positive).^3,8 Positive Melan-A staining varies in the literature from 0% to 50% of cases.³ Our patient's neoplasm expressed the characteristic myomelanocytic immunophenotype with both HMB-45 and desmin positivity. 

Given the histologic characteristics, these lesions can be mistaken for melanocytic and other nonmelanocytic tumors with a clear cell morphology such as balloon cell nevus, hypomelanotic blue nevus, and melanoma.^2,3 A pigmented case of pcPEComa was reported in 2015 and was originally diagnosed as metastatic melanoma.⁶ Unlike pcPEComa, melanoma usually stains positive with S-100 protein in up to 99% of cases⁸ and is negative for muscle markers; however, a case series reported S-100 protein positivity in 38% of pcPEComas.³ Nonmelanocytic neoplasms in the histologic differential diagnosis include clear cell sarcoma and clear cell renal cell carcinoma, both of which show immunoreactivity for cytokeratin.⁹  

Histologic criteria exist for establishing malignancy potential for visceral PEComas but not for pcPEComas, though it has been suggested that the same malignancy criteria should be applied to pcPEComas.^3,9 Features associated with malignancy include size greater than 8 cm, mitotic activity greater than 1 mitosis per 50 high-power fields, infiltrative growth pattern, high nuclear grade, necrosis, and vascular invasion. Based on these criteria, fulfilling 2 or more features technically classifies the lesion as malignant, 1 feature classifies it as uncertain malignant potential, and a lack of these features renders the lesion benign.⁹  

The overwhelming majority of pcPEComas are considered benign. One case of pcPEComa was considered malignant with a high mitotic rate (5 mitoses per 10 high-power fields) and nuclear atypia.¹⁰ Further workup with thoracic computed tomography and positron emission tomography-computed tomography was negative for metastasis. Treatment with wide excision and radiotherapy was performed with no sign of recurrence at 24-month follow-up.¹⁰  

Although pcPEComas arising from the dermis seem to be benign overall, PEComas originating from the subcutaneous tissue may have greater malignancy potential. Two cases of subcutaneous PEComas presenting as nodules resulted in metastasis; one case had local nodal metastasis and another developed metastasis to the lungs months later.^10,11 

To the Editor:

The tongue is composed of 4 different types of papillae: fungiform, foliate, circumvallate, and filiform. Fungiform papillae, primarily located on the tip and sides of the tongue, are mushroom-shaped epithelial elevations composed of taste buds at the upper surface overlying a core of connective tissue.¹ Foliate and circumvallate papillae are likewise associated with taste buds, while the filiform papillae are hypothesized to exclusively provide a frictional surface for proper food manipulation. Pigmented fungiform papillae of the tongue (PFPT) was first reported by Leonard² in 1905, who described discrete hyperpigmentation present only on the surface of fungiform papillae, mainly in black patients. Although they have been primarily described in black individuals, PFPT also has been occasionally reported in Asian and Middle Eastern individuals as well as Indian women.^3-6

A 36-year-old Indian man initially presented to his primary care provider with brown discoloration of the dorsolateral aspects of the tongue that had been present since childhood. His primary care provider was concerned about a potential syndrome or systemic illness and referred the patient to dermatology for further evaluation. The patient denied any oral mucosal bleeding or discomfort, and a review of systems was unremarkable. His medical and family history were otherwise noncontributory, and he denied a history of tobacco use.

Physical examination of the tongue and oral mucosa revealed numerous 0.5- to 1.0-mm brown papillae in a symmetric distribution, primarily located on the tip and lateral aspects of the tongue (Figure). No hyperpigmentation was present on the posterior aspect of the tongue or on any other mucosal surface. Routine laboratory values were notable for mild elevations in aspartate aminotransferase and alanine aminotransferase (47 U/L [reference range, 10–30 U/L] and 64 U/L [reference range, 10–40 U/L], respectively) and mild hyperbilirubinemia (total bilirubin, 1.8 mg/dL [reference range, 0.3–1.2 mg/dL]). A complete blood cell count and electrolytes were within reference range. Based on the clinical appearance of the lesions and their presence since childhood, the patient was diagnosed with PFPT. No intervention was undertaken, and the patient was reassured of the benign nature of the lesions.

Pigmented fungiform papillae of the tongue presents in 3 variants. The first variant involves hyperpigmentation of all fungiform papillae located on the lateral and frontal aspects of the tongue and is the most common manifestation of PFPT.³ Our patient falls into this category. The second and third variants involve the dorsal surface, with the former involving only a few fungiform papillae on the dorsal aspect of the tongue and the latter variant involving all papillae.³ In 1974, Holzwanger et al³ conducted a survey of 300 random individuals, finding that 30% of black women and 25% of black men had some hyperpigmentation of the tongue, while only 1 white individual demonstrated lingual pigmentation. The physiology of PFPT remains largely unknown. Dermoscopic evaluation often demonstrates elevations with pigmented borders in a rose petal shape.⁷ Histopathologic evaluation reveals melanophages without inflammation that are positive for melanin on Fontana-Masson silver staining but negative for iron on Prussian blue staining.⁸

Despite the fact that PFPT is not a rare condition, the diagnosis remains notably missing from many standard dermatology textbooks and online dermatology resources, making it a potentially overlooked clinical entity.^4-6 The tongue has a number of normal variations that are unlikely to be fully appreciated or acknowledged by dermatologists on routine physical examination but may cause distress to patients and raise concerns from primary care providers. Given that PFPT are benign, physicians should be aware of this diagnosis so as to provide reassurance to patients and avoid unnecessary testing. However, because the tongue can represent a harbinger of systemic disease, the differential diagnosis for the hyperpigmented lesions must always be considered, including Peutz-Jeghers syndrome, hemochromatosis, Addison disease, and Laugier-Hunziker syndrome (a rarer condition causing pigmented lesions on the lips, palate, and tongue), particularly if the hyperpigmented lesions extend beyond the fungiform papillae and do not fit into the 3 categories of PFPT.⁹

To the Editor:

The tongue is composed of 4 different types of papillae: fungiform, foliate, circumvallate, and filiform. Fungiform papillae, primarily located on the tip and sides of the tongue, are mushroom-shaped epithelial elevations composed of taste buds at the upper surface overlying a core of connective tissue.¹ Foliate and circumvallate papillae are likewise associated with taste buds, while the filiform papillae are hypothesized to exclusively provide a frictional surface for proper food manipulation. Pigmented fungiform papillae of the tongue (PFPT) was first reported by Leonard² in 1905, who described discrete hyperpigmentation present only on the surface of fungiform papillae, mainly in black patients. Although they have been primarily described in black individuals, PFPT also has been occasionally reported in Asian and Middle Eastern individuals as well as Indian women.^3-6

A 36-year-old Indian man initially presented to his primary care provider with brown discoloration of the dorsolateral aspects of the tongue that had been present since childhood. His primary care provider was concerned about a potential syndrome or systemic illness and referred the patient to dermatology for further evaluation. The patient denied any oral mucosal bleeding or discomfort, and a review of systems was unremarkable. His medical and family history were otherwise noncontributory, and he denied a history of tobacco use.

Physical examination of the tongue and oral mucosa revealed numerous 0.5- to 1.0-mm brown papillae in a symmetric distribution, primarily located on the tip and lateral aspects of the tongue (Figure). No hyperpigmentation was present on the posterior aspect of the tongue or on any other mucosal surface. Routine laboratory values were notable for mild elevations in aspartate aminotransferase and alanine aminotransferase (47 U/L [reference range, 10–30 U/L] and 64 U/L [reference range, 10–40 U/L], respectively) and mild hyperbilirubinemia (total bilirubin, 1.8 mg/dL [reference range, 0.3–1.2 mg/dL]). A complete blood cell count and electrolytes were within reference range. Based on the clinical appearance of the lesions and their presence since childhood, the patient was diagnosed with PFPT. No intervention was undertaken, and the patient was reassured of the benign nature of the lesions.

Pigmented fungiform papillae of the tongue presents in 3 variants. The first variant involves hyperpigmentation of all fungiform papillae located on the lateral and frontal aspects of the tongue and is the most common manifestation of PFPT.³ Our patient falls into this category. The second and third variants involve the dorsal surface, with the former involving only a few fungiform papillae on the dorsal aspect of the tongue and the latter variant involving all papillae.³ In 1974, Holzwanger et al³ conducted a survey of 300 random individuals, finding that 30% of black women and 25% of black men had some hyperpigmentation of the tongue, while only 1 white individual demonstrated lingual pigmentation. The physiology of PFPT remains largely unknown. Dermoscopic evaluation often demonstrates elevations with pigmented borders in a rose petal shape.⁷ Histopathologic evaluation reveals melanophages without inflammation that are positive for melanin on Fontana-Masson silver staining but negative for iron on Prussian blue staining.⁸

Despite the fact that PFPT is not a rare condition, the diagnosis remains notably missing from many standard dermatology textbooks and online dermatology resources, making it a potentially overlooked clinical entity.^4-6 The tongue has a number of normal variations that are unlikely to be fully appreciated or acknowledged by dermatologists on routine physical examination but may cause distress to patients and raise concerns from primary care providers. Given that PFPT are benign, physicians should be aware of this diagnosis so as to provide reassurance to patients and avoid unnecessary testing. However, because the tongue can represent a harbinger of systemic disease, the differential diagnosis for the hyperpigmented lesions must always be considered, including Peutz-Jeghers syndrome, hemochromatosis, Addison disease, and Laugier-Hunziker syndrome (a rarer condition causing pigmented lesions on the lips, palate, and tongue), particularly if the hyperpigmented lesions extend beyond the fungiform papillae and do not fit into the 3 categories of PFPT.⁹

To the Editor:

The tongue is composed of 4 different types of papillae: fungiform, foliate, circumvallate, and filiform. Fungiform papillae, primarily located on the tip and sides of the tongue, are mushroom-shaped epithelial elevations composed of taste buds at the upper surface overlying a core of connective tissue.¹ Foliate and circumvallate papillae are likewise associated with taste buds, while the filiform papillae are hypothesized to exclusively provide a frictional surface for proper food manipulation. Pigmented fungiform papillae of the tongue (PFPT) was first reported by Leonard² in 1905, who described discrete hyperpigmentation present only on the surface of fungiform papillae, mainly in black patients. Although they have been primarily described in black individuals, PFPT also has been occasionally reported in Asian and Middle Eastern individuals as well as Indian women.^3-6

A 36-year-old Indian man initially presented to his primary care provider with brown discoloration of the dorsolateral aspects of the tongue that had been present since childhood. His primary care provider was concerned about a potential syndrome or systemic illness and referred the patient to dermatology for further evaluation. The patient denied any oral mucosal bleeding or discomfort, and a review of systems was unremarkable. His medical and family history were otherwise noncontributory, and he denied a history of tobacco use.

Physical examination of the tongue and oral mucosa revealed numerous 0.5- to 1.0-mm brown papillae in a symmetric distribution, primarily located on the tip and lateral aspects of the tongue (Figure). No hyperpigmentation was present on the posterior aspect of the tongue or on any other mucosal surface. Routine laboratory values were notable for mild elevations in aspartate aminotransferase and alanine aminotransferase (47 U/L [reference range, 10–30 U/L] and 64 U/L [reference range, 10–40 U/L], respectively) and mild hyperbilirubinemia (total bilirubin, 1.8 mg/dL [reference range, 0.3–1.2 mg/dL]). A complete blood cell count and electrolytes were within reference range. Based on the clinical appearance of the lesions and their presence since childhood, the patient was diagnosed with PFPT. No intervention was undertaken, and the patient was reassured of the benign nature of the lesions.

Pigmented fungiform papillae of the tongue presents in 3 variants. The first variant involves hyperpigmentation of all fungiform papillae located on the lateral and frontal aspects of the tongue and is the most common manifestation of PFPT.³ Our patient falls into this category. The second and third variants involve the dorsal surface, with the former involving only a few fungiform papillae on the dorsal aspect of the tongue and the latter variant involving all papillae.³ In 1974, Holzwanger et al³ conducted a survey of 300 random individuals, finding that 30% of black women and 25% of black men had some hyperpigmentation of the tongue, while only 1 white individual demonstrated lingual pigmentation. The physiology of PFPT remains largely unknown. Dermoscopic evaluation often demonstrates elevations with pigmented borders in a rose petal shape.⁷ Histopathologic evaluation reveals melanophages without inflammation that are positive for melanin on Fontana-Masson silver staining but negative for iron on Prussian blue staining.⁸

Despite the fact that PFPT is not a rare condition, the diagnosis remains notably missing from many standard dermatology textbooks and online dermatology resources, making it a potentially overlooked clinical entity.^4-6 The tongue has a number of normal variations that are unlikely to be fully appreciated or acknowledged by dermatologists on routine physical examination but may cause distress to patients and raise concerns from primary care providers. Given that PFPT are benign, physicians should be aware of this diagnosis so as to provide reassurance to patients and avoid unnecessary testing. However, because the tongue can represent a harbinger of systemic disease, the differential diagnosis for the hyperpigmented lesions must always be considered, including Peutz-Jeghers syndrome, hemochromatosis, Addison disease, and Laugier-Hunziker syndrome (a rarer condition causing pigmented lesions on the lips, palate, and tongue), particularly if the hyperpigmented lesions extend beyond the fungiform papillae and do not fit into the 3 categories of PFPT.⁹

The Diagnosis: Disseminated Fusariosis  

Histologic evaluation of the punch biopsy demonstrated thrombosed vessels in the deep dermis and along fibrous septae of subcutaneous tissue, as well as delicate, thin-walled, branching hyphae with vesicular swellings (Figure). The hyphae were present within the vascular thrombi and extended into surrounding tissue. The fungal tissue culture eventually grew scant Fusarium. At the time of biopsy, there was a high index of suspicion for fungal infection, which supported the decision to empirically treat with anidulafungin and voriconazole.  

Differentiating the diagnosis in this case was done primarily with histopathology. Although Aspergillus also has slender hyphae, it lacks the vesicular swellings characteristic of fusariosis. Disseminated candidiasis would demonstrate budding yeast and pseudohyphae in the dermis. Ecthyma gangrenosum histologically presents as necrotizing hemorrhagic vasculitis with gram-negative rods in the walls of deeper vessels, characteristically sparing the intima. Leukemia cutis histologically varies but would display a neoplastic infiltrate of atypical monocytoid cells with nuclear pleomorphism.  

Our patient had been treated with palliative chemotherapy as a salvage regimen with idarubicin and cytarabine. She had persistent pancytopenia despite granulocyte-macrophage colony-stimulating factor therapy. The mortality rate for disseminated Fusarium infection approaches 100% when risk factors such as angiotropism and prolonged neutropenia are present.^1,2 Additionally, our patient's susceptibility profile subsequently demonstrated an elevated minimum inhibitory concentration to amphotericin B, itraconazole, voriconazole, and posaconazole. The neutropenia and Fusarium infection were not responsive to treatment. She was discharged on palliative voriconazole with home hospice care.  

Fusarium species are soil-dwelling saprophytes and important plant pathogens that have increasingly emerged as rare but notable causes of morbidity and mortality in immunocompromised patients.^1-3 More specifically, Fusarium infection is most commonly observed in patients with hematologic malignancy complicated by persistent neutropenia. The 3 most frequently encountered Fusarium species in human disease are Fusarium solani, Fusarium oxysporum, and Fusarium moniliforme, with F solani being the most virulent.^1,2 Infection with Fusarium may manifest as a broad range of presentations depending on the route of entry, such as endophthalmitis, sinusitis, pneumonia, and cutaneous lesions.¹ Disseminated infection is marked by skin lesions or positive blood cultures for Fusarium.³ This fungus is notorious for its limited susceptibility profile.¹ It requires systemic antifungal medications such as triazoles and amphotericin B. Fusarium is most susceptible in vitro to amphotericin B but often requires toxic dosages to be effective in decreasing fungal load.^2,3 The high mortality rate of disseminated fusariosis further emphasizes that prevention is an important component to protecting high-risk patients. Keeping patients in rooms with high-efficiency particulate arresting filters and limiting exposure to unsanitized tap water faucets can help decrease exposure; however, reducing immunosuppression and improving neutropenia are the most effective ways to prevent fusariosis.¹ Although skin breakdown can facilitate the spread of infection, it has been observed that immunosuppressed individuals do not necessarily have this finding.⁴ 

This case emphasizes the importance of considering disseminated fusariosis in patients with hematologic malignancy or other immunosuppressed conditions. The most important factors that should raise clinical suspicion are persistent neutropenia and recent corticosteroid therapy.¹ A clinical picture that suggests fungal infection should warrant consideration of prophylactic treatment as well as tissue and blood cultures to determine species and susceptibility.  
 

The Diagnosis: Disseminated Fusariosis  

Histologic evaluation of the punch biopsy demonstrated thrombosed vessels in the deep dermis and along fibrous septae of subcutaneous tissue, as well as delicate, thin-walled, branching hyphae with vesicular swellings (Figure). The hyphae were present within the vascular thrombi and extended into surrounding tissue. The fungal tissue culture eventually grew scant Fusarium. At the time of biopsy, there was a high index of suspicion for fungal infection, which supported the decision to empirically treat with anidulafungin and voriconazole.  

Differentiating the diagnosis in this case was done primarily with histopathology. Although Aspergillus also has slender hyphae, it lacks the vesicular swellings characteristic of fusariosis. Disseminated candidiasis would demonstrate budding yeast and pseudohyphae in the dermis. Ecthyma gangrenosum histologically presents as necrotizing hemorrhagic vasculitis with gram-negative rods in the walls of deeper vessels, characteristically sparing the intima. Leukemia cutis histologically varies but would display a neoplastic infiltrate of atypical monocytoid cells with nuclear pleomorphism.  

Our patient had been treated with palliative chemotherapy as a salvage regimen with idarubicin and cytarabine. She had persistent pancytopenia despite granulocyte-macrophage colony-stimulating factor therapy. The mortality rate for disseminated Fusarium infection approaches 100% when risk factors such as angiotropism and prolonged neutropenia are present.^1,2 Additionally, our patient's susceptibility profile subsequently demonstrated an elevated minimum inhibitory concentration to amphotericin B, itraconazole, voriconazole, and posaconazole. The neutropenia and Fusarium infection were not responsive to treatment. She was discharged on palliative voriconazole with home hospice care.  

Fusarium species are soil-dwelling saprophytes and important plant pathogens that have increasingly emerged as rare but notable causes of morbidity and mortality in immunocompromised patients.^1-3 More specifically, Fusarium infection is most commonly observed in patients with hematologic malignancy complicated by persistent neutropenia. The 3 most frequently encountered Fusarium species in human disease are Fusarium solani, Fusarium oxysporum, and Fusarium moniliforme, with F solani being the most virulent.^1,2 Infection with Fusarium may manifest as a broad range of presentations depending on the route of entry, such as endophthalmitis, sinusitis, pneumonia, and cutaneous lesions.¹ Disseminated infection is marked by skin lesions or positive blood cultures for Fusarium.³ This fungus is notorious for its limited susceptibility profile.¹ It requires systemic antifungal medications such as triazoles and amphotericin B. Fusarium is most susceptible in vitro to amphotericin B but often requires toxic dosages to be effective in decreasing fungal load.^2,3 The high mortality rate of disseminated fusariosis further emphasizes that prevention is an important component to protecting high-risk patients. Keeping patients in rooms with high-efficiency particulate arresting filters and limiting exposure to unsanitized tap water faucets can help decrease exposure; however, reducing immunosuppression and improving neutropenia are the most effective ways to prevent fusariosis.¹ Although skin breakdown can facilitate the spread of infection, it has been observed that immunosuppressed individuals do not necessarily have this finding.⁴ 

This case emphasizes the importance of considering disseminated fusariosis in patients with hematologic malignancy or other immunosuppressed conditions. The most important factors that should raise clinical suspicion are persistent neutropenia and recent corticosteroid therapy.¹ A clinical picture that suggests fungal infection should warrant consideration of prophylactic treatment as well as tissue and blood cultures to determine species and susceptibility.  
 

The Diagnosis: Disseminated Fusariosis  

Histologic evaluation of the punch biopsy demonstrated thrombosed vessels in the deep dermis and along fibrous septae of subcutaneous tissue, as well as delicate, thin-walled, branching hyphae with vesicular swellings (Figure). The hyphae were present within the vascular thrombi and extended into surrounding tissue. The fungal tissue culture eventually grew scant Fusarium. At the time of biopsy, there was a high index of suspicion for fungal infection, which supported the decision to empirically treat with anidulafungin and voriconazole.  

Differentiating the diagnosis in this case was done primarily with histopathology. Although Aspergillus also has slender hyphae, it lacks the vesicular swellings characteristic of fusariosis. Disseminated candidiasis would demonstrate budding yeast and pseudohyphae in the dermis. Ecthyma gangrenosum histologically presents as necrotizing hemorrhagic vasculitis with gram-negative rods in the walls of deeper vessels, characteristically sparing the intima. Leukemia cutis histologically varies but would display a neoplastic infiltrate of atypical monocytoid cells with nuclear pleomorphism.  

Our patient had been treated with palliative chemotherapy as a salvage regimen with idarubicin and cytarabine. She had persistent pancytopenia despite granulocyte-macrophage colony-stimulating factor therapy. The mortality rate for disseminated Fusarium infection approaches 100% when risk factors such as angiotropism and prolonged neutropenia are present.^1,2 Additionally, our patient's susceptibility profile subsequently demonstrated an elevated minimum inhibitory concentration to amphotericin B, itraconazole, voriconazole, and posaconazole. The neutropenia and Fusarium infection were not responsive to treatment. She was discharged on palliative voriconazole with home hospice care.  

Fusarium species are soil-dwelling saprophytes and important plant pathogens that have increasingly emerged as rare but notable causes of morbidity and mortality in immunocompromised patients.^1-3 More specifically, Fusarium infection is most commonly observed in patients with hematologic malignancy complicated by persistent neutropenia. The 3 most frequently encountered Fusarium species in human disease are Fusarium solani, Fusarium oxysporum, and Fusarium moniliforme, with F solani being the most virulent.^1,2 Infection with Fusarium may manifest as a broad range of presentations depending on the route of entry, such as endophthalmitis, sinusitis, pneumonia, and cutaneous lesions.¹ Disseminated infection is marked by skin lesions or positive blood cultures for Fusarium.³ This fungus is notorious for its limited susceptibility profile.¹ It requires systemic antifungal medications such as triazoles and amphotericin B. Fusarium is most susceptible in vitro to amphotericin B but often requires toxic dosages to be effective in decreasing fungal load.^2,3 The high mortality rate of disseminated fusariosis further emphasizes that prevention is an important component to protecting high-risk patients. Keeping patients in rooms with high-efficiency particulate arresting filters and limiting exposure to unsanitized tap water faucets can help decrease exposure; however, reducing immunosuppression and improving neutropenia are the most effective ways to prevent fusariosis.¹ Although skin breakdown can facilitate the spread of infection, it has been observed that immunosuppressed individuals do not necessarily have this finding.⁴ 

This case emphasizes the importance of considering disseminated fusariosis in patients with hematologic malignancy or other immunosuppressed conditions. The most important factors that should raise clinical suspicion are persistent neutropenia and recent corticosteroid therapy.¹ A clinical picture that suggests fungal infection should warrant consideration of prophylactic treatment as well as tissue and blood cultures to determine species and susceptibility.  
 

To the Editor:

A 40-year-old white woman presented with a waxing and waning erythematous pruritic rash on the chest, back, and axillae of 3 years’ duration. The appearance of the rash coincided with an intentional weight loss of more than 100 lb, achieved through various diets, most recently a Paleolithic (paleo) diet that was high in protein; low in carbohydrates; and specifically restricted dairy, cereal grains, refined sugars, processed foods, white potatoes, salt, refined oils, and legumes.¹ The patient had been monitoring blood glucose and ketone levels. Prior to presentation, she received various treatments including clotrimazole cream and topical steroids with no improvement. 

On physical examination, there were scaly, pink-red, reticulated papules and plaques coexisting with tan reticulated patches that were symmetrically distributed on the central back, lateral and central chest (Figure 1A), breasts, and inframammary areas. During the most severe flare-up, the blood ketones measured 1 mmol/L. There was no relevant medical history. She was of Spanish and Italian descent.

Prurigo pigmentosa is a rare inflammatory dermatosis that was initially described in 1971 as “a peculiar pruriginous dermatosis with gross reticular pigmentation” by Nagashima et al.² Prurigo pigmentosa is most frequently diagnosed in Japan, and since its discovery, it has been reported in more than 300 cases worldwide.^2-4

Fewer than 50 non-Japanese cases have been reported, with the possibility of an additional ethnic predisposition among the Turkish and Sicilian populations, though only 6 cases have been reported in the United States.^3-6 Prurigo pigmentosa tends to occur in the spring and summer months and is most common among young females, with a mean age of 24 years. The typical lesions of PP are symmetrically distributed on the trunk with a tendency to localize on the upper back, nape of the neck, and intermammary and inframammary regions. Eruptions have been reported to occur on additional areas; however, mucus membranes are always spared.⁶

Individual lesions differ in appearance depending on the stage of presentation and are categorized as early, fully developed, resolving, and late lesions.⁶ Pruritic macules and papules are present early in the disease state and resolve into crusted and/or scaly papules followed by pigmented macules. Early lesions tend to be intensely pruritic with signs of excoriation, while resolving lesions lack symptoms. Lesions last approximately 1 week but tend to reappear at the site where they were previously present, which allows for lesions of different ages to coexist, appearing in a reticular arrangement with hyperpigmented mottling lasting from a few weeks to months.⁶

Just as the clinical picture transpires rapidly within 1 week, so do the histopathologic findings.⁶ Early lesions are categorized by a superficial perivascular and interstitial infiltrate of neutrophils, spongiosis, ballooning, and necrotic keratinocytes. These early lesions are present for less than 48 hours, and these histopathologic findings are diagnostic of PP. Within 2 days, lymphocytes predominate in the dermal infiltrate, and a patchy lichenoid aspect is established in the fully developed lesion along with reticular and vacuolar alterations. Late lesions show a parakeratotic and hyperpigmented epidermis with melanophages present in the papillary and reticular dermis. At this last stage, the histopathologic features of PP are indistinguishable from any other disease that results in postinflammatory hyperpigmentation, making diagnosis difficult.⁶

A variety of therapeutic options are used in the treatment of PP, with the most effective agents being oral antibiotics including dapsone, minocycline, and doxycycline, all of which limit the local tissue inflammatory response and cytotoxic effects. Topical and systemic antihistamines as well as corticosteroids are ineffective and have not been shown to prevent the postinflammatory reticular pigmentation.^6-10

Various underlying factors have been associated with PP, including friction, heat, sunlight, sweating, allergic contact sensitization, and ketosis due to nutritional deficiency or diabetes mellitus; however; the exact etiology remains ambiguous.^2-7 The association with ketosis and nutrition is of particular interest in this case. Onset of PP has been reported to coincide with dieting, fasting, weight loss, anorexia nervosa, and diabetes mellitus.^3,6-9 Roughly 50 patients with PP had ketosis subsequent to these metabolic disturbances.^3,6-10 As of now, the only reported correlation between ketosis and PP is that upon diet modification, lesions resolved following ketone normalization, as was observed in our patient.^3,6-8 Reports of PP in diabetic patients while in ketoacidosis describe resolution of lesions with insulin administration.^6-9 The pathophysiology of ketosis and its association with PP is unclear; however, the similarities seen in the immune response of PP and that stimulated by ketosis may expose an associated mechanism.

Ketosis is a temporary condition characterized by elevated serum ketones that are used as an alternative energy source when blood glucose is low or insulin is deficient.¹¹ The most common causes of ketosis are the physiologic responses to fasting, prolonged exercise, or a high-protein/low-carbohydrate diet, though pathologic causes include insulin-dependent diabetes mellitus, alcoholism, and salicylate overdose.¹¹ In healthy individuals, blood ketone levels rarely approach 0.5 mmol/L. Prolonged fasting or restricting intake of carbohydrates to less than 40 g daily can induce mild ketosis that resolves with re-introduction of carbohydrates.¹¹

Ketone bodies pass from the circulating blood into tissues or remain near the blood vessels, inducing cytotoxic effects and perivascular inflammation.^10,11 Increased ketone bodies have been shown to upregulate intercellular adhesion molecule 1 (ICAM-1) and leukocyte function-associated antigen 1 (LFA-1), a phenomenon also seen in lesional keratinocytes of PP.^12,13 Teraki et al¹³ observed that epidermal keratinocytes exhibited increased expression of ICAM-1 as well as intense expression of LFA-1 on dermal and epidermotropic leukocytes, which was thought to be due to cell-mediated cytotoxicity. Not only do increased ketone bodies upregulate ICAM-1 and LFA-1, but they also are involved in increasing many proinflammatory mediators that may be capable of inducing the response seen in PP keratinocytes.^12,13

Intercellular adhesion molecule 1 is important in initiating cellular interactions in the immune response and is the ligand for LFA-1 found on most leukocytes.¹⁴ Increased ICAM-1/LFA-1 interaction is thought to be the major pathway by which leukocytes are able to attach to keratinocytes and endothelial cells, allowing for leukocyte tissue migration and specific immunologic reactions, including leukocyte-mediated cytotoxicity. Interestingly, glucocorticoids are ineffective in reducing the expression of ICAM-1 in cultured keratinocytes.¹⁴ This connection between ketosis and inflammation that results in leukocyte migration and ultimately keratinocyte cytotoxicity may well be fundamental to the pathophysiology of PP and may provide a possible explanation for the ineffectiveness of corticosteroid treatment.

Middleton and Norris¹⁵ observed that individual keratinocyte strains show considerable variability in ICAM-1 expression that was found to be attributable to genetic polymorphisms. The presence of a particular polymorphism affecting ICAM-1 expression on human keratinocytes may explain the apparent ethnogeographic predisposition of PP as well as the ease at which ICAM-1 is expressed in the presence of ketones.

We describe a case of a 40-year-old white woman who was diagnosed with PP that was prompted by a 100-lb weight loss and self-induced ketosis while following a paleo diet with carbohydrate restriction. Successful treatment was attained through diet modification alone. This interesting case was another instance in which the pathophysiology of PP was attributed to ketosis. Because not all patients that are in ketosis have PP, larger prospective cohort studies are needed to further elucidate the association of PP and ketosis.

To the Editor:

A 40-year-old white woman presented with a waxing and waning erythematous pruritic rash on the chest, back, and axillae of 3 years’ duration. The appearance of the rash coincided with an intentional weight loss of more than 100 lb, achieved through various diets, most recently a Paleolithic (paleo) diet that was high in protein; low in carbohydrates; and specifically restricted dairy, cereal grains, refined sugars, processed foods, white potatoes, salt, refined oils, and legumes.¹ The patient had been monitoring blood glucose and ketone levels. Prior to presentation, she received various treatments including clotrimazole cream and topical steroids with no improvement. 

On physical examination, there were scaly, pink-red, reticulated papules and plaques coexisting with tan reticulated patches that were symmetrically distributed on the central back, lateral and central chest (Figure 1A), breasts, and inframammary areas. During the most severe flare-up, the blood ketones measured 1 mmol/L. There was no relevant medical history. She was of Spanish and Italian descent.

Prurigo pigmentosa is a rare inflammatory dermatosis that was initially described in 1971 as “a peculiar pruriginous dermatosis with gross reticular pigmentation” by Nagashima et al.² Prurigo pigmentosa is most frequently diagnosed in Japan, and since its discovery, it has been reported in more than 300 cases worldwide.^2-4

Fewer than 50 non-Japanese cases have been reported, with the possibility of an additional ethnic predisposition among the Turkish and Sicilian populations, though only 6 cases have been reported in the United States.^3-6 Prurigo pigmentosa tends to occur in the spring and summer months and is most common among young females, with a mean age of 24 years. The typical lesions of PP are symmetrically distributed on the trunk with a tendency to localize on the upper back, nape of the neck, and intermammary and inframammary regions. Eruptions have been reported to occur on additional areas; however, mucus membranes are always spared.⁶

Individual lesions differ in appearance depending on the stage of presentation and are categorized as early, fully developed, resolving, and late lesions.⁶ Pruritic macules and papules are present early in the disease state and resolve into crusted and/or scaly papules followed by pigmented macules. Early lesions tend to be intensely pruritic with signs of excoriation, while resolving lesions lack symptoms. Lesions last approximately 1 week but tend to reappear at the site where they were previously present, which allows for lesions of different ages to coexist, appearing in a reticular arrangement with hyperpigmented mottling lasting from a few weeks to months.⁶

Just as the clinical picture transpires rapidly within 1 week, so do the histopathologic findings.⁶ Early lesions are categorized by a superficial perivascular and interstitial infiltrate of neutrophils, spongiosis, ballooning, and necrotic keratinocytes. These early lesions are present for less than 48 hours, and these histopathologic findings are diagnostic of PP. Within 2 days, lymphocytes predominate in the dermal infiltrate, and a patchy lichenoid aspect is established in the fully developed lesion along with reticular and vacuolar alterations. Late lesions show a parakeratotic and hyperpigmented epidermis with melanophages present in the papillary and reticular dermis. At this last stage, the histopathologic features of PP are indistinguishable from any other disease that results in postinflammatory hyperpigmentation, making diagnosis difficult.⁶

A variety of therapeutic options are used in the treatment of PP, with the most effective agents being oral antibiotics including dapsone, minocycline, and doxycycline, all of which limit the local tissue inflammatory response and cytotoxic effects. Topical and systemic antihistamines as well as corticosteroids are ineffective and have not been shown to prevent the postinflammatory reticular pigmentation.^6-10

Various underlying factors have been associated with PP, including friction, heat, sunlight, sweating, allergic contact sensitization, and ketosis due to nutritional deficiency or diabetes mellitus; however; the exact etiology remains ambiguous.^2-7 The association with ketosis and nutrition is of particular interest in this case. Onset of PP has been reported to coincide with dieting, fasting, weight loss, anorexia nervosa, and diabetes mellitus.^3,6-9 Roughly 50 patients with PP had ketosis subsequent to these metabolic disturbances.^3,6-10 As of now, the only reported correlation between ketosis and PP is that upon diet modification, lesions resolved following ketone normalization, as was observed in our patient.^3,6-8 Reports of PP in diabetic patients while in ketoacidosis describe resolution of lesions with insulin administration.^6-9 The pathophysiology of ketosis and its association with PP is unclear; however, the similarities seen in the immune response of PP and that stimulated by ketosis may expose an associated mechanism.

Ketosis is a temporary condition characterized by elevated serum ketones that are used as an alternative energy source when blood glucose is low or insulin is deficient.¹¹ The most common causes of ketosis are the physiologic responses to fasting, prolonged exercise, or a high-protein/low-carbohydrate diet, though pathologic causes include insulin-dependent diabetes mellitus, alcoholism, and salicylate overdose.¹¹ In healthy individuals, blood ketone levels rarely approach 0.5 mmol/L. Prolonged fasting or restricting intake of carbohydrates to less than 40 g daily can induce mild ketosis that resolves with re-introduction of carbohydrates.¹¹

Ketone bodies pass from the circulating blood into tissues or remain near the blood vessels, inducing cytotoxic effects and perivascular inflammation.^10,11 Increased ketone bodies have been shown to upregulate intercellular adhesion molecule 1 (ICAM-1) and leukocyte function-associated antigen 1 (LFA-1), a phenomenon also seen in lesional keratinocytes of PP.^12,13 Teraki et al¹³ observed that epidermal keratinocytes exhibited increased expression of ICAM-1 as well as intense expression of LFA-1 on dermal and epidermotropic leukocytes, which was thought to be due to cell-mediated cytotoxicity. Not only do increased ketone bodies upregulate ICAM-1 and LFA-1, but they also are involved in increasing many proinflammatory mediators that may be capable of inducing the response seen in PP keratinocytes.^12,13

Intercellular adhesion molecule 1 is important in initiating cellular interactions in the immune response and is the ligand for LFA-1 found on most leukocytes.¹⁴ Increased ICAM-1/LFA-1 interaction is thought to be the major pathway by which leukocytes are able to attach to keratinocytes and endothelial cells, allowing for leukocyte tissue migration and specific immunologic reactions, including leukocyte-mediated cytotoxicity. Interestingly, glucocorticoids are ineffective in reducing the expression of ICAM-1 in cultured keratinocytes.¹⁴ This connection between ketosis and inflammation that results in leukocyte migration and ultimately keratinocyte cytotoxicity may well be fundamental to the pathophysiology of PP and may provide a possible explanation for the ineffectiveness of corticosteroid treatment.

Middleton and Norris¹⁵ observed that individual keratinocyte strains show considerable variability in ICAM-1 expression that was found to be attributable to genetic polymorphisms. The presence of a particular polymorphism affecting ICAM-1 expression on human keratinocytes may explain the apparent ethnogeographic predisposition of PP as well as the ease at which ICAM-1 is expressed in the presence of ketones.

We describe a case of a 40-year-old white woman who was diagnosed with PP that was prompted by a 100-lb weight loss and self-induced ketosis while following a paleo diet with carbohydrate restriction. Successful treatment was attained through diet modification alone. This interesting case was another instance in which the pathophysiology of PP was attributed to ketosis. Because not all patients that are in ketosis have PP, larger prospective cohort studies are needed to further elucidate the association of PP and ketosis.

To the Editor:

A 40-year-old white woman presented with a waxing and waning erythematous pruritic rash on the chest, back, and axillae of 3 years’ duration. The appearance of the rash coincided with an intentional weight loss of more than 100 lb, achieved through various diets, most recently a Paleolithic (paleo) diet that was high in protein; low in carbohydrates; and specifically restricted dairy, cereal grains, refined sugars, processed foods, white potatoes, salt, refined oils, and legumes.¹ The patient had been monitoring blood glucose and ketone levels. Prior to presentation, she received various treatments including clotrimazole cream and topical steroids with no improvement. 

On physical examination, there were scaly, pink-red, reticulated papules and plaques coexisting with tan reticulated patches that were symmetrically distributed on the central back, lateral and central chest (Figure 1A), breasts, and inframammary areas. During the most severe flare-up, the blood ketones measured 1 mmol/L. There was no relevant medical history. She was of Spanish and Italian descent.

Prurigo pigmentosa is a rare inflammatory dermatosis that was initially described in 1971 as “a peculiar pruriginous dermatosis with gross reticular pigmentation” by Nagashima et al.² Prurigo pigmentosa is most frequently diagnosed in Japan, and since its discovery, it has been reported in more than 300 cases worldwide.^2-4

Fewer than 50 non-Japanese cases have been reported, with the possibility of an additional ethnic predisposition among the Turkish and Sicilian populations, though only 6 cases have been reported in the United States.^3-6 Prurigo pigmentosa tends to occur in the spring and summer months and is most common among young females, with a mean age of 24 years. The typical lesions of PP are symmetrically distributed on the trunk with a tendency to localize on the upper back, nape of the neck, and intermammary and inframammary regions. Eruptions have been reported to occur on additional areas; however, mucus membranes are always spared.⁶

Individual lesions differ in appearance depending on the stage of presentation and are categorized as early, fully developed, resolving, and late lesions.⁶ Pruritic macules and papules are present early in the disease state and resolve into crusted and/or scaly papules followed by pigmented macules. Early lesions tend to be intensely pruritic with signs of excoriation, while resolving lesions lack symptoms. Lesions last approximately 1 week but tend to reappear at the site where they were previously present, which allows for lesions of different ages to coexist, appearing in a reticular arrangement with hyperpigmented mottling lasting from a few weeks to months.⁶

Just as the clinical picture transpires rapidly within 1 week, so do the histopathologic findings.⁶ Early lesions are categorized by a superficial perivascular and interstitial infiltrate of neutrophils, spongiosis, ballooning, and necrotic keratinocytes. These early lesions are present for less than 48 hours, and these histopathologic findings are diagnostic of PP. Within 2 days, lymphocytes predominate in the dermal infiltrate, and a patchy lichenoid aspect is established in the fully developed lesion along with reticular and vacuolar alterations. Late lesions show a parakeratotic and hyperpigmented epidermis with melanophages present in the papillary and reticular dermis. At this last stage, the histopathologic features of PP are indistinguishable from any other disease that results in postinflammatory hyperpigmentation, making diagnosis difficult.⁶

A variety of therapeutic options are used in the treatment of PP, with the most effective agents being oral antibiotics including dapsone, minocycline, and doxycycline, all of which limit the local tissue inflammatory response and cytotoxic effects. Topical and systemic antihistamines as well as corticosteroids are ineffective and have not been shown to prevent the postinflammatory reticular pigmentation.^6-10

Various underlying factors have been associated with PP, including friction, heat, sunlight, sweating, allergic contact sensitization, and ketosis due to nutritional deficiency or diabetes mellitus; however; the exact etiology remains ambiguous.^2-7 The association with ketosis and nutrition is of particular interest in this case. Onset of PP has been reported to coincide with dieting, fasting, weight loss, anorexia nervosa, and diabetes mellitus.^3,6-9 Roughly 50 patients with PP had ketosis subsequent to these metabolic disturbances.^3,6-10 As of now, the only reported correlation between ketosis and PP is that upon diet modification, lesions resolved following ketone normalization, as was observed in our patient.^3,6-8 Reports of PP in diabetic patients while in ketoacidosis describe resolution of lesions with insulin administration.^6-9 The pathophysiology of ketosis and its association with PP is unclear; however, the similarities seen in the immune response of PP and that stimulated by ketosis may expose an associated mechanism.

Ketosis is a temporary condition characterized by elevated serum ketones that are used as an alternative energy source when blood glucose is low or insulin is deficient.¹¹ The most common causes of ketosis are the physiologic responses to fasting, prolonged exercise, or a high-protein/low-carbohydrate diet, though pathologic causes include insulin-dependent diabetes mellitus, alcoholism, and salicylate overdose.¹¹ In healthy individuals, blood ketone levels rarely approach 0.5 mmol/L. Prolonged fasting or restricting intake of carbohydrates to less than 40 g daily can induce mild ketosis that resolves with re-introduction of carbohydrates.¹¹

Ketone bodies pass from the circulating blood into tissues or remain near the blood vessels, inducing cytotoxic effects and perivascular inflammation.^10,11 Increased ketone bodies have been shown to upregulate intercellular adhesion molecule 1 (ICAM-1) and leukocyte function-associated antigen 1 (LFA-1), a phenomenon also seen in lesional keratinocytes of PP.^12,13 Teraki et al¹³ observed that epidermal keratinocytes exhibited increased expression of ICAM-1 as well as intense expression of LFA-1 on dermal and epidermotropic leukocytes, which was thought to be due to cell-mediated cytotoxicity. Not only do increased ketone bodies upregulate ICAM-1 and LFA-1, but they also are involved in increasing many proinflammatory mediators that may be capable of inducing the response seen in PP keratinocytes.^12,13

Intercellular adhesion molecule 1 is important in initiating cellular interactions in the immune response and is the ligand for LFA-1 found on most leukocytes.¹⁴ Increased ICAM-1/LFA-1 interaction is thought to be the major pathway by which leukocytes are able to attach to keratinocytes and endothelial cells, allowing for leukocyte tissue migration and specific immunologic reactions, including leukocyte-mediated cytotoxicity. Interestingly, glucocorticoids are ineffective in reducing the expression of ICAM-1 in cultured keratinocytes.¹⁴ This connection between ketosis and inflammation that results in leukocyte migration and ultimately keratinocyte cytotoxicity may well be fundamental to the pathophysiology of PP and may provide a possible explanation for the ineffectiveness of corticosteroid treatment.

Middleton and Norris¹⁵ observed that individual keratinocyte strains show considerable variability in ICAM-1 expression that was found to be attributable to genetic polymorphisms. The presence of a particular polymorphism affecting ICAM-1 expression on human keratinocytes may explain the apparent ethnogeographic predisposition of PP as well as the ease at which ICAM-1 is expressed in the presence of ketones.

We describe a case of a 40-year-old white woman who was diagnosed with PP that was prompted by a 100-lb weight loss and self-induced ketosis while following a paleo diet with carbohydrate restriction. Successful treatment was attained through diet modification alone. This interesting case was another instance in which the pathophysiology of PP was attributed to ketosis. Because not all patients that are in ketosis have PP, larger prospective cohort studies are needed to further elucidate the association of PP and ketosis.

To the Editor: 
A 60-year-old woman presented for evaluation of a 1-year history of left hallux nail plate dystrophy and proximal nail fold inflammation. Her medical history included Cushing disease with associated uncontrolled diabetes mellitus (DM) and a remote history of cutaneous lichen planus (LP) that resolved 15 years prior to presentation. She noted improvement during intravenous courses of antibiotics for other infections.   

Examination of the left hallux revealed onycholysis, loss of the nail plate, and a yellow fibrinous base alongside erosion, erythema, and edema of the proximal toenail fold (Figure 1). The left second toe pad was markedly tender to palpation with scant exudate expressed from underneath the nail bed. Two biopsies of the hallux were performed. The proximal nail fold specimen revealed mild epidermal hyperplasia, and the nail bed demonstrated a nonspecific ulcer that was negative for acid-fast bacilli and fungi.  

Treatment over 2 months with cephalexin yielded improvement in both erythema and edema. Initial and repeat nail plate cultures grew ampicillin- and penicillin-sensitive Enterococcus faecalis. Magnetic resonance imaging was performed to evaluate for osteomyelitis because of lack of resolution. Results demonstrated osteomyelitis of the distal tuft of the left hallux and the distal phalanx of the second toe (Figure 2). Vascular surgery evaluation revealed no evidence of large vessel arterial insufficiency. She was started on amoxicillin for superficial Enterococcus and ciprofloxacin for underlying enteric bacilli. The persistence of infection was attributed to microvascular disease secondary to the patient's associated DM. Months later, due to suspected worsening of osteomyelitis, she underwent treatment with oral fluconazole to cover potential fungal co-infection and intravenous vancomycin and piperacillin-tazobactam for broad-spectrum antibacterial coverage. She was eventually transitioned to antimicrobial agents including amoxicillin-clavulanate potassium and topical mupirocin with improvement in periungual erythema and edema.  

On subsequent dermatologic evaluation after 1 month, she presented with pterygium and loss of all nail plates on the left foot. The nail bed now had a violaceous color and was studded with milia. The clinical findings were suggestive of LP, consistent with her history of LP. In light of these new findings, both topical corticosteroids and retinoids were utilized for treatment without remarkable benefit. The patient declined further management with systemic medications. 

We report a case of nail LP associated with underlying radiographic osteomyelitis. Erosive nail LP has been associated with underlying osteomyelitis of the phalanx.¹ Our patient developed these manifestations in the setting of Cushing disease, a unique finding given that many report improvement of LP with systemic corticosteroids.^2,3 Tacrolimus, a calcineurin inhibitor, has been used in oral or topical formulations for lower extremity ulcers caused by LP as well as nail LP.^1,4 Long-term prognosis of nail LP is poor, with high relapse rates and permanent damage to the nail unit.² It is important to be aware that LP of the nail unit may cause radiographic changes of osteomyelitis that are not infectious in nature. 
 
 

To the Editor: 
A 60-year-old woman presented for evaluation of a 1-year history of left hallux nail plate dystrophy and proximal nail fold inflammation. Her medical history included Cushing disease with associated uncontrolled diabetes mellitus (DM) and a remote history of cutaneous lichen planus (LP) that resolved 15 years prior to presentation. She noted improvement during intravenous courses of antibiotics for other infections.   

Examination of the left hallux revealed onycholysis, loss of the nail plate, and a yellow fibrinous base alongside erosion, erythema, and edema of the proximal toenail fold (Figure 1). The left second toe pad was markedly tender to palpation with scant exudate expressed from underneath the nail bed. Two biopsies of the hallux were performed. The proximal nail fold specimen revealed mild epidermal hyperplasia, and the nail bed demonstrated a nonspecific ulcer that was negative for acid-fast bacilli and fungi.  

Treatment over 2 months with cephalexin yielded improvement in both erythema and edema. Initial and repeat nail plate cultures grew ampicillin- and penicillin-sensitive Enterococcus faecalis. Magnetic resonance imaging was performed to evaluate for osteomyelitis because of lack of resolution. Results demonstrated osteomyelitis of the distal tuft of the left hallux and the distal phalanx of the second toe (Figure 2). Vascular surgery evaluation revealed no evidence of large vessel arterial insufficiency. She was started on amoxicillin for superficial Enterococcus and ciprofloxacin for underlying enteric bacilli. The persistence of infection was attributed to microvascular disease secondary to the patient's associated DM. Months later, due to suspected worsening of osteomyelitis, she underwent treatment with oral fluconazole to cover potential fungal co-infection and intravenous vancomycin and piperacillin-tazobactam for broad-spectrum antibacterial coverage. She was eventually transitioned to antimicrobial agents including amoxicillin-clavulanate potassium and topical mupirocin with improvement in periungual erythema and edema.  

On subsequent dermatologic evaluation after 1 month, she presented with pterygium and loss of all nail plates on the left foot. The nail bed now had a violaceous color and was studded with milia. The clinical findings were suggestive of LP, consistent with her history of LP. In light of these new findings, both topical corticosteroids and retinoids were utilized for treatment without remarkable benefit. The patient declined further management with systemic medications. 

We report a case of nail LP associated with underlying radiographic osteomyelitis. Erosive nail LP has been associated with underlying osteomyelitis of the phalanx.¹ Our patient developed these manifestations in the setting of Cushing disease, a unique finding given that many report improvement of LP with systemic corticosteroids.^2,3 Tacrolimus, a calcineurin inhibitor, has been used in oral or topical formulations for lower extremity ulcers caused by LP as well as nail LP.^1,4 Long-term prognosis of nail LP is poor, with high relapse rates and permanent damage to the nail unit.² It is important to be aware that LP of the nail unit may cause radiographic changes of osteomyelitis that are not infectious in nature. 
 
 

To the Editor: 
A 60-year-old woman presented for evaluation of a 1-year history of left hallux nail plate dystrophy and proximal nail fold inflammation. Her medical history included Cushing disease with associated uncontrolled diabetes mellitus (DM) and a remote history of cutaneous lichen planus (LP) that resolved 15 years prior to presentation. She noted improvement during intravenous courses of antibiotics for other infections.   

Examination of the left hallux revealed onycholysis, loss of the nail plate, and a yellow fibrinous base alongside erosion, erythema, and edema of the proximal toenail fold (Figure 1). The left second toe pad was markedly tender to palpation with scant exudate expressed from underneath the nail bed. Two biopsies of the hallux were performed. The proximal nail fold specimen revealed mild epidermal hyperplasia, and the nail bed demonstrated a nonspecific ulcer that was negative for acid-fast bacilli and fungi.  

Treatment over 2 months with cephalexin yielded improvement in both erythema and edema. Initial and repeat nail plate cultures grew ampicillin- and penicillin-sensitive Enterococcus faecalis. Magnetic resonance imaging was performed to evaluate for osteomyelitis because of lack of resolution. Results demonstrated osteomyelitis of the distal tuft of the left hallux and the distal phalanx of the second toe (Figure 2). Vascular surgery evaluation revealed no evidence of large vessel arterial insufficiency. She was started on amoxicillin for superficial Enterococcus and ciprofloxacin for underlying enteric bacilli. The persistence of infection was attributed to microvascular disease secondary to the patient's associated DM. Months later, due to suspected worsening of osteomyelitis, she underwent treatment with oral fluconazole to cover potential fungal co-infection and intravenous vancomycin and piperacillin-tazobactam for broad-spectrum antibacterial coverage. She was eventually transitioned to antimicrobial agents including amoxicillin-clavulanate potassium and topical mupirocin with improvement in periungual erythema and edema.  

On subsequent dermatologic evaluation after 1 month, she presented with pterygium and loss of all nail plates on the left foot. The nail bed now had a violaceous color and was studded with milia. The clinical findings were suggestive of LP, consistent with her history of LP. In light of these new findings, both topical corticosteroids and retinoids were utilized for treatment without remarkable benefit. The patient declined further management with systemic medications. 

We report a case of nail LP associated with underlying radiographic osteomyelitis. Erosive nail LP has been associated with underlying osteomyelitis of the phalanx.¹ Our patient developed these manifestations in the setting of Cushing disease, a unique finding given that many report improvement of LP with systemic corticosteroids.^2,3 Tacrolimus, a calcineurin inhibitor, has been used in oral or topical formulations for lower extremity ulcers caused by LP as well as nail LP.^1,4 Long-term prognosis of nail LP is poor, with high relapse rates and permanent damage to the nail unit.² It is important to be aware that LP of the nail unit may cause radiographic changes of osteomyelitis that are not infectious in nature.