Cutis

The term climate refers to the average weather conditions of a specific geographic location measured over several decades.¹ While a certain degree of variation in the Earth’s climate is expected, a persistent warming or cooling trend is not. The factors driving the Earth’s warming remain difficult to prove.² We know the Earth previously has undergone dramatic climate changes and that natural factors driving these changes are varied (eg, the relationship between the Earth and the Sun, volcanic eruptions, solar irradiance).^1,3 These factors ideally change over protracted periods of time in a way that allows organisms to adapt to new environments.

Anthropogenic climate change refers to human-caused climate change. This is thought to be a major driving factor in the Earth’s recent warming trend, partly due to the rapidity of warming in recent years.³ According to climate scientists, the Earth’s temperature has risen 4°C to 7°C over the past 5000 years, but it has risen 0.7°C in just the past 100 years alone.⁴ Greenhouse gases such as carbon dioxide are emitted by various natural processes and human activities and play a central role in current warming because they trap solar heat and increase ambient temperature.³

In a recent edition of the commonly cited textbook Dermatology, Bolognia et al⁵ referenced climate change only once in a figure legend regarding the expansion of dengue fever in the Americas. However, climate change may have the potential to cause outright skin disease epidemics worldwide, and the Climate Change Committee of the International Society of Dermatology has called upon dermatologists across the globe to help raise awareness of this issue.⁶

Much of the literature regarding the effects of climate change on human health focuses on insect-borne diseases, but over the past decade other areas of impact also have been investigated, such as increases in airborne diseases, zoonoses, newly endemic saprophytic and dimorphic fungal infections, fecal-oral diseases, and severe allergic disease.^7,8 It is postulated that climate change leads to region-specific increases in human disease because it creates newly favorable habitats for infectious agents, their vectors. and their reservoirs, allowing expansion of their ranges and access to immunologically naïve populations.⁹ Furthermore, extreme weather events such as heat waves, hurricanes, and flooding, which are expected to increase in frequency as a result of climate change, have all been linked to infectious disease outbreaks.¹⁰

Lyme Disease

In the past 20 years, Lyme disease incidence has tripled in the United States.¹¹ It has been hypothesized that the increase may be occurring as a result of the expanding geographic distribution of the Ixodes tick and its mammalian hosts (eg, white-tailed deer) under the influence of climate change.¹² Lyme disease is a multisystem disease affecting the skin, joints, heart, and nervous system. Its most characteristic manifestation is cutaneous in the form of erythema migrans. Dermatologists may be called upon to play an increasingly important role in early detection and treatment of this potentially chronic and debilitating condition.

Arboviruses

Arboviruses are transmitted by arthropods and are an important category of climate change–related diseases due to the expansion of the mosquito habitat worldwide. The vectorial capacity for the transmission of dengue fever has increased worldwide by 9.4% via Aedes aegypti and 11.1% via Aedes albopictus since 1950.¹³ Dengue fever, also known as breakbone fever, presents with intense joint pain, fevers, headaches, and a transient morbilliform rash that desquamates with defervescence and in some cases will incite hemorrhagic skin lesions.¹⁴ Dengue fever previously was considered to be a tropical disease but locally acquired cases have been reported in the United States, including Texas, Hawaii, and Florida.^15,16

Reports of local transmission of chikungunya, another arbovirus transmitted by A albopictus and A aegypti mosquitoes in Florida, the US Virgin Islands, and Puerto Rico, began in 2014.¹⁷ A higher prevalence of these diseases within the United States also may be related to increased globalization, with US travelers returning from endemic regions with infections. Prior to 2014, transmission occurred in traditional endemic regions, primarily in Asia, Africa, or island nations in the Indian Ocean. Like dengue fever, chikungunya causes high fevers, cutaneous manifestations (eg, urticarial papules, morbilliform eruption, hypermelanosis, intertriginous lesions, lymphedema),¹⁷ and intense joint pain. Unlike dengue fever, however, joint involvement can be chronic, erosive, and debilitating.

Lastly, New World leishmaniasis, an arboviral disease characterized by mucocutaneous ulcers and transmitted by phlebotomine sand flies, has been acquired locally in Oklahoma and Texas when it was previously considered to be endemic to Mexico and Central and South America.^14,18 The habitats of New World Leishmania species are expected to expand northward, with an ecological niche model predicting that they reach southern Canada by the year 2080 due to the expanding habitats of sand fly and rodent vectors.¹⁹

Fungal Infections

In the Pacific Northwest, there have been reports of newly endemic Cryptococcus gattii and Coccidioides immitis, both of which previously had been confined to the southwestern United States.⁸ Endemic ranges of these mycotic pathogens may be expanding for a variety of reasons, with climate change creating new regions conducive to the colonization of these species.^8,20,21Coccidioides immitis is a soil-dwelling fungus that usually presents with primary pulmonary disease that can disseminate acutely or even months later. Prompt recognition of disseminated disease may allow life-saving therapy to be initiated. Cryptococcus gattii is a fungus with multiple niches, including oil, trees, and birds.²⁰ This fungus also is acquired via inhalation, with dissemination occurring most commonly in immunosuppressed patients to the central nervous system, bone, and skin. Primary or secondary infection with both of these fungi may present with cutaneous manifestations presenting as polymorphous lesions, including umbilicated or ulcerated papules, indurated nodules, and acneiform pustules.

Final Thoughts

Awareness of the shifting habitats of microorganisms and vectors locally is important in order for clinicians to make correct diagnoses in a timely fashion. Regional or endemic diseases are presenting outside their traditional boundaries due to changing habitats of microbes and vectors and may be easily overlooked, resulting in a delayed diagnosis. Being prepared to diagnose diseases with increasing incidence secondary to climate change and discussing this with patients is an important physician obligation, but it is not the only one. We cannot effectively advocate for the health of patients and the community while ignoring the destruction of the environment. Our additional responsibility is straightforward—being advocates for good stewardship of the Earth’s resources now on both a personal and a policy level.²²

The term climate refers to the average weather conditions of a specific geographic location measured over several decades.¹ While a certain degree of variation in the Earth’s climate is expected, a persistent warming or cooling trend is not. The factors driving the Earth’s warming remain difficult to prove.² We know the Earth previously has undergone dramatic climate changes and that natural factors driving these changes are varied (eg, the relationship between the Earth and the Sun, volcanic eruptions, solar irradiance).^1,3 These factors ideally change over protracted periods of time in a way that allows organisms to adapt to new environments.

Anthropogenic climate change refers to human-caused climate change. This is thought to be a major driving factor in the Earth’s recent warming trend, partly due to the rapidity of warming in recent years.³ According to climate scientists, the Earth’s temperature has risen 4°C to 7°C over the past 5000 years, but it has risen 0.7°C in just the past 100 years alone.⁴ Greenhouse gases such as carbon dioxide are emitted by various natural processes and human activities and play a central role in current warming because they trap solar heat and increase ambient temperature.³

In a recent edition of the commonly cited textbook Dermatology, Bolognia et al⁵ referenced climate change only once in a figure legend regarding the expansion of dengue fever in the Americas. However, climate change may have the potential to cause outright skin disease epidemics worldwide, and the Climate Change Committee of the International Society of Dermatology has called upon dermatologists across the globe to help raise awareness of this issue.⁶

Much of the literature regarding the effects of climate change on human health focuses on insect-borne diseases, but over the past decade other areas of impact also have been investigated, such as increases in airborne diseases, zoonoses, newly endemic saprophytic and dimorphic fungal infections, fecal-oral diseases, and severe allergic disease.^7,8 It is postulated that climate change leads to region-specific increases in human disease because it creates newly favorable habitats for infectious agents, their vectors. and their reservoirs, allowing expansion of their ranges and access to immunologically naïve populations.⁹ Furthermore, extreme weather events such as heat waves, hurricanes, and flooding, which are expected to increase in frequency as a result of climate change, have all been linked to infectious disease outbreaks.¹⁰

Lyme Disease

In the past 20 years, Lyme disease incidence has tripled in the United States.¹¹ It has been hypothesized that the increase may be occurring as a result of the expanding geographic distribution of the Ixodes tick and its mammalian hosts (eg, white-tailed deer) under the influence of climate change.¹² Lyme disease is a multisystem disease affecting the skin, joints, heart, and nervous system. Its most characteristic manifestation is cutaneous in the form of erythema migrans. Dermatologists may be called upon to play an increasingly important role in early detection and treatment of this potentially chronic and debilitating condition.

Arboviruses

Arboviruses are transmitted by arthropods and are an important category of climate change–related diseases due to the expansion of the mosquito habitat worldwide. The vectorial capacity for the transmission of dengue fever has increased worldwide by 9.4% via Aedes aegypti and 11.1% via Aedes albopictus since 1950.¹³ Dengue fever, also known as breakbone fever, presents with intense joint pain, fevers, headaches, and a transient morbilliform rash that desquamates with defervescence and in some cases will incite hemorrhagic skin lesions.¹⁴ Dengue fever previously was considered to be a tropical disease but locally acquired cases have been reported in the United States, including Texas, Hawaii, and Florida.^15,16

Reports of local transmission of chikungunya, another arbovirus transmitted by A albopictus and A aegypti mosquitoes in Florida, the US Virgin Islands, and Puerto Rico, began in 2014.¹⁷ A higher prevalence of these diseases within the United States also may be related to increased globalization, with US travelers returning from endemic regions with infections. Prior to 2014, transmission occurred in traditional endemic regions, primarily in Asia, Africa, or island nations in the Indian Ocean. Like dengue fever, chikungunya causes high fevers, cutaneous manifestations (eg, urticarial papules, morbilliform eruption, hypermelanosis, intertriginous lesions, lymphedema),¹⁷ and intense joint pain. Unlike dengue fever, however, joint involvement can be chronic, erosive, and debilitating.

Lastly, New World leishmaniasis, an arboviral disease characterized by mucocutaneous ulcers and transmitted by phlebotomine sand flies, has been acquired locally in Oklahoma and Texas when it was previously considered to be endemic to Mexico and Central and South America.^14,18 The habitats of New World Leishmania species are expected to expand northward, with an ecological niche model predicting that they reach southern Canada by the year 2080 due to the expanding habitats of sand fly and rodent vectors.¹⁹

Fungal Infections

In the Pacific Northwest, there have been reports of newly endemic Cryptococcus gattii and Coccidioides immitis, both of which previously had been confined to the southwestern United States.⁸ Endemic ranges of these mycotic pathogens may be expanding for a variety of reasons, with climate change creating new regions conducive to the colonization of these species.^8,20,21Coccidioides immitis is a soil-dwelling fungus that usually presents with primary pulmonary disease that can disseminate acutely or even months later. Prompt recognition of disseminated disease may allow life-saving therapy to be initiated. Cryptococcus gattii is a fungus with multiple niches, including oil, trees, and birds.²⁰ This fungus also is acquired via inhalation, with dissemination occurring most commonly in immunosuppressed patients to the central nervous system, bone, and skin. Primary or secondary infection with both of these fungi may present with cutaneous manifestations presenting as polymorphous lesions, including umbilicated or ulcerated papules, indurated nodules, and acneiform pustules.

Final Thoughts

Awareness of the shifting habitats of microorganisms and vectors locally is important in order for clinicians to make correct diagnoses in a timely fashion. Regional or endemic diseases are presenting outside their traditional boundaries due to changing habitats of microbes and vectors and may be easily overlooked, resulting in a delayed diagnosis. Being prepared to diagnose diseases with increasing incidence secondary to climate change and discussing this with patients is an important physician obligation, but it is not the only one. We cannot effectively advocate for the health of patients and the community while ignoring the destruction of the environment. Our additional responsibility is straightforward—being advocates for good stewardship of the Earth’s resources now on both a personal and a policy level.²²

The term climate refers to the average weather conditions of a specific geographic location measured over several decades.¹ While a certain degree of variation in the Earth’s climate is expected, a persistent warming or cooling trend is not. The factors driving the Earth’s warming remain difficult to prove.² We know the Earth previously has undergone dramatic climate changes and that natural factors driving these changes are varied (eg, the relationship between the Earth and the Sun, volcanic eruptions, solar irradiance).^1,3 These factors ideally change over protracted periods of time in a way that allows organisms to adapt to new environments.

Anthropogenic climate change refers to human-caused climate change. This is thought to be a major driving factor in the Earth’s recent warming trend, partly due to the rapidity of warming in recent years.³ According to climate scientists, the Earth’s temperature has risen 4°C to 7°C over the past 5000 years, but it has risen 0.7°C in just the past 100 years alone.⁴ Greenhouse gases such as carbon dioxide are emitted by various natural processes and human activities and play a central role in current warming because they trap solar heat and increase ambient temperature.³

In a recent edition of the commonly cited textbook Dermatology, Bolognia et al⁵ referenced climate change only once in a figure legend regarding the expansion of dengue fever in the Americas. However, climate change may have the potential to cause outright skin disease epidemics worldwide, and the Climate Change Committee of the International Society of Dermatology has called upon dermatologists across the globe to help raise awareness of this issue.⁶

Much of the literature regarding the effects of climate change on human health focuses on insect-borne diseases, but over the past decade other areas of impact also have been investigated, such as increases in airborne diseases, zoonoses, newly endemic saprophytic and dimorphic fungal infections, fecal-oral diseases, and severe allergic disease.^7,8 It is postulated that climate change leads to region-specific increases in human disease because it creates newly favorable habitats for infectious agents, their vectors. and their reservoirs, allowing expansion of their ranges and access to immunologically naïve populations.⁹ Furthermore, extreme weather events such as heat waves, hurricanes, and flooding, which are expected to increase in frequency as a result of climate change, have all been linked to infectious disease outbreaks.¹⁰

Lyme Disease

In the past 20 years, Lyme disease incidence has tripled in the United States.¹¹ It has been hypothesized that the increase may be occurring as a result of the expanding geographic distribution of the Ixodes tick and its mammalian hosts (eg, white-tailed deer) under the influence of climate change.¹² Lyme disease is a multisystem disease affecting the skin, joints, heart, and nervous system. Its most characteristic manifestation is cutaneous in the form of erythema migrans. Dermatologists may be called upon to play an increasingly important role in early detection and treatment of this potentially chronic and debilitating condition.

Arboviruses

Arboviruses are transmitted by arthropods and are an important category of climate change–related diseases due to the expansion of the mosquito habitat worldwide. The vectorial capacity for the transmission of dengue fever has increased worldwide by 9.4% via Aedes aegypti and 11.1% via Aedes albopictus since 1950.¹³ Dengue fever, also known as breakbone fever, presents with intense joint pain, fevers, headaches, and a transient morbilliform rash that desquamates with defervescence and in some cases will incite hemorrhagic skin lesions.¹⁴ Dengue fever previously was considered to be a tropical disease but locally acquired cases have been reported in the United States, including Texas, Hawaii, and Florida.^15,16

Reports of local transmission of chikungunya, another arbovirus transmitted by A albopictus and A aegypti mosquitoes in Florida, the US Virgin Islands, and Puerto Rico, began in 2014.¹⁷ A higher prevalence of these diseases within the United States also may be related to increased globalization, with US travelers returning from endemic regions with infections. Prior to 2014, transmission occurred in traditional endemic regions, primarily in Asia, Africa, or island nations in the Indian Ocean. Like dengue fever, chikungunya causes high fevers, cutaneous manifestations (eg, urticarial papules, morbilliform eruption, hypermelanosis, intertriginous lesions, lymphedema),¹⁷ and intense joint pain. Unlike dengue fever, however, joint involvement can be chronic, erosive, and debilitating.

Lastly, New World leishmaniasis, an arboviral disease characterized by mucocutaneous ulcers and transmitted by phlebotomine sand flies, has been acquired locally in Oklahoma and Texas when it was previously considered to be endemic to Mexico and Central and South America.^14,18 The habitats of New World Leishmania species are expected to expand northward, with an ecological niche model predicting that they reach southern Canada by the year 2080 due to the expanding habitats of sand fly and rodent vectors.¹⁹

Fungal Infections

In the Pacific Northwest, there have been reports of newly endemic Cryptococcus gattii and Coccidioides immitis, both of which previously had been confined to the southwestern United States.⁸ Endemic ranges of these mycotic pathogens may be expanding for a variety of reasons, with climate change creating new regions conducive to the colonization of these species.^8,20,21Coccidioides immitis is a soil-dwelling fungus that usually presents with primary pulmonary disease that can disseminate acutely or even months later. Prompt recognition of disseminated disease may allow life-saving therapy to be initiated. Cryptococcus gattii is a fungus with multiple niches, including oil, trees, and birds.²⁰ This fungus also is acquired via inhalation, with dissemination occurring most commonly in immunosuppressed patients to the central nervous system, bone, and skin. Primary or secondary infection with both of these fungi may present with cutaneous manifestations presenting as polymorphous lesions, including umbilicated or ulcerated papules, indurated nodules, and acneiform pustules.

Final Thoughts

Awareness of the shifting habitats of microorganisms and vectors locally is important in order for clinicians to make correct diagnoses in a timely fashion. Regional or endemic diseases are presenting outside their traditional boundaries due to changing habitats of microbes and vectors and may be easily overlooked, resulting in a delayed diagnosis. Being prepared to diagnose diseases with increasing incidence secondary to climate change and discussing this with patients is an important physician obligation, but it is not the only one. We cannot effectively advocate for the health of patients and the community while ignoring the destruction of the environment. Our additional responsibility is straightforward—being advocates for good stewardship of the Earth’s resources now on both a personal and a policy level.²²

The Diagnosis: Polypoid Dermatofibroma

Histologic examination revealed a poorly demarcated lesion localized in the dermis that was composed of an admixture of fibroblastlike cells, histiocytes, siderophages, multinucleated giant cells, and hemorrhage (Figure). Based on these findings, a diagnosis of polypoid dermatofibroma (DF) was made. No further treatment was necessary because the lesion was completely excised.

Dermatofibromas, also known as benign fibrous histiocytomas, are common, benign, mesenchymal, fibrosing tumors of the skin that appear predominantly on the legs in in women, but any part of the body in either sex can be affected. Clinically, DFs show the dimple sign when laterally squeezed and can be painful spontaneously or when rubbed. Histologically, DFs are poorly demarcated lesions composed of a variable admixture of fibroblastlike cells, histiocytes (some of which may be xanthomatous or multinucleated), and blood vessels. The etiology still remains unclear. Most investigators consider DF to be a reactive process, but some think that it is a benign mesenchymal tumor.^1,2

Many subtypes of DF have been described based on their unique architectural, cellular, stromal, and clinical features.^2,3 Polypoid DF is a rare variant that comprises only 3% of reported cases4 and tends to be larger than other DF subtypes. Requena et al⁵ reported 12 cases of giant DF, another clinical subtype, that were larger than 5 cm in diameter, most of which had a polypoid appearance.

Moreover, 3 distinct variants of DF with unique histologic features tend to show polypoid morphology.^3,4 In epithelioid fibrous histiocytoma, also known as epithelioid cell histiocytoma, at least 50% of the lesion is composed of rounded or polygonal epithelioid cells with abundant eosinophilic cytoplasm and round to oval nuclei containing small eosinophilic nucleoli.⁴ A grenz zone generally is lacking and numerous small blood vessels are a constant feature of epithelioid fibrous histiocytoma. The other variant of DF that also tends to have a polypoid appearance is lipidized fibrous histiocytoma, or ankle-type fibrous histiocytoma, which usually arises below the knee, especially around the ankle, and often becomes larger than common DF.⁴ Lastly, atypical polypoid DF is a benign, polyp-shaped lesion that shows hypercellularity with striking nuclear atypism and scattered mitotic figures in addition to the ordinary histologic features of DF.³

Acquired fibrokeratomas manifest as solitary dome-shaped, flesh-colored protrusions usually located on the feet and hands. Sclerotic fibroma is a rare cutaneous neoplasm that presents as a solitary, translucent or waxy nodule or as multiple nodules when it is part of Cowden disease. Fibromas, also known as skin tags, are common cutaneous tumors that appear in intertriginous areas and frequently adopt a pedunculated morphology. Although clinically some of these lesions may resemble polypoid DF, the differential diagnosis is made by histologic examination.

Dermatofibroma is a common cutaneous tumor that follows a benign course. It can adopt multiple morphologies. Awareness of this rare variant may aid in its appropriate diagnosis and management. Dermatofibromas are benign neoplasms, and therefore they usually do not require treatment. If they become symptomatic or are bothersome to the patient, the treatment of choice is surgical removal.
 

The Diagnosis: Polypoid Dermatofibroma

Histologic examination revealed a poorly demarcated lesion localized in the dermis that was composed of an admixture of fibroblastlike cells, histiocytes, siderophages, multinucleated giant cells, and hemorrhage (Figure). Based on these findings, a diagnosis of polypoid dermatofibroma (DF) was made. No further treatment was necessary because the lesion was completely excised.

Dermatofibromas, also known as benign fibrous histiocytomas, are common, benign, mesenchymal, fibrosing tumors of the skin that appear predominantly on the legs in in women, but any part of the body in either sex can be affected. Clinically, DFs show the dimple sign when laterally squeezed and can be painful spontaneously or when rubbed. Histologically, DFs are poorly demarcated lesions composed of a variable admixture of fibroblastlike cells, histiocytes (some of which may be xanthomatous or multinucleated), and blood vessels. The etiology still remains unclear. Most investigators consider DF to be a reactive process, but some think that it is a benign mesenchymal tumor.^1,2

Many subtypes of DF have been described based on their unique architectural, cellular, stromal, and clinical features.^2,3 Polypoid DF is a rare variant that comprises only 3% of reported cases4 and tends to be larger than other DF subtypes. Requena et al⁵ reported 12 cases of giant DF, another clinical subtype, that were larger than 5 cm in diameter, most of which had a polypoid appearance.

Moreover, 3 distinct variants of DF with unique histologic features tend to show polypoid morphology.^3,4 In epithelioid fibrous histiocytoma, also known as epithelioid cell histiocytoma, at least 50% of the lesion is composed of rounded or polygonal epithelioid cells with abundant eosinophilic cytoplasm and round to oval nuclei containing small eosinophilic nucleoli.⁴ A grenz zone generally is lacking and numerous small blood vessels are a constant feature of epithelioid fibrous histiocytoma. The other variant of DF that also tends to have a polypoid appearance is lipidized fibrous histiocytoma, or ankle-type fibrous histiocytoma, which usually arises below the knee, especially around the ankle, and often becomes larger than common DF.⁴ Lastly, atypical polypoid DF is a benign, polyp-shaped lesion that shows hypercellularity with striking nuclear atypism and scattered mitotic figures in addition to the ordinary histologic features of DF.³

Acquired fibrokeratomas manifest as solitary dome-shaped, flesh-colored protrusions usually located on the feet and hands. Sclerotic fibroma is a rare cutaneous neoplasm that presents as a solitary, translucent or waxy nodule or as multiple nodules when it is part of Cowden disease. Fibromas, also known as skin tags, are common cutaneous tumors that appear in intertriginous areas and frequently adopt a pedunculated morphology. Although clinically some of these lesions may resemble polypoid DF, the differential diagnosis is made by histologic examination.

Dermatofibroma is a common cutaneous tumor that follows a benign course. It can adopt multiple morphologies. Awareness of this rare variant may aid in its appropriate diagnosis and management. Dermatofibromas are benign neoplasms, and therefore they usually do not require treatment. If they become symptomatic or are bothersome to the patient, the treatment of choice is surgical removal.
 

The Diagnosis: Polypoid Dermatofibroma

Histologic examination revealed a poorly demarcated lesion localized in the dermis that was composed of an admixture of fibroblastlike cells, histiocytes, siderophages, multinucleated giant cells, and hemorrhage (Figure). Based on these findings, a diagnosis of polypoid dermatofibroma (DF) was made. No further treatment was necessary because the lesion was completely excised.

Dermatofibromas, also known as benign fibrous histiocytomas, are common, benign, mesenchymal, fibrosing tumors of the skin that appear predominantly on the legs in in women, but any part of the body in either sex can be affected. Clinically, DFs show the dimple sign when laterally squeezed and can be painful spontaneously or when rubbed. Histologically, DFs are poorly demarcated lesions composed of a variable admixture of fibroblastlike cells, histiocytes (some of which may be xanthomatous or multinucleated), and blood vessels. The etiology still remains unclear. Most investigators consider DF to be a reactive process, but some think that it is a benign mesenchymal tumor.^1,2

Many subtypes of DF have been described based on their unique architectural, cellular, stromal, and clinical features.^2,3 Polypoid DF is a rare variant that comprises only 3% of reported cases4 and tends to be larger than other DF subtypes. Requena et al⁵ reported 12 cases of giant DF, another clinical subtype, that were larger than 5 cm in diameter, most of which had a polypoid appearance.

Moreover, 3 distinct variants of DF with unique histologic features tend to show polypoid morphology.^3,4 In epithelioid fibrous histiocytoma, also known as epithelioid cell histiocytoma, at least 50% of the lesion is composed of rounded or polygonal epithelioid cells with abundant eosinophilic cytoplasm and round to oval nuclei containing small eosinophilic nucleoli.⁴ A grenz zone generally is lacking and numerous small blood vessels are a constant feature of epithelioid fibrous histiocytoma. The other variant of DF that also tends to have a polypoid appearance is lipidized fibrous histiocytoma, or ankle-type fibrous histiocytoma, which usually arises below the knee, especially around the ankle, and often becomes larger than common DF.⁴ Lastly, atypical polypoid DF is a benign, polyp-shaped lesion that shows hypercellularity with striking nuclear atypism and scattered mitotic figures in addition to the ordinary histologic features of DF.³

Acquired fibrokeratomas manifest as solitary dome-shaped, flesh-colored protrusions usually located on the feet and hands. Sclerotic fibroma is a rare cutaneous neoplasm that presents as a solitary, translucent or waxy nodule or as multiple nodules when it is part of Cowden disease. Fibromas, also known as skin tags, are common cutaneous tumors that appear in intertriginous areas and frequently adopt a pedunculated morphology. Although clinically some of these lesions may resemble polypoid DF, the differential diagnosis is made by histologic examination.

Dermatofibroma is a common cutaneous tumor that follows a benign course. It can adopt multiple morphologies. Awareness of this rare variant may aid in its appropriate diagnosis and management. Dermatofibromas are benign neoplasms, and therefore they usually do not require treatment. If they become symptomatic or are bothersome to the patient, the treatment of choice is surgical removal.
 

Avène Mineral Light Mattifying Sunscreen Lotion

Pierre Fabre Dermo-Cosmetique introduces the Avène Mineral Light Mattifying Sunscreen Lotion with SPF 50+. This sunscreen offers broad-spectrum sun protection without irritation while delivering oil control and providing a natural mattifying finish for oily and acne-prone skin. This product absorbs quickly into the skin and can be worn under makeup. Avène Mineral Light Mattifying Sunscreen Lotion should be applied to the face 15 minutes prior to sun exposure and reapplied after 80 minutes of swimming or sweating, immediately after towel drying, or every 2 hours. For more information, visit www.aveneusa.com.

Ducray Anacaps Activ+ Dietary Supplement

Pierre Fabre Dermo-Cosmetique introduces Ducray Anacaps Activ+ Dietary Supplement, a once-daily capsule that contains zinc, molybdenum, iron, and selenium. This supplement targets factors that trigger sudden hair loss, including seasonal changes, stress, and diet. It also targets chronic hair loss with genetic, hormonal, and vascular causes. This formula provides essential nutrients needed to promote healthy hair growth from within, preserve hair density, and maintain the strength and vitality of hair. This supplement also is used for weak, devitalized nails and has a vegan formula with good digestive tolerance. For more information, visit www.ducray.com/en-us/.

Luzu

Ortho Dermatologics receives US Food and Drug Administration approval of the Supplemental New Drug Application to expand the use of Luzu (luliconazole) Cream 1% to pediatric patients. This new indication is for the topical treatment of interdigital tinea pedis and tinea cruris in patients 12 years of age and older and for tinea corporis in patients 2 years of age and older. Luzu is a topical azole antifungal agent with a 1-week, once-daily treatment regimen with results available 3 weeks post-treatment. Luzu previously was approved for use in adult patients. For more information, visit www.luzurx.com/HCP.

Xeljanz and Xeljanz XR

Pfizer Inc announces US Food and Drug Administration approval of twice-daily Xeljanz 5 mg and once-daily Xeljanz XR extended release 11 mg (tofacitinib) for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs. Xeljanz and Xeljanz XR are Janus kinase inhibitors that previously were approved for the treatment of rheumatoid arthritis. For more information, visit www.xeljanz.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

Avène Mineral Light Mattifying Sunscreen Lotion

Pierre Fabre Dermo-Cosmetique introduces the Avène Mineral Light Mattifying Sunscreen Lotion with SPF 50+. This sunscreen offers broad-spectrum sun protection without irritation while delivering oil control and providing a natural mattifying finish for oily and acne-prone skin. This product absorbs quickly into the skin and can be worn under makeup. Avène Mineral Light Mattifying Sunscreen Lotion should be applied to the face 15 minutes prior to sun exposure and reapplied after 80 minutes of swimming or sweating, immediately after towel drying, or every 2 hours. For more information, visit www.aveneusa.com.

Ducray Anacaps Activ+ Dietary Supplement

Pierre Fabre Dermo-Cosmetique introduces Ducray Anacaps Activ+ Dietary Supplement, a once-daily capsule that contains zinc, molybdenum, iron, and selenium. This supplement targets factors that trigger sudden hair loss, including seasonal changes, stress, and diet. It also targets chronic hair loss with genetic, hormonal, and vascular causes. This formula provides essential nutrients needed to promote healthy hair growth from within, preserve hair density, and maintain the strength and vitality of hair. This supplement also is used for weak, devitalized nails and has a vegan formula with good digestive tolerance. For more information, visit www.ducray.com/en-us/.

Luzu

Ortho Dermatologics receives US Food and Drug Administration approval of the Supplemental New Drug Application to expand the use of Luzu (luliconazole) Cream 1% to pediatric patients. This new indication is for the topical treatment of interdigital tinea pedis and tinea cruris in patients 12 years of age and older and for tinea corporis in patients 2 years of age and older. Luzu is a topical azole antifungal agent with a 1-week, once-daily treatment regimen with results available 3 weeks post-treatment. Luzu previously was approved for use in adult patients. For more information, visit www.luzurx.com/HCP.

Xeljanz and Xeljanz XR

Pfizer Inc announces US Food and Drug Administration approval of twice-daily Xeljanz 5 mg and once-daily Xeljanz XR extended release 11 mg (tofacitinib) for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs. Xeljanz and Xeljanz XR are Janus kinase inhibitors that previously were approved for the treatment of rheumatoid arthritis. For more information, visit www.xeljanz.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

Avène Mineral Light Mattifying Sunscreen Lotion

Pierre Fabre Dermo-Cosmetique introduces the Avène Mineral Light Mattifying Sunscreen Lotion with SPF 50+. This sunscreen offers broad-spectrum sun protection without irritation while delivering oil control and providing a natural mattifying finish for oily and acne-prone skin. This product absorbs quickly into the skin and can be worn under makeup. Avène Mineral Light Mattifying Sunscreen Lotion should be applied to the face 15 minutes prior to sun exposure and reapplied after 80 minutes of swimming or sweating, immediately after towel drying, or every 2 hours. For more information, visit www.aveneusa.com.

Ducray Anacaps Activ+ Dietary Supplement

Pierre Fabre Dermo-Cosmetique introduces Ducray Anacaps Activ+ Dietary Supplement, a once-daily capsule that contains zinc, molybdenum, iron, and selenium. This supplement targets factors that trigger sudden hair loss, including seasonal changes, stress, and diet. It also targets chronic hair loss with genetic, hormonal, and vascular causes. This formula provides essential nutrients needed to promote healthy hair growth from within, preserve hair density, and maintain the strength and vitality of hair. This supplement also is used for weak, devitalized nails and has a vegan formula with good digestive tolerance. For more information, visit www.ducray.com/en-us/.

Luzu

Ortho Dermatologics receives US Food and Drug Administration approval of the Supplemental New Drug Application to expand the use of Luzu (luliconazole) Cream 1% to pediatric patients. This new indication is for the topical treatment of interdigital tinea pedis and tinea cruris in patients 12 years of age and older and for tinea corporis in patients 2 years of age and older. Luzu is a topical azole antifungal agent with a 1-week, once-daily treatment regimen with results available 3 weeks post-treatment. Luzu previously was approved for use in adult patients. For more information, visit www.luzurx.com/HCP.

Xeljanz and Xeljanz XR

Pfizer Inc announces US Food and Drug Administration approval of twice-daily Xeljanz 5 mg and once-daily Xeljanz XR extended release 11 mg (tofacitinib) for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs. Xeljanz and Xeljanz XR are Janus kinase inhibitors that previously were approved for the treatment of rheumatoid arthritis. For more information, visit www.xeljanz.com.

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The Diagnosis: Aneurysmal Dermatofibroma

Biopsy of the lesion revealed a circumscribed dermal nodule comprised of storiform arrangements of enlarged, plump, fibrohistiocytic cells punctuated by variably sized clefts and large cystic spaces filled with blood that lacked an endothelial lining. No bizarre nuclear pleomorphism, atypical mitoses, or tumor necrosis were identified. The overlying epidermis exhibited mild acanthosis with broadening of the rete ridges. Proliferative spindled cells entrapped dermal collagen bundles at the periphery. Hemosiderin-laden macrophages were present throughout the proliferation and in the adjacent dermis (Figure). These findings supported the diagnosis of aneurysmal dermatofibroma (ADF).

Aneurysmal dermatofibroma, also known as aneurysmal fibrous histiocytoma, is a rare variant of dermatofibroma that was described by Santa Cruz et al¹ in 1981 and represents 2% to 6% of dermatofibromas.^1,2 Aneurysmal dermatofibromas often lack the characteristic clinical and dermoscopic findings of conventional dermatofibromas, creating a diagnostic challenge for the clinician.³ Incomplete excision of this benign tumor was associated with a local recurrence rate of 19% (5/26) in one study,⁴ in contrast with the exceedingly low rate of local recurrence (<2%) attributed to conventional dermatofibromas.^2,4

Clinically, ADFs commonly appear as blue-brown nodules on the arms and legs, often with a history of rapid and sometimes painful growth.¹ Clinically, an ADF can have vascular, cystic, or melanocytic features that, in the context of lacking typical clinical findings of a dermatofibroma, can complicate clinical diagnosis; for example, ADFs can demonstrate several melanomalike features including atypical vessels, chrysalis structures, blue-white structures, a pinkish-white veil, irregular brown globulelike structures, an atypical pigment network, color variegation, a multicomponent pattern, and ulceration.³ Alternatively, ADFs can present with a vascular tumor-like pattern consisting of white areas and globular blue-red areas or a polymorphous vascular pattern with a peripheral collarette.

Our case illustrates the classic histologic appearance of an ADF. Large cavities and slitlike spaces filled with blood distinguish this entity from conventional dermatofibroma and other dermatofibroma variants; for example, cellular dermatofibroma is a benign variant of dermatofibroma that exhibits crowded fascicular architecture without an increase in vascular spaces. Aneurysmal dermatofibromas also should be distinguished from angiomatoid fibrous histiocytoma, which has intermediate malignant potential despite a similar-sounding name and a similar nodular appearance with large blood-filled spaces; however, many cases are located predominantly in the subcutis with epithelioid morphology, desmin immunohistochemical reactivity, and prominent tumor-associated lymphoid proliferation that can be mistaken for a lymph node.⁵ Furthermore, in contrast with vascular tumors, the blood-filled spaces of ADFs do not have an endothelial lining.

In summary, ADF is a rare dermatofibroma variant that has a variety of clinical presentations, often masquerading as a cyst, vascular tumor, or melanocytic neoplasm. The classic histopathologic features confirm the diagnosis. Although ADFs can be painful and have a tendency to recur, these lesions have a benign clinical course.

The Diagnosis: Aneurysmal Dermatofibroma

Biopsy of the lesion revealed a circumscribed dermal nodule comprised of storiform arrangements of enlarged, plump, fibrohistiocytic cells punctuated by variably sized clefts and large cystic spaces filled with blood that lacked an endothelial lining. No bizarre nuclear pleomorphism, atypical mitoses, or tumor necrosis were identified. The overlying epidermis exhibited mild acanthosis with broadening of the rete ridges. Proliferative spindled cells entrapped dermal collagen bundles at the periphery. Hemosiderin-laden macrophages were present throughout the proliferation and in the adjacent dermis (Figure). These findings supported the diagnosis of aneurysmal dermatofibroma (ADF).

Aneurysmal dermatofibroma, also known as aneurysmal fibrous histiocytoma, is a rare variant of dermatofibroma that was described by Santa Cruz et al¹ in 1981 and represents 2% to 6% of dermatofibromas.^1,2 Aneurysmal dermatofibromas often lack the characteristic clinical and dermoscopic findings of conventional dermatofibromas, creating a diagnostic challenge for the clinician.³ Incomplete excision of this benign tumor was associated with a local recurrence rate of 19% (5/26) in one study,⁴ in contrast with the exceedingly low rate of local recurrence (<2%) attributed to conventional dermatofibromas.^2,4

Clinically, ADFs commonly appear as blue-brown nodules on the arms and legs, often with a history of rapid and sometimes painful growth.¹ Clinically, an ADF can have vascular, cystic, or melanocytic features that, in the context of lacking typical clinical findings of a dermatofibroma, can complicate clinical diagnosis; for example, ADFs can demonstrate several melanomalike features including atypical vessels, chrysalis structures, blue-white structures, a pinkish-white veil, irregular brown globulelike structures, an atypical pigment network, color variegation, a multicomponent pattern, and ulceration.³ Alternatively, ADFs can present with a vascular tumor-like pattern consisting of white areas and globular blue-red areas or a polymorphous vascular pattern with a peripheral collarette.

Our case illustrates the classic histologic appearance of an ADF. Large cavities and slitlike spaces filled with blood distinguish this entity from conventional dermatofibroma and other dermatofibroma variants; for example, cellular dermatofibroma is a benign variant of dermatofibroma that exhibits crowded fascicular architecture without an increase in vascular spaces. Aneurysmal dermatofibromas also should be distinguished from angiomatoid fibrous histiocytoma, which has intermediate malignant potential despite a similar-sounding name and a similar nodular appearance with large blood-filled spaces; however, many cases are located predominantly in the subcutis with epithelioid morphology, desmin immunohistochemical reactivity, and prominent tumor-associated lymphoid proliferation that can be mistaken for a lymph node.⁵ Furthermore, in contrast with vascular tumors, the blood-filled spaces of ADFs do not have an endothelial lining.

In summary, ADF is a rare dermatofibroma variant that has a variety of clinical presentations, often masquerading as a cyst, vascular tumor, or melanocytic neoplasm. The classic histopathologic features confirm the diagnosis. Although ADFs can be painful and have a tendency to recur, these lesions have a benign clinical course.

The Diagnosis: Aneurysmal Dermatofibroma

Biopsy of the lesion revealed a circumscribed dermal nodule comprised of storiform arrangements of enlarged, plump, fibrohistiocytic cells punctuated by variably sized clefts and large cystic spaces filled with blood that lacked an endothelial lining. No bizarre nuclear pleomorphism, atypical mitoses, or tumor necrosis were identified. The overlying epidermis exhibited mild acanthosis with broadening of the rete ridges. Proliferative spindled cells entrapped dermal collagen bundles at the periphery. Hemosiderin-laden macrophages were present throughout the proliferation and in the adjacent dermis (Figure). These findings supported the diagnosis of aneurysmal dermatofibroma (ADF).

Aneurysmal dermatofibroma, also known as aneurysmal fibrous histiocytoma, is a rare variant of dermatofibroma that was described by Santa Cruz et al¹ in 1981 and represents 2% to 6% of dermatofibromas.^1,2 Aneurysmal dermatofibromas often lack the characteristic clinical and dermoscopic findings of conventional dermatofibromas, creating a diagnostic challenge for the clinician.³ Incomplete excision of this benign tumor was associated with a local recurrence rate of 19% (5/26) in one study,⁴ in contrast with the exceedingly low rate of local recurrence (<2%) attributed to conventional dermatofibromas.^2,4

Clinically, ADFs commonly appear as blue-brown nodules on the arms and legs, often with a history of rapid and sometimes painful growth.¹ Clinically, an ADF can have vascular, cystic, or melanocytic features that, in the context of lacking typical clinical findings of a dermatofibroma, can complicate clinical diagnosis; for example, ADFs can demonstrate several melanomalike features including atypical vessels, chrysalis structures, blue-white structures, a pinkish-white veil, irregular brown globulelike structures, an atypical pigment network, color variegation, a multicomponent pattern, and ulceration.³ Alternatively, ADFs can present with a vascular tumor-like pattern consisting of white areas and globular blue-red areas or a polymorphous vascular pattern with a peripheral collarette.

Our case illustrates the classic histologic appearance of an ADF. Large cavities and slitlike spaces filled with blood distinguish this entity from conventional dermatofibroma and other dermatofibroma variants; for example, cellular dermatofibroma is a benign variant of dermatofibroma that exhibits crowded fascicular architecture without an increase in vascular spaces. Aneurysmal dermatofibromas also should be distinguished from angiomatoid fibrous histiocytoma, which has intermediate malignant potential despite a similar-sounding name and a similar nodular appearance with large blood-filled spaces; however, many cases are located predominantly in the subcutis with epithelioid morphology, desmin immunohistochemical reactivity, and prominent tumor-associated lymphoid proliferation that can be mistaken for a lymph node.⁵ Furthermore, in contrast with vascular tumors, the blood-filled spaces of ADFs do not have an endothelial lining.

In summary, ADF is a rare dermatofibroma variant that has a variety of clinical presentations, often masquerading as a cyst, vascular tumor, or melanocytic neoplasm. The classic histopathologic features confirm the diagnosis. Although ADFs can be painful and have a tendency to recur, these lesions have a benign clinical course.

The Ixodes tick is prevalent in temperate climates worldwide. During a blood meal, pathogens may be transmitted from the tick to its host. Borrelia burgdorferi, a spirochete responsible for Lyme disease, is the most prevalent pathogen transmitted by Ixodes ticks.¹ Borrelia mayonii recently was identified as an additional cause of Lyme disease in the United States.²

The Ixodes tick also is associated with several less common pathogens, including Babesia microti and the tick-borne encephalitis virus, which have been recognized as Ixodes-associated pathogens for many years.^3,4 Other pathogens have been identified, including Anaplasma phagocytophilum, recognized in the 1990s as the cause of human granulocytic anaplasmosis, as well as the Powassan virus and Borrelia miyamotoi.^5-7 Additionally, tick paralysis has been associated with toxins in the saliva of various species of several genera of ticks, including some Ixodes species.⁸ Due to an overlap in geographic distribution (Figure) and disease presentations (eTable), it is important that physicians be familiar with these regional pathogens transmitted by Ixodes ticks.

Human Granulocytic Anaplasmosis

Formerly known as human granulocytic ehrlichiosis, human granulocytic anaplasmosis is caused by A phagocytophilum and is transmitted by Ixodes scapularis, Ixodes pacificus, and Ixodes persulcatus. The incidence of human granulocytic anaplasmosis in the United States increased 12-fold from 2001 to 2011.⁹

Presenting symptoms generally are nonspecific, including fever, night sweats, headache, myalgias, and arthralgias, often resulting in misdiagnosis as a viral infection. Laboratory abnormalities include mild transaminitis, leukopenia, and thrombocytopenia.^9,10 Although most infections resolve spontaneously, 3% of patients develop serious complications. The mortality rate is 0.6%.¹¹

A diagnosis of human granulocytic anaplasmosis should be suspected in patients with a viral-like illness and exposure to ticks in an endemic area. The diagnosis can be confirmed by polymerase chain reaction (PCR), acute- and convalescent-phase serologic testing, or direct fluorescent antibody screening. Characteristic morulae may be present in granulocytes.¹² Treatment typically includes doxycycline, which also covers B burgdorferi coinfection. When a diagnosis of human granulocytic anaplasmosis is suspected, treatment should never be delayed to await laboratory confirmation. If no clinical improvement is seen within 48 hours, alternate diagnoses or coinfection with B microti should be considered.¹⁰

Babesiosis

The protozoan B microti causes babesiosis in the United States, with Babesia divergens being more common in Europe.¹³ Reported cases of babesiosis in New York increased as much as 20-fold from 2001 to 2008.¹⁴ Transmission primarily is from the Ixodes tick but rarely can occur from blood transfusion.¹⁵ Tick attachment for at least 36 hours is required for transmission.¹³

The clinical presentation of babesiosis ranges from asymptomatic to fatal. Symptoms generally are nonspecific, resembling a viral infection and including headache, nausea, diarrhea, arthralgia, and myalgia. Laboratory evaluation may reveal hemolytic anemia, thrombocytopenia, transaminitis, and elevated blood urea nitrogen and creatinine levels.¹⁶ Rash is not typical. Resolution of symptoms generally occurs within 2 weeks of presentation, although anemia may persist for months.¹³ Severe disease is more common among elderly and immunocompromised patients. Complications include respiratory failure, renal failure, congestive heart failure, and disseminated intravascular coagulation. The mortality rate in the United States is approximately 10%.^10,16

A diagnosis of babesiosis is made based on the presence of flulike symptoms, laboratory results, and history of recent travel to an endemic area. A thin blood smear allows identification of the organism in erythrocytes as ring forms or tetrads (a “Maltese cross” appearance).¹⁷ Polymerase chain reaction is more sensitive than a blood smear, especially in early disease.¹⁸ Indirect fluorescent antibody testing is species-specific but cannot verify active infection.¹⁰

Treatment of babesiosis is indicated for symptomatic patients with active infection. Positive serology alone is not an indication for treatment. Asymptomatic patients with positive serology should have diagnostic testing repeated in 3 months with subsequent treatment if parasitemia persists. Mild disease is treated with atovaquone plus azithromycin or clindamycin plus quinine. Severe babesiosis is treated with quinine and intravenous clindamycin and may require exchange transfusion.¹⁰ Coinfection with B burgdorferi should be considered in patients with flulike symptoms and erythema migrans or treatment failure. Coinfection is diagnosed by Lyme serology plus PCR for B microti. This is an important consideration because treatment of babesiosis does not eradicate B burgdorferi infection.¹⁹

Powassan Virus

Powassan virus is a flavivirus that causes encephalitis. It is transmitted by Ixodes cookei (Powassan virus, lineage I) in the Great Lakes region and by I scapularis (Powassan virus, lineage II, or deer tick virus) in the northeastern United States. Transmission can occur within 15 minutes of tick attachment.^6,20,21

Patients typically present with fever, headache, altered mental status, seizures, and focal neurologic deficits. Gastrointestinal symptoms and rash also have been reported.²¹ The diagnosis is made based on clinical presentation and laboratory testing with PCR or enzyme-linked immunosorbent assay (ELISA). Cross-reactivity on ELISA exists, necessitating confirmation with a neutralizing antibody or PCR. Treatment is supportive. Corticosteroids and intravenous immunoglobulin have been proposed as treatment modalities, but evidence of their efficacy is limited.²²

Tick-borne Encephalitis

Tick-borne encephalitis is caused by the flavivirus tick-borne encephalitis virus in Europe and Asia. The tick-borne encephalitis virus is transmitted by Ixodes ricinus in Europe and by Ixodes persulcatus in eastern Russia, China, and Japan. It also has been associated with consumption of unpasteurized milk.^23,24

Tick-borne encephalitis presents in a biphasic pattern. The initial viremic phase can persist for as long as 8 days with headache, nausea, myalgia, and fever. One-third of patients then enter an asymptomatic phase, followed by virus penetration into the central nervous system. The neurologic phase produces continued headache and fever with photophobia, focal neurologic deficits, seizures, respiratory depression, or coma. Neurologic sequelae persist in 10% to 20% of patients.^25,26

In the viremic stage, diagnosis is made with PCR or culture. During the latent phase or neurologic phase, serologic testing for tick-borne encephalitis virus antibodies is indicated. Neutralizing antibody evaluation may be necessary due to cross-reactivity among flaviviruses.²⁷ Treatment is supportive. An inactivated vaccine is available for high-risk populations.²⁸

Borrelia miyamotoi Disease

Borrelia miyamotoi is a symbiont of the Ixodes tick formerly believed to have no pathogenic significance; however, B miyamotoi was isolated in febrile patients in Russia in 2011⁷ and was identified as a pathogen in both North America²⁹ and Europe in 2013.³⁰ Disease presentation includes nonspecific symptoms of fever, fatigue, headache, arthralgia, myalgia, and nausea. Rash is uncommon. Laboratory abnormalities include leukopenia, thrombocytopenia, and transaminitis.^31,32 Meningoencephalitis may occur in immunocompromised patients.^29,30

The diagnosis of B miyamotoi disease is confirmed by PCR or serology. An ELISA that is positive for B burgdorferi IgM but negative with confirmatory immunoblot suggests B miyamotoi disease. Seroconversion using a glpQ protein ELISA also can be assessed.³¹ If ELISA is positive, Lyme disease can be excluded because B burgdorferi does not possess g1pQ. Treatment is with doxycycline.³²

Tick Paralysis

Tick paralysis is an intoxication with holocyclotoxin from the saliva of gravid hard ticks. In the United States, intoxication is associated with ticks of various species of Amblyomma, Dermacentor, and Ixodes in the Northwest, Southeast, and Northeast. In Australia, intoxication is associated with Ixodes.³³ Patients present with weakness and fatigue, progressing to ascending flaccid paralysis with sensory sparing. The treatment is tick removal.^8,33

Conclusion

Arthropods carry many regional pathogens. Physicians outside of those regions should seek a travel history and be alert for imported disease.

The Ixodes tick is prevalent in temperate climates worldwide. During a blood meal, pathogens may be transmitted from the tick to its host. Borrelia burgdorferi, a spirochete responsible for Lyme disease, is the most prevalent pathogen transmitted by Ixodes ticks.¹ Borrelia mayonii recently was identified as an additional cause of Lyme disease in the United States.²

The Ixodes tick also is associated with several less common pathogens, including Babesia microti and the tick-borne encephalitis virus, which have been recognized as Ixodes-associated pathogens for many years.^3,4 Other pathogens have been identified, including Anaplasma phagocytophilum, recognized in the 1990s as the cause of human granulocytic anaplasmosis, as well as the Powassan virus and Borrelia miyamotoi.^5-7 Additionally, tick paralysis has been associated with toxins in the saliva of various species of several genera of ticks, including some Ixodes species.⁸ Due to an overlap in geographic distribution (Figure) and disease presentations (eTable), it is important that physicians be familiar with these regional pathogens transmitted by Ixodes ticks.

Human Granulocytic Anaplasmosis

Formerly known as human granulocytic ehrlichiosis, human granulocytic anaplasmosis is caused by A phagocytophilum and is transmitted by Ixodes scapularis, Ixodes pacificus, and Ixodes persulcatus. The incidence of human granulocytic anaplasmosis in the United States increased 12-fold from 2001 to 2011.⁹

Presenting symptoms generally are nonspecific, including fever, night sweats, headache, myalgias, and arthralgias, often resulting in misdiagnosis as a viral infection. Laboratory abnormalities include mild transaminitis, leukopenia, and thrombocytopenia.^9,10 Although most infections resolve spontaneously, 3% of patients develop serious complications. The mortality rate is 0.6%.¹¹

A diagnosis of human granulocytic anaplasmosis should be suspected in patients with a viral-like illness and exposure to ticks in an endemic area. The diagnosis can be confirmed by polymerase chain reaction (PCR), acute- and convalescent-phase serologic testing, or direct fluorescent antibody screening. Characteristic morulae may be present in granulocytes.¹² Treatment typically includes doxycycline, which also covers B burgdorferi coinfection. When a diagnosis of human granulocytic anaplasmosis is suspected, treatment should never be delayed to await laboratory confirmation. If no clinical improvement is seen within 48 hours, alternate diagnoses or coinfection with B microti should be considered.¹⁰

Babesiosis

The protozoan B microti causes babesiosis in the United States, with Babesia divergens being more common in Europe.¹³ Reported cases of babesiosis in New York increased as much as 20-fold from 2001 to 2008.¹⁴ Transmission primarily is from the Ixodes tick but rarely can occur from blood transfusion.¹⁵ Tick attachment for at least 36 hours is required for transmission.¹³

The clinical presentation of babesiosis ranges from asymptomatic to fatal. Symptoms generally are nonspecific, resembling a viral infection and including headache, nausea, diarrhea, arthralgia, and myalgia. Laboratory evaluation may reveal hemolytic anemia, thrombocytopenia, transaminitis, and elevated blood urea nitrogen and creatinine levels.¹⁶ Rash is not typical. Resolution of symptoms generally occurs within 2 weeks of presentation, although anemia may persist for months.¹³ Severe disease is more common among elderly and immunocompromised patients. Complications include respiratory failure, renal failure, congestive heart failure, and disseminated intravascular coagulation. The mortality rate in the United States is approximately 10%.^10,16

A diagnosis of babesiosis is made based on the presence of flulike symptoms, laboratory results, and history of recent travel to an endemic area. A thin blood smear allows identification of the organism in erythrocytes as ring forms or tetrads (a “Maltese cross” appearance).¹⁷ Polymerase chain reaction is more sensitive than a blood smear, especially in early disease.¹⁸ Indirect fluorescent antibody testing is species-specific but cannot verify active infection.¹⁰

Treatment of babesiosis is indicated for symptomatic patients with active infection. Positive serology alone is not an indication for treatment. Asymptomatic patients with positive serology should have diagnostic testing repeated in 3 months with subsequent treatment if parasitemia persists. Mild disease is treated with atovaquone plus azithromycin or clindamycin plus quinine. Severe babesiosis is treated with quinine and intravenous clindamycin and may require exchange transfusion.¹⁰ Coinfection with B burgdorferi should be considered in patients with flulike symptoms and erythema migrans or treatment failure. Coinfection is diagnosed by Lyme serology plus PCR for B microti. This is an important consideration because treatment of babesiosis does not eradicate B burgdorferi infection.¹⁹

Powassan Virus

Powassan virus is a flavivirus that causes encephalitis. It is transmitted by Ixodes cookei (Powassan virus, lineage I) in the Great Lakes region and by I scapularis (Powassan virus, lineage II, or deer tick virus) in the northeastern United States. Transmission can occur within 15 minutes of tick attachment.^6,20,21

Patients typically present with fever, headache, altered mental status, seizures, and focal neurologic deficits. Gastrointestinal symptoms and rash also have been reported.²¹ The diagnosis is made based on clinical presentation and laboratory testing with PCR or enzyme-linked immunosorbent assay (ELISA). Cross-reactivity on ELISA exists, necessitating confirmation with a neutralizing antibody or PCR. Treatment is supportive. Corticosteroids and intravenous immunoglobulin have been proposed as treatment modalities, but evidence of their efficacy is limited.²²

Tick-borne Encephalitis

Tick-borne encephalitis is caused by the flavivirus tick-borne encephalitis virus in Europe and Asia. The tick-borne encephalitis virus is transmitted by Ixodes ricinus in Europe and by Ixodes persulcatus in eastern Russia, China, and Japan. It also has been associated with consumption of unpasteurized milk.^23,24

Tick-borne encephalitis presents in a biphasic pattern. The initial viremic phase can persist for as long as 8 days with headache, nausea, myalgia, and fever. One-third of patients then enter an asymptomatic phase, followed by virus penetration into the central nervous system. The neurologic phase produces continued headache and fever with photophobia, focal neurologic deficits, seizures, respiratory depression, or coma. Neurologic sequelae persist in 10% to 20% of patients.^25,26

In the viremic stage, diagnosis is made with PCR or culture. During the latent phase or neurologic phase, serologic testing for tick-borne encephalitis virus antibodies is indicated. Neutralizing antibody evaluation may be necessary due to cross-reactivity among flaviviruses.²⁷ Treatment is supportive. An inactivated vaccine is available for high-risk populations.²⁸

Borrelia miyamotoi Disease

Borrelia miyamotoi is a symbiont of the Ixodes tick formerly believed to have no pathogenic significance; however, B miyamotoi was isolated in febrile patients in Russia in 2011⁷ and was identified as a pathogen in both North America²⁹ and Europe in 2013.³⁰ Disease presentation includes nonspecific symptoms of fever, fatigue, headache, arthralgia, myalgia, and nausea. Rash is uncommon. Laboratory abnormalities include leukopenia, thrombocytopenia, and transaminitis.^31,32 Meningoencephalitis may occur in immunocompromised patients.^29,30

The diagnosis of B miyamotoi disease is confirmed by PCR or serology. An ELISA that is positive for B burgdorferi IgM but negative with confirmatory immunoblot suggests B miyamotoi disease. Seroconversion using a glpQ protein ELISA also can be assessed.³¹ If ELISA is positive, Lyme disease can be excluded because B burgdorferi does not possess g1pQ. Treatment is with doxycycline.³²

Tick Paralysis

Tick paralysis is an intoxication with holocyclotoxin from the saliva of gravid hard ticks. In the United States, intoxication is associated with ticks of various species of Amblyomma, Dermacentor, and Ixodes in the Northwest, Southeast, and Northeast. In Australia, intoxication is associated with Ixodes.³³ Patients present with weakness and fatigue, progressing to ascending flaccid paralysis with sensory sparing. The treatment is tick removal.^8,33

Conclusion

Arthropods carry many regional pathogens. Physicians outside of those regions should seek a travel history and be alert for imported disease.

The Ixodes tick is prevalent in temperate climates worldwide. During a blood meal, pathogens may be transmitted from the tick to its host. Borrelia burgdorferi, a spirochete responsible for Lyme disease, is the most prevalent pathogen transmitted by Ixodes ticks.¹ Borrelia mayonii recently was identified as an additional cause of Lyme disease in the United States.²

The Ixodes tick also is associated with several less common pathogens, including Babesia microti and the tick-borne encephalitis virus, which have been recognized as Ixodes-associated pathogens for many years.^3,4 Other pathogens have been identified, including Anaplasma phagocytophilum, recognized in the 1990s as the cause of human granulocytic anaplasmosis, as well as the Powassan virus and Borrelia miyamotoi.^5-7 Additionally, tick paralysis has been associated with toxins in the saliva of various species of several genera of ticks, including some Ixodes species.⁸ Due to an overlap in geographic distribution (Figure) and disease presentations (eTable), it is important that physicians be familiar with these regional pathogens transmitted by Ixodes ticks.

Human Granulocytic Anaplasmosis

Formerly known as human granulocytic ehrlichiosis, human granulocytic anaplasmosis is caused by A phagocytophilum and is transmitted by Ixodes scapularis, Ixodes pacificus, and Ixodes persulcatus. The incidence of human granulocytic anaplasmosis in the United States increased 12-fold from 2001 to 2011.⁹

Presenting symptoms generally are nonspecific, including fever, night sweats, headache, myalgias, and arthralgias, often resulting in misdiagnosis as a viral infection. Laboratory abnormalities include mild transaminitis, leukopenia, and thrombocytopenia.^9,10 Although most infections resolve spontaneously, 3% of patients develop serious complications. The mortality rate is 0.6%.¹¹

A diagnosis of human granulocytic anaplasmosis should be suspected in patients with a viral-like illness and exposure to ticks in an endemic area. The diagnosis can be confirmed by polymerase chain reaction (PCR), acute- and convalescent-phase serologic testing, or direct fluorescent antibody screening. Characteristic morulae may be present in granulocytes.¹² Treatment typically includes doxycycline, which also covers B burgdorferi coinfection. When a diagnosis of human granulocytic anaplasmosis is suspected, treatment should never be delayed to await laboratory confirmation. If no clinical improvement is seen within 48 hours, alternate diagnoses or coinfection with B microti should be considered.¹⁰

Babesiosis

The protozoan B microti causes babesiosis in the United States, with Babesia divergens being more common in Europe.¹³ Reported cases of babesiosis in New York increased as much as 20-fold from 2001 to 2008.¹⁴ Transmission primarily is from the Ixodes tick but rarely can occur from blood transfusion.¹⁵ Tick attachment for at least 36 hours is required for transmission.¹³

The clinical presentation of babesiosis ranges from asymptomatic to fatal. Symptoms generally are nonspecific, resembling a viral infection and including headache, nausea, diarrhea, arthralgia, and myalgia. Laboratory evaluation may reveal hemolytic anemia, thrombocytopenia, transaminitis, and elevated blood urea nitrogen and creatinine levels.¹⁶ Rash is not typical. Resolution of symptoms generally occurs within 2 weeks of presentation, although anemia may persist for months.¹³ Severe disease is more common among elderly and immunocompromised patients. Complications include respiratory failure, renal failure, congestive heart failure, and disseminated intravascular coagulation. The mortality rate in the United States is approximately 10%.^10,16

A diagnosis of babesiosis is made based on the presence of flulike symptoms, laboratory results, and history of recent travel to an endemic area. A thin blood smear allows identification of the organism in erythrocytes as ring forms or tetrads (a “Maltese cross” appearance).¹⁷ Polymerase chain reaction is more sensitive than a blood smear, especially in early disease.¹⁸ Indirect fluorescent antibody testing is species-specific but cannot verify active infection.¹⁰

Treatment of babesiosis is indicated for symptomatic patients with active infection. Positive serology alone is not an indication for treatment. Asymptomatic patients with positive serology should have diagnostic testing repeated in 3 months with subsequent treatment if parasitemia persists. Mild disease is treated with atovaquone plus azithromycin or clindamycin plus quinine. Severe babesiosis is treated with quinine and intravenous clindamycin and may require exchange transfusion.¹⁰ Coinfection with B burgdorferi should be considered in patients with flulike symptoms and erythema migrans or treatment failure. Coinfection is diagnosed by Lyme serology plus PCR for B microti. This is an important consideration because treatment of babesiosis does not eradicate B burgdorferi infection.¹⁹

Powassan Virus

Powassan virus is a flavivirus that causes encephalitis. It is transmitted by Ixodes cookei (Powassan virus, lineage I) in the Great Lakes region and by I scapularis (Powassan virus, lineage II, or deer tick virus) in the northeastern United States. Transmission can occur within 15 minutes of tick attachment.^6,20,21

Patients typically present with fever, headache, altered mental status, seizures, and focal neurologic deficits. Gastrointestinal symptoms and rash also have been reported.²¹ The diagnosis is made based on clinical presentation and laboratory testing with PCR or enzyme-linked immunosorbent assay (ELISA). Cross-reactivity on ELISA exists, necessitating confirmation with a neutralizing antibody or PCR. Treatment is supportive. Corticosteroids and intravenous immunoglobulin have been proposed as treatment modalities, but evidence of their efficacy is limited.²²

Tick-borne Encephalitis

Tick-borne encephalitis is caused by the flavivirus tick-borne encephalitis virus in Europe and Asia. The tick-borne encephalitis virus is transmitted by Ixodes ricinus in Europe and by Ixodes persulcatus in eastern Russia, China, and Japan. It also has been associated with consumption of unpasteurized milk.^23,24

Tick-borne encephalitis presents in a biphasic pattern. The initial viremic phase can persist for as long as 8 days with headache, nausea, myalgia, and fever. One-third of patients then enter an asymptomatic phase, followed by virus penetration into the central nervous system. The neurologic phase produces continued headache and fever with photophobia, focal neurologic deficits, seizures, respiratory depression, or coma. Neurologic sequelae persist in 10% to 20% of patients.^25,26

In the viremic stage, diagnosis is made with PCR or culture. During the latent phase or neurologic phase, serologic testing for tick-borne encephalitis virus antibodies is indicated. Neutralizing antibody evaluation may be necessary due to cross-reactivity among flaviviruses.²⁷ Treatment is supportive. An inactivated vaccine is available for high-risk populations.²⁸

Borrelia miyamotoi Disease

Borrelia miyamotoi is a symbiont of the Ixodes tick formerly believed to have no pathogenic significance; however, B miyamotoi was isolated in febrile patients in Russia in 2011⁷ and was identified as a pathogen in both North America²⁹ and Europe in 2013.³⁰ Disease presentation includes nonspecific symptoms of fever, fatigue, headache, arthralgia, myalgia, and nausea. Rash is uncommon. Laboratory abnormalities include leukopenia, thrombocytopenia, and transaminitis.^31,32 Meningoencephalitis may occur in immunocompromised patients.^29,30

The diagnosis of B miyamotoi disease is confirmed by PCR or serology. An ELISA that is positive for B burgdorferi IgM but negative with confirmatory immunoblot suggests B miyamotoi disease. Seroconversion using a glpQ protein ELISA also can be assessed.³¹ If ELISA is positive, Lyme disease can be excluded because B burgdorferi does not possess g1pQ. Treatment is with doxycycline.³²

Tick Paralysis

Tick paralysis is an intoxication with holocyclotoxin from the saliva of gravid hard ticks. In the United States, intoxication is associated with ticks of various species of Amblyomma, Dermacentor, and Ixodes in the Northwest, Southeast, and Northeast. In Australia, intoxication is associated with Ixodes.³³ Patients present with weakness and fatigue, progressing to ascending flaccid paralysis with sensory sparing. The treatment is tick removal.^8,33

Conclusion

Arthropods carry many regional pathogens. Physicians outside of those regions should seek a travel history and be alert for imported disease.

Merkel cell carcinoma (MCC) is a rare, rapidly growing, aggressive neoplasm with a generally poor prognosis. The cells of origin are highly anaplastic and share structural and immunohistochemical features with various neuroectodermally derived cells. Although Merkel cells, which are slow-acting cutaneous mechanoreceptors located in the basal layer of the epidermis, and MCC share immunohistochemical and ultrastructural features, there is limited evidence of a direct histogenetic relationship between the two.^1,2 Additionally, some extracutaneous neuroendocrine tumors have features similar to MCC; therefore, although it may be more accurate and perhaps more practical to describe these lesions as primary neuroendocrine carcinomas of the skin, the term MCC is more commonly used both in the literature and in clinical practice.^1,2

Merkel cell carcinoma typically presents in the head and neck region in white patients older than 70 years of age and in the immunocompromised population.^3-6 The mean age of diagnosis is 76 years for women and 74 years for men.⁷ The incidence of MCC in the United States tripled over a 15-year period, and there are approximately 1500 new cases of MCC diagnosed each year, making it about 40 times less common than melanoma.⁸ The 5-year survival rate for patients without lymph node involvement is 75%, whereas the 5-year survival rate for patients with distant metastases is 25%.⁹

Merkel cell carcinoma is thought to develop through 1 of 2 distinct pathways. In a virally mediated pathway, which represents at least 80% of cases, the Merkel cell polyomavirus (MCV) monoclonally integrates into the host genome and promotes oncogenesis via altered p53 and retinoblastoma protein expression.^10-12 The remainder of cases are believed to develop via a nonvirally mediated pathway in which genetic anomalies, immune status, and environmental factors influence oncogenesis.^10-13

Due to the similarity between MCC and metastatic neuroendocrine neoplasms, especially small-cell lung carcinomas, immunohistochemistry is important in making the diagnosis. Cytokeratin 20 and neuron-specific enolase positivity and thyroid transcription factor 1 negativity are the most useful markers in identifying MCC.

Regression of MCC is a very rare and poorly understood event. A 2010 review of the literature described 22 cases of spontaneous regression.¹⁴ We report a rare case of rapid and complete regression of MCC following punch biopsy in a 96-year-old woman.

Case Report

A 96-year-old woman presented with a rapidly enlarging lesion overlying the suprasternal notch of 8 weeks’ duration (Figure 1). The lesion consisted of a 5.0×4.5-cm, friable, erythematous, flesh-colored nodule with ulceration and heavy crusting. Surrounding the nodule was an erythematous to violaceous patch extending to the anterior chest and bilateral supraclavicular area. No cervical or clavicular lymphadenopathy was observed. According to the patient’s caregiver, the lesion originated as a small, erythematous, scaly macule that rapidly increased in size over an 8-week period to a maximum of 5.0×4.5 cm at presentation. The lesion bled on 2 or 3 occasions during the 8-week period and was controlled with a warm compress. The patient’s caregiver had treated the lesion with topical tea tree oil (for malodor) and antibiotic ointment as needed. The clinical differential diagnosis included squamous cell carcinoma, keratoacanthoma, amelanotic melanoma, cutaneous metastasis of a primary visceral malignancy, basal cell carcinoma, and MCC. Biopsy of the lesion was recommended at this time but the patient’s family declined.

A 4-mm punch biopsy was obtained at a follow-up visit 4 weeks later (12 weeks after the reported onset of the lesion). Hematoxylin and eosin staining showed a small-cell neoplasm with stippled nuclei and scant cytoplasm forming a nested and somewhat trabecular pattern. Mitotic activity, apoptosis, and nuclear molding also were present (Figure 2). The tumor cells were positive for cytokeratin 20 with a dotlike, paranuclear pattern (Figure 3). Staining for CAM 5.2 also was positive. Cytokeratin 5/6, human melanoma black 45, and leukocyte common antigen were negative. The immunophenotyping of the lymphocytic response to the tumor showed that the majority of intratumoral lymphocytes were CD8 positive (Figure 4). CD4-positive lymphocytes were predominantly seen at the periphery of the tumor nests without tumor infiltration (Figure 5). Based on these findings, a diagnosis of MCC was made. The patient’s family declined treatment based on her advanced age and current health status, which included advanced dementia.

Two weeks after the punch biopsy, the lesion had noticeably decreased in size and lost its dome-shaped appearance. Within 8 weeks after biopsy (20 weeks since the lesion first appeared), the lesion had completely resolved (Figure 6). The patient was lost to follow-up months later, but no recurrence of the lesion was reported.

Comment

Spontaneous regression is not unique to MCC, as this phenomenon also has been reported in keratoacanthoma, lymphoma, basal cell carcinoma, and melanoma.¹⁵ Complete spontaneous regression is defined as occurring in the absence of therapy that is intended to have a treatment effect.^15,16 Spontaneous regression is estimated to occur in malignant neoplasms at a rate of 1 case per 60,000 to 100,000 (approximately 0.0013% of all malignant neoplasms).¹⁷ Considering the reported prevalence of MCC and the number of cases that have been known to regress, the estimated incidence of complete spontaneous regression may be as high as 1.5%.¹⁴ Though spontaneous regression of MCC is more prevalent than expected, it still is considered a rare phenomenon. A 2010 review of the literature yielded 22 cases of complete spontaneous regression of MCC.¹⁴ No recurrences have been observed; however, follow-up was relatively short in some cases.

In a unique report by Bertolotti et al,¹⁸ a patient with MCC on the nasal tip presented 4 weeks after biopsy with complete spontaneous regression of the tumor, which was associated with bilateral cervical lymph node involvement as noted by hypermetabolic uptake on positron emission tomography scanning. The patient underwent radiation therapy and was disease free at 12 months’ follow-up.¹⁸

Complete spontaneous regression has been described in MCC patients with local disease, regional recurrences, and metastatic disease.¹⁹ In all reviewed cases, the regression is a fairly quick phenomenon occurring over the course of 1 to 5 months.^16,19,20,21 Our patient presented with advanced age and a tumor location characteristic of MCC. In our search of PubMed articles indexed for MEDLINE using the terms MCC, Merkel cell carcinoma, regression, and spontaneous regression, all but 1 case of MCC regression involved tumors that were located on the head.¹⁴

The histopathologic features observed in our case, specifically intratumoral CD8-positive cytotoxic lymphocytes and peritumoral CD4-positive cells, were similar to the findings in other reported cases. In one series of 2 cases, the one case showed scar tissue with a moderate, predominantly T-lymphocytic infiltrate and no tumor cells, and the second showed cellular proliferation in the deep dermis with dense lymphocytic infiltrates primarily composed of CD3-positive T cells.¹⁴ Other studies of regression of both localized and metastatic MCC demonstrated infiltration by CD4-positive, CD8-positive, and CD3-positive lymphocytes and foamy macrophages.^21-23

The discovery of the MCV was one of the most important advances in elucidating the pathogenesis of MCC.^10,24-26 Merkel cell polyomavirus DNA has been detected in a majority of MCC cases.^25,27 Viral integration has been shown to take place early, prior to tumor clonal expansion.¹⁰ Importantly, not all cases of MCC show MCV infection, and MCV infection is not exclusive to MCC.²⁸ Merkel cell polyomavirus is considered to be part of the normal human flora, and asymptomatic infection is quite common.²⁹ It has been identified in 80% of adults older than 50 years of age and, interestingly, in 35% of children by 13 years of age or younger.^30,31 It remains unclear what role the presence of MCV plays in determining MCC prognosis. Several reports have demonstrated lower disease-specific mortality associated with MCV-positive MCC.^32-35 In contrast, Schrama et al³⁶ correlated the MCV status of 174 MCC tumors and found no difference in clinical behavior or prognosis between MCV-positive and MCV-negative MCCs.

Immunosuppression also may play a role in the development of MCC.^5,25 There is increased prevalence of MCC in the human immunodeficiency virus–positive population, as well as in organ-transplant recipients and patients with leukemia. Chronic lymphocytic leukemia seems to be the most frequent neoplasia associated with development of MCC.³⁷

The mechanism of MCC regression remains unclear, but many investigators emphasize the importance of T-cell–mediated immunity.^{16,21-23,38,39} Apoptosis also has been shown to play an important role.⁴⁰ Our case showed tumor-infiltrating CD8-positive lymphocytes and CD4-positive lymphocytes present predominantly at the periphery of the tumor, with close proximity to the tumor nests but with no tumor infiltration (Figure 3). This distribution was consistently present in multiple sections of the tumor. These findings are consistent with prior reports of both CD4-positive and CD8-positive T lymphocytes associated with MCC regression. Our findings confirm that immune response may play an important role in spontaneous regression of MCC.

There is much speculation regarding the initial biopsy of an MCC lesion (or other traumatic event) and its role in tumor regression. Koba et al⁴¹ examined the effect of biopsy on CD8-positive lymphocytic infiltration of MCC tumor cells and found that biopsy does not commonly alter intratumoral CD8-positive infiltration. These findings suggest trauma does not directly induce immunologic recognition of this cancer.

Conclusion

We report a case of complete spontaneous regression of a localized MCC following a punch biopsy. The histopathology showed a brisk T-lymphocyte response with intratumoral CD8-positive cytotoxic lymphocytes and peritumoral CD4-positive cells. The age and clinical profile of our patient as well as the clinicopathologic characteristics of the tumor regression are similar to other reported cases. Further research is needed to elucidate the mechanism of MCC regression, and a better understanding of this fascinating phenomenon could help in development of new immunotherapeutic approaches.

Merkel cell carcinoma (MCC) is a rare, rapidly growing, aggressive neoplasm with a generally poor prognosis. The cells of origin are highly anaplastic and share structural and immunohistochemical features with various neuroectodermally derived cells. Although Merkel cells, which are slow-acting cutaneous mechanoreceptors located in the basal layer of the epidermis, and MCC share immunohistochemical and ultrastructural features, there is limited evidence of a direct histogenetic relationship between the two.^1,2 Additionally, some extracutaneous neuroendocrine tumors have features similar to MCC; therefore, although it may be more accurate and perhaps more practical to describe these lesions as primary neuroendocrine carcinomas of the skin, the term MCC is more commonly used both in the literature and in clinical practice.^1,2

Merkel cell carcinoma typically presents in the head and neck region in white patients older than 70 years of age and in the immunocompromised population.^3-6 The mean age of diagnosis is 76 years for women and 74 years for men.⁷ The incidence of MCC in the United States tripled over a 15-year period, and there are approximately 1500 new cases of MCC diagnosed each year, making it about 40 times less common than melanoma.⁸ The 5-year survival rate for patients without lymph node involvement is 75%, whereas the 5-year survival rate for patients with distant metastases is 25%.⁹

Merkel cell carcinoma is thought to develop through 1 of 2 distinct pathways. In a virally mediated pathway, which represents at least 80% of cases, the Merkel cell polyomavirus (MCV) monoclonally integrates into the host genome and promotes oncogenesis via altered p53 and retinoblastoma protein expression.^10-12 The remainder of cases are believed to develop via a nonvirally mediated pathway in which genetic anomalies, immune status, and environmental factors influence oncogenesis.^10-13

Due to the similarity between MCC and metastatic neuroendocrine neoplasms, especially small-cell lung carcinomas, immunohistochemistry is important in making the diagnosis. Cytokeratin 20 and neuron-specific enolase positivity and thyroid transcription factor 1 negativity are the most useful markers in identifying MCC.

Regression of MCC is a very rare and poorly understood event. A 2010 review of the literature described 22 cases of spontaneous regression.¹⁴ We report a rare case of rapid and complete regression of MCC following punch biopsy in a 96-year-old woman.

Case Report

A 96-year-old woman presented with a rapidly enlarging lesion overlying the suprasternal notch of 8 weeks’ duration (Figure 1). The lesion consisted of a 5.0×4.5-cm, friable, erythematous, flesh-colored nodule with ulceration and heavy crusting. Surrounding the nodule was an erythematous to violaceous patch extending to the anterior chest and bilateral supraclavicular area. No cervical or clavicular lymphadenopathy was observed. According to the patient’s caregiver, the lesion originated as a small, erythematous, scaly macule that rapidly increased in size over an 8-week period to a maximum of 5.0×4.5 cm at presentation. The lesion bled on 2 or 3 occasions during the 8-week period and was controlled with a warm compress. The patient’s caregiver had treated the lesion with topical tea tree oil (for malodor) and antibiotic ointment as needed. The clinical differential diagnosis included squamous cell carcinoma, keratoacanthoma, amelanotic melanoma, cutaneous metastasis of a primary visceral malignancy, basal cell carcinoma, and MCC. Biopsy of the lesion was recommended at this time but the patient’s family declined.

A 4-mm punch biopsy was obtained at a follow-up visit 4 weeks later (12 weeks after the reported onset of the lesion). Hematoxylin and eosin staining showed a small-cell neoplasm with stippled nuclei and scant cytoplasm forming a nested and somewhat trabecular pattern. Mitotic activity, apoptosis, and nuclear molding also were present (Figure 2). The tumor cells were positive for cytokeratin 20 with a dotlike, paranuclear pattern (Figure 3). Staining for CAM 5.2 also was positive. Cytokeratin 5/6, human melanoma black 45, and leukocyte common antigen were negative. The immunophenotyping of the lymphocytic response to the tumor showed that the majority of intratumoral lymphocytes were CD8 positive (Figure 4). CD4-positive lymphocytes were predominantly seen at the periphery of the tumor nests without tumor infiltration (Figure 5). Based on these findings, a diagnosis of MCC was made. The patient’s family declined treatment based on her advanced age and current health status, which included advanced dementia.

Two weeks after the punch biopsy, the lesion had noticeably decreased in size and lost its dome-shaped appearance. Within 8 weeks after biopsy (20 weeks since the lesion first appeared), the lesion had completely resolved (Figure 6). The patient was lost to follow-up months later, but no recurrence of the lesion was reported.

Comment

Spontaneous regression is not unique to MCC, as this phenomenon also has been reported in keratoacanthoma, lymphoma, basal cell carcinoma, and melanoma.¹⁵ Complete spontaneous regression is defined as occurring in the absence of therapy that is intended to have a treatment effect.^15,16 Spontaneous regression is estimated to occur in malignant neoplasms at a rate of 1 case per 60,000 to 100,000 (approximately 0.0013% of all malignant neoplasms).¹⁷ Considering the reported prevalence of MCC and the number of cases that have been known to regress, the estimated incidence of complete spontaneous regression may be as high as 1.5%.¹⁴ Though spontaneous regression of MCC is more prevalent than expected, it still is considered a rare phenomenon. A 2010 review of the literature yielded 22 cases of complete spontaneous regression of MCC.¹⁴ No recurrences have been observed; however, follow-up was relatively short in some cases.

In a unique report by Bertolotti et al,¹⁸ a patient with MCC on the nasal tip presented 4 weeks after biopsy with complete spontaneous regression of the tumor, which was associated with bilateral cervical lymph node involvement as noted by hypermetabolic uptake on positron emission tomography scanning. The patient underwent radiation therapy and was disease free at 12 months’ follow-up.¹⁸

Complete spontaneous regression has been described in MCC patients with local disease, regional recurrences, and metastatic disease.¹⁹ In all reviewed cases, the regression is a fairly quick phenomenon occurring over the course of 1 to 5 months.^16,19,20,21 Our patient presented with advanced age and a tumor location characteristic of MCC. In our search of PubMed articles indexed for MEDLINE using the terms MCC, Merkel cell carcinoma, regression, and spontaneous regression, all but 1 case of MCC regression involved tumors that were located on the head.¹⁴

The histopathologic features observed in our case, specifically intratumoral CD8-positive cytotoxic lymphocytes and peritumoral CD4-positive cells, were similar to the findings in other reported cases. In one series of 2 cases, the one case showed scar tissue with a moderate, predominantly T-lymphocytic infiltrate and no tumor cells, and the second showed cellular proliferation in the deep dermis with dense lymphocytic infiltrates primarily composed of CD3-positive T cells.¹⁴ Other studies of regression of both localized and metastatic MCC demonstrated infiltration by CD4-positive, CD8-positive, and CD3-positive lymphocytes and foamy macrophages.^21-23

The discovery of the MCV was one of the most important advances in elucidating the pathogenesis of MCC.^10,24-26 Merkel cell polyomavirus DNA has been detected in a majority of MCC cases.^25,27 Viral integration has been shown to take place early, prior to tumor clonal expansion.¹⁰ Importantly, not all cases of MCC show MCV infection, and MCV infection is not exclusive to MCC.²⁸ Merkel cell polyomavirus is considered to be part of the normal human flora, and asymptomatic infection is quite common.²⁹ It has been identified in 80% of adults older than 50 years of age and, interestingly, in 35% of children by 13 years of age or younger.^30,31 It remains unclear what role the presence of MCV plays in determining MCC prognosis. Several reports have demonstrated lower disease-specific mortality associated with MCV-positive MCC.^32-35 In contrast, Schrama et al³⁶ correlated the MCV status of 174 MCC tumors and found no difference in clinical behavior or prognosis between MCV-positive and MCV-negative MCCs.

Immunosuppression also may play a role in the development of MCC.^5,25 There is increased prevalence of MCC in the human immunodeficiency virus–positive population, as well as in organ-transplant recipients and patients with leukemia. Chronic lymphocytic leukemia seems to be the most frequent neoplasia associated with development of MCC.³⁷

The mechanism of MCC regression remains unclear, but many investigators emphasize the importance of T-cell–mediated immunity.^{16,21-23,38,39} Apoptosis also has been shown to play an important role.⁴⁰ Our case showed tumor-infiltrating CD8-positive lymphocytes and CD4-positive lymphocytes present predominantly at the periphery of the tumor, with close proximity to the tumor nests but with no tumor infiltration (Figure 3). This distribution was consistently present in multiple sections of the tumor. These findings are consistent with prior reports of both CD4-positive and CD8-positive T lymphocytes associated with MCC regression. Our findings confirm that immune response may play an important role in spontaneous regression of MCC.

There is much speculation regarding the initial biopsy of an MCC lesion (or other traumatic event) and its role in tumor regression. Koba et al⁴¹ examined the effect of biopsy on CD8-positive lymphocytic infiltration of MCC tumor cells and found that biopsy does not commonly alter intratumoral CD8-positive infiltration. These findings suggest trauma does not directly induce immunologic recognition of this cancer.

Conclusion

We report a case of complete spontaneous regression of a localized MCC following a punch biopsy. The histopathology showed a brisk T-lymphocyte response with intratumoral CD8-positive cytotoxic lymphocytes and peritumoral CD4-positive cells. The age and clinical profile of our patient as well as the clinicopathologic characteristics of the tumor regression are similar to other reported cases. Further research is needed to elucidate the mechanism of MCC regression, and a better understanding of this fascinating phenomenon could help in development of new immunotherapeutic approaches.

Merkel cell carcinoma (MCC) is a rare, rapidly growing, aggressive neoplasm with a generally poor prognosis. The cells of origin are highly anaplastic and share structural and immunohistochemical features with various neuroectodermally derived cells. Although Merkel cells, which are slow-acting cutaneous mechanoreceptors located in the basal layer of the epidermis, and MCC share immunohistochemical and ultrastructural features, there is limited evidence of a direct histogenetic relationship between the two.^1,2 Additionally, some extracutaneous neuroendocrine tumors have features similar to MCC; therefore, although it may be more accurate and perhaps more practical to describe these lesions as primary neuroendocrine carcinomas of the skin, the term MCC is more commonly used both in the literature and in clinical practice.^1,2

Merkel cell carcinoma typically presents in the head and neck region in white patients older than 70 years of age and in the immunocompromised population.^3-6 The mean age of diagnosis is 76 years for women and 74 years for men.⁷ The incidence of MCC in the United States tripled over a 15-year period, and there are approximately 1500 new cases of MCC diagnosed each year, making it about 40 times less common than melanoma.⁸ The 5-year survival rate for patients without lymph node involvement is 75%, whereas the 5-year survival rate for patients with distant metastases is 25%.⁹

Merkel cell carcinoma is thought to develop through 1 of 2 distinct pathways. In a virally mediated pathway, which represents at least 80% of cases, the Merkel cell polyomavirus (MCV) monoclonally integrates into the host genome and promotes oncogenesis via altered p53 and retinoblastoma protein expression.^10-12 The remainder of cases are believed to develop via a nonvirally mediated pathway in which genetic anomalies, immune status, and environmental factors influence oncogenesis.^10-13

Due to the similarity between MCC and metastatic neuroendocrine neoplasms, especially small-cell lung carcinomas, immunohistochemistry is important in making the diagnosis. Cytokeratin 20 and neuron-specific enolase positivity and thyroid transcription factor 1 negativity are the most useful markers in identifying MCC.

Regression of MCC is a very rare and poorly understood event. A 2010 review of the literature described 22 cases of spontaneous regression.¹⁴ We report a rare case of rapid and complete regression of MCC following punch biopsy in a 96-year-old woman.

Case Report

A 96-year-old woman presented with a rapidly enlarging lesion overlying the suprasternal notch of 8 weeks’ duration (Figure 1). The lesion consisted of a 5.0×4.5-cm, friable, erythematous, flesh-colored nodule with ulceration and heavy crusting. Surrounding the nodule was an erythematous to violaceous patch extending to the anterior chest and bilateral supraclavicular area. No cervical or clavicular lymphadenopathy was observed. According to the patient’s caregiver, the lesion originated as a small, erythematous, scaly macule that rapidly increased in size over an 8-week period to a maximum of 5.0×4.5 cm at presentation. The lesion bled on 2 or 3 occasions during the 8-week period and was controlled with a warm compress. The patient’s caregiver had treated the lesion with topical tea tree oil (for malodor) and antibiotic ointment as needed. The clinical differential diagnosis included squamous cell carcinoma, keratoacanthoma, amelanotic melanoma, cutaneous metastasis of a primary visceral malignancy, basal cell carcinoma, and MCC. Biopsy of the lesion was recommended at this time but the patient’s family declined.

A 4-mm punch biopsy was obtained at a follow-up visit 4 weeks later (12 weeks after the reported onset of the lesion). Hematoxylin and eosin staining showed a small-cell neoplasm with stippled nuclei and scant cytoplasm forming a nested and somewhat trabecular pattern. Mitotic activity, apoptosis, and nuclear molding also were present (Figure 2). The tumor cells were positive for cytokeratin 20 with a dotlike, paranuclear pattern (Figure 3). Staining for CAM 5.2 also was positive. Cytokeratin 5/6, human melanoma black 45, and leukocyte common antigen were negative. The immunophenotyping of the lymphocytic response to the tumor showed that the majority of intratumoral lymphocytes were CD8 positive (Figure 4). CD4-positive lymphocytes were predominantly seen at the periphery of the tumor nests without tumor infiltration (Figure 5). Based on these findings, a diagnosis of MCC was made. The patient’s family declined treatment based on her advanced age and current health status, which included advanced dementia.

Two weeks after the punch biopsy, the lesion had noticeably decreased in size and lost its dome-shaped appearance. Within 8 weeks after biopsy (20 weeks since the lesion first appeared), the lesion had completely resolved (Figure 6). The patient was lost to follow-up months later, but no recurrence of the lesion was reported.

Comment

Spontaneous regression is not unique to MCC, as this phenomenon also has been reported in keratoacanthoma, lymphoma, basal cell carcinoma, and melanoma.¹⁵ Complete spontaneous regression is defined as occurring in the absence of therapy that is intended to have a treatment effect.^15,16 Spontaneous regression is estimated to occur in malignant neoplasms at a rate of 1 case per 60,000 to 100,000 (approximately 0.0013% of all malignant neoplasms).¹⁷ Considering the reported prevalence of MCC and the number of cases that have been known to regress, the estimated incidence of complete spontaneous regression may be as high as 1.5%.¹⁴ Though spontaneous regression of MCC is more prevalent than expected, it still is considered a rare phenomenon. A 2010 review of the literature yielded 22 cases of complete spontaneous regression of MCC.¹⁴ No recurrences have been observed; however, follow-up was relatively short in some cases.

In a unique report by Bertolotti et al,¹⁸ a patient with MCC on the nasal tip presented 4 weeks after biopsy with complete spontaneous regression of the tumor, which was associated with bilateral cervical lymph node involvement as noted by hypermetabolic uptake on positron emission tomography scanning. The patient underwent radiation therapy and was disease free at 12 months’ follow-up.¹⁸

Complete spontaneous regression has been described in MCC patients with local disease, regional recurrences, and metastatic disease.¹⁹ In all reviewed cases, the regression is a fairly quick phenomenon occurring over the course of 1 to 5 months.^16,19,20,21 Our patient presented with advanced age and a tumor location characteristic of MCC. In our search of PubMed articles indexed for MEDLINE using the terms MCC, Merkel cell carcinoma, regression, and spontaneous regression, all but 1 case of MCC regression involved tumors that were located on the head.¹⁴

The histopathologic features observed in our case, specifically intratumoral CD8-positive cytotoxic lymphocytes and peritumoral CD4-positive cells, were similar to the findings in other reported cases. In one series of 2 cases, the one case showed scar tissue with a moderate, predominantly T-lymphocytic infiltrate and no tumor cells, and the second showed cellular proliferation in the deep dermis with dense lymphocytic infiltrates primarily composed of CD3-positive T cells.¹⁴ Other studies of regression of both localized and metastatic MCC demonstrated infiltration by CD4-positive, CD8-positive, and CD3-positive lymphocytes and foamy macrophages.^21-23

The discovery of the MCV was one of the most important advances in elucidating the pathogenesis of MCC.^10,24-26 Merkel cell polyomavirus DNA has been detected in a majority of MCC cases.^25,27 Viral integration has been shown to take place early, prior to tumor clonal expansion.¹⁰ Importantly, not all cases of MCC show MCV infection, and MCV infection is not exclusive to MCC.²⁸ Merkel cell polyomavirus is considered to be part of the normal human flora, and asymptomatic infection is quite common.²⁹ It has been identified in 80% of adults older than 50 years of age and, interestingly, in 35% of children by 13 years of age or younger.^30,31 It remains unclear what role the presence of MCV plays in determining MCC prognosis. Several reports have demonstrated lower disease-specific mortality associated with MCV-positive MCC.^32-35 In contrast, Schrama et al³⁶ correlated the MCV status of 174 MCC tumors and found no difference in clinical behavior or prognosis between MCV-positive and MCV-negative MCCs.

Immunosuppression also may play a role in the development of MCC.^5,25 There is increased prevalence of MCC in the human immunodeficiency virus–positive population, as well as in organ-transplant recipients and patients with leukemia. Chronic lymphocytic leukemia seems to be the most frequent neoplasia associated with development of MCC.³⁷

The mechanism of MCC regression remains unclear, but many investigators emphasize the importance of T-cell–mediated immunity.^{16,21-23,38,39} Apoptosis also has been shown to play an important role.⁴⁰ Our case showed tumor-infiltrating CD8-positive lymphocytes and CD4-positive lymphocytes present predominantly at the periphery of the tumor, with close proximity to the tumor nests but with no tumor infiltration (Figure 3). This distribution was consistently present in multiple sections of the tumor. These findings are consistent with prior reports of both CD4-positive and CD8-positive T lymphocytes associated with MCC regression. Our findings confirm that immune response may play an important role in spontaneous regression of MCC.

There is much speculation regarding the initial biopsy of an MCC lesion (or other traumatic event) and its role in tumor regression. Koba et al⁴¹ examined the effect of biopsy on CD8-positive lymphocytic infiltration of MCC tumor cells and found that biopsy does not commonly alter intratumoral CD8-positive infiltration. These findings suggest trauma does not directly induce immunologic recognition of this cancer.

Conclusion

We report a case of complete spontaneous regression of a localized MCC following a punch biopsy. The histopathology showed a brisk T-lymphocyte response with intratumoral CD8-positive cytotoxic lymphocytes and peritumoral CD4-positive cells. The age and clinical profile of our patient as well as the clinicopathologic characteristics of the tumor regression are similar to other reported cases. Further research is needed to elucidate the mechanism of MCC regression, and a better understanding of this fascinating phenomenon could help in development of new immunotherapeutic approaches.

Progressive macular hypomelanosis (PMH) is a noninflammatory skin disorder characterized by ill-defined, nummular, hypopigmented, and nonscaly macules. Historically, various names have been used to describe this entity. Several of these terms, including cutis trunci variata and nummular and confluent hypomelanosis of the trunk, reflected its predominantly truncal distribution.^1,2 Less frequently, involvement on the neck, buttocks, and arms and legs has been noted.^1,2 A lack of facial involvement previously has been highlighted as a key clinical feature of PMH.³

Progressive macular hypomelanosis is a diagnosis of exclusion. Hypopigmented diseases commonly considered in the differential include those caused by fungi and yeasts (eg, tinea versicolor, seborrheic dermatitis), inflammatory skin disorders (eg, pityriasis alba, postinflammatory dyschromia), and mycosis fungoides (MF) as well as leprosy.

The hypopigmented macules of PMH have nonspecific histopathologic findings; lesional skin often shows minimal alterations as compared to normal skin. A sparse perivascular lymphocytic infiltrate often is observed,^4,5 and at times, a decrease in epidermal melanin content can be detected.^1-3,6,7

We report 4 cases with considerable facial involvement of hypopigmented macules that were determined to be consistent with PMH. We propose that characteristic macules that are not clinically or histopathologically consistent with other disease entities are compatible with a diagnosis of PMH, regardless of the distribution. A diagnosis of PMH should be considered in the differential when there are suggestive facial lesions in addition to truncal lesions.

Case Reports

Patient 1
A 40-year-old man presented with hypopigmented macules on the face (Figure 1), trunk, chest, arms, and legs of 2 years’ duration. The lesions were asymptomatic and had started on the forehead as hypopigmented macules, then progressed to the trunk, arms, and legs. The patient denied any prior rash, injury, or hyperpigmentation associated with the distribution of the lesions.

A rapid plasma reagin (RPR) test was conducted to rule out secondary syphilis and was nonreactive. During a series of clinical encounters over several months, a total of 5 biopsies of lesions on the face and back were performed. All specimens contained mild mononuclear perivascular inflammation (Figure 2). In some foci, staining for Melan-A revealed a decrease in epidermal melanocytes (Figure 3). Periodic acid–Schiff staining performed on one section revealed a few pityriasis spores but no hyphal elements, suggesting colonization rather than infection.

The patient initially was started on tacrolimus ointment 0.1% once daily and narrowband UVB phototherapy twice weekly for 3 months without benefit. A diagnosis of tinea versicolor was revisited and the patient was switched to ketoconazole shampoo 1% two to 3 times weekly on the face, trunk, arms, and legs for 10 to 15 minutes prior to rinsing, and ketoconazole cream 2% was applied twice daily to the affected areas for 2 months without notable improvement. Once-weekly 150-mg pulse doses of oral fluconazole for 8 weeks were started but proved equally ineffective. Antibiotic therapy aimed at eradicating Propionibacterium acnes was considered following a provisional diagnosis of PMH after the patient failed 5 months of therapy for tinea versicolor.

Patient 2
A 54-year-old man presented with hypopigmented to depigmented nonscaly macules on the face, trunk, chest, and arms of several months’ duration. The patient initially noted hypopigmentation on the face that gradually spread to the rest of the body. The patient denied any prior rash or hyperpigmentation in the affected areas. At the initial visit to our clinic, a potassium hydroxide (KOH) preparation of the face and back was positive for tinea versicolor. The patient was treated with ketoconazole shampoo 1% two to 3 times weekly for several weeks on the scalp, face, trunk, arms, and legs for 10 to 15 minutes prior to rinsing and 2 total doses of oral fluconazole 150 mg taken 1 week apart.

Three months later the patient returned with no improvement of the existing lesions and with progression of the disease to previously uninvolved areas of the trunk, arms, and legs. Biopsy of a facial lesion was performed, and laboratory studies including RPR, thyroid-stimulating hormone, and antinuclear antibody tests were conducted to screen for possible systemic disease. Microscopic analysis of the biopsied facial lesion revealed a sparse perivascular infiltrate of lymphocytes and plasma cells but no evidence of yeast or hyphal elements. Melan-A staining did not reveal a decreased number of epidermal melanocytes. All laboratory studies were negative or within normal limits. Desonide ointment 0.05% was prescribed to relieve the patient’s occasional pruritus. Although the patient’s symptoms resolved, the hypopigmented macules continued to progress, making a diagnosis of PMH more likely given the lack of improvement on treatment for tinea versicolor. Pimecrolimus cream 1% was started with discontinuation of desonide for steroid-sparing therapy.

Patient 3
A 63-year-old man presented with progressive nonscaly and asymptomatic hypopigmented macules on the face, trunk, abdomen, and back of 5 years’ duration. He first noted lesions on the abdomen and they subsequently spread to the rest of the body. The patient denied any prior rash, hyperpigmentation, or other lesions in the involved areas.

One year prior to the current presentation, KOH scrapings from the lesions performed by an outside physician were negative. During his initial visit to our clinic, an abdominal biopsy was performed, and histopathologic analysis showed postinflammatory pigmentary alteration; however, the patient denied any prior history of rash or injury in the distribution of the lesions that would correlate with the histopathologic findings of postinflammatory pigmentation. Because the histopathologic findings showed postinflammatory pigmentary alteration, additional stains including Melan-A were not performed.

The patient was provisionally treated with ketoconazole shampoo 1% two to 3 times weekly on the face, trunk, arms, and legs for 10 to 15 minutes prior to rinsing and ketoconazole cream 2% twice daily to the affected areas. After several months on this regimen, the patient did not report any improvement. An abdominal skin biopsy was again performed and revealed similar histopathology. Periodic acid–Schiff staining was negative for fungus. A diagnosis of PMH was made, and the patient was started on benzoyl peroxide wash 5% and clindamycin lotion.

Patient 4
A 45-year-old woman presented with hypopigmented, nonscaly macules on the face, neck, chest, trunk, and back. She first noted the lesions on the face and trunk more than 8 years prior, and they subsequently progressed. Potassium hydroxide scrapings performed on the lesions at the current presentation were negative, and a skin biopsy from the neck revealed postinflammatory pigmentary alteration, although the patient had no history of rash or injury in the areas in which the lesions were distributed.

Fontana-Masson and Melan-A staining of the skin biopsy of the neck revealed a normal distribution of melanocytes and pigment at the dermoepidermal junction. An RPR test was nonreactive. A diagnosis of PMH was made, and the patient was started on benzoyl peroxide wash 5% and clindamycin phosphate lotion 1%.

Comment

The 4 cases of PMH reported here showed extensive facial involvement in addition to the characteristic hypopigmented lesions on the trunk, arms, and legs. It is unclear why the lesions in these patients had a predominantly facial distribution. Involvement of the face in PMH has not been commonly reported in the literature. Martínez-Martínez et al³ reported 12 PMH patients with lesions only presenting in lumbar and abdominal distributions. Kim et al⁸ presented a series of 23 PMH patients treated with narrowband UVB in whom 56% (9/16) saw repigmentation in 90% of the lesions following treatment. The most commonly affected area was the lower back, followed by the abdomen, upper back, chest, sacral region, flank, and shoulders, respectively.⁸ In a review by Relyveld et al,¹ PMH is described as a predominantly truncal disease that can occasionally extend to the neck, face, and proximal arms and legs; however, no specific cases were reported.

Previous case series have reported PMH primarily in adolescents and young adults, with mean ages ranging from 26 to 30 years.^1,3 The 4 patients reported here were older, ranging in age from 40 to 65 years. This discrepancy in age may contribute to the facial distribution encountered in this patient population; however, given the small number of patients in our case series, such extrapolation is premature. Most recently, Westerhof et al⁶ demonstrated a relationship between the presence of P acnes, a common skin commensal of the face, and the hypopigmented macules of PMH. The investigators suggested that some strains of P acnes produce a factor that is yet to be identified that interferes with melanogenesis. The response of PMH lesions to topical treatments such as benzoyl peroxide, clindamycin, and phototherapy has lent credence to the potential etiologic role of P acnes in this condition.^9,10 The interplay between age, PMH distribution, and P acnes requires further investigation.

The biopsies in our 4 patients were consistent with the nonspecific histopathologic characteristics of PMH lesions. Biopsies in all 4 patients revealed a sparse perivascular lymphocytic infiltrate, and in 2 of the cases, postinflammatory pigmentary alteration was noted. Such changes often are described in PMH lesions.^4,5 In other cases detailed in the literature, lesional and nonlesional skin often are indistinguishable on hematoxylin and eosin staining.¹¹ In the 3 patients for whom we performed additional immunohistochemical studies, results were mixed: Melan-A staining revealed a decreased number of melanocytes in Patient 1 but not in Patients 2 or 4. Many reported cases in the literature have not demonstrated a decrease in melanocyte density but instead show a decrease in melanin content in lesional skin.^1-3,6,7 Although additional stains performed in Patient 4 revealed neither a decrease in the number of melanocytes nor a decrease in the melanin content, such histopathologic findings of PMH often are subtle. Additional stains were not performed in Patient 3. More studies are needed to characterize the immunohistochemical staining patterns of lesional skin in patients with PMH.

Tinea versicolor, pityriasis alba, mycosis fungoides, sarcoidosis, leprosy, and syphilis typically are included in the differential diagnosis for PMH. Tinea versicolor traditionally is diagnosed based on the combination of irregular hypopigmented or hyperpigmented scaly macules and a KOH preparation that is positive for hyphae and spores. Similar to PMH, tinea versicolor is most often found on the trunk, but unusual cases have been reported involving the face.¹²

Patient 2 reflected how it can be difficult diagnostically to distinguish between tinea versicolor and PMH. Although this patient initially had a KOH scraping suggestive for tinea versicolor, adequate treatment with oral fluconazole and ketoconazole shampoo did not result in improvement. The hypopigmented lesions in this patient continued to progress despite therapy. Additionally, his hypopigmented to depigmented nonscaly macules were more clinically consistent with the characteristic description of lesion configuration in PMH than with the irregular, more sharply defined, asymmetric, and scaly spots of tinea versicolor. Furthermore, the inflammatory findings on biopsy favored a diagnosis of PMH.

Pityriasis alba, most frequently presents on the face in the form of hypopigmented, sometimes slightly scaly macules but also can occur on the body. It usually occurs in younger patients who often have an atopic diathesis. Histologic findings generally are nonspecific, but discrete eczematous changes can sometimes be appreciated in the epidermis and dermis. None of our patients had histories suggestive of an atopic diathesis or lesion distributions typical of pityriasis alba. Histologic findings also were more consistent with PMH than pityriasis alba.

A diagnosis of patch-stage hypopigmented MF should also be entertained in patients with hypopigmented macules, as it can appear similar to the lesions of PMH. Hypopigmented MF often is associated with subtle atrophy, scaling, poikiloderma, and erythema. These features were not present in the 4 cases presented here. Histologically, atypical lymphocytes with prominent epidermotropism and tagging of the epidermis by large lymphocytic infiltrates are seen in cases of hypopigmented MF. These findings were not present in biopsies from our patients.

Hypopigmented sarcoidosis, leprosy, and syphilis are other systemic diseases associated with hypopigmented lesions. Histologically, noncaseasting granulomas in the dermis or subcutaneous tissue would favor a diagnosis of sarcoidosis over PMH. In patients who live in endemic areas, a diagnosis of leprosy for an anesthetic hypopigmented lesion would be higher in the differential. Finally, it is important to rule out secondary syphilis when diagnosing PMH. Known as the great imitator, secondary syphilis may present in a patient in the form of hypopigmented macules. Patients 1, 2, and 4 had nonreactive RPR tests; unfortunately, RPR was not checked in Patient 3. He denied all risk factors for syphilis.

Various topical and oral treatments were prescribed for each patient, but so far none have been unequivocally effective. In the literature, there are reports supporting the efficacy of topical antimicrobial agents targeting P acnes.^9,10 One case report noted improvement in a patient with PMH after isotretinoin use.¹³ Phototherapy also has been reported to improve PMH in several case reports^4-8; however, consistent response to these therapies has not been documented. Unfortunately for patients with a diagnosis of PMH, a lack of effective treatment options often exists.

This series of 4 cases highlights the importance of considering PMH in the differential of hypopigmented macules, even when they appear predominantly on the face.

Progressive macular hypomelanosis (PMH) is a noninflammatory skin disorder characterized by ill-defined, nummular, hypopigmented, and nonscaly macules. Historically, various names have been used to describe this entity. Several of these terms, including cutis trunci variata and nummular and confluent hypomelanosis of the trunk, reflected its predominantly truncal distribution.^1,2 Less frequently, involvement on the neck, buttocks, and arms and legs has been noted.^1,2 A lack of facial involvement previously has been highlighted as a key clinical feature of PMH.³

Progressive macular hypomelanosis is a diagnosis of exclusion. Hypopigmented diseases commonly considered in the differential include those caused by fungi and yeasts (eg, tinea versicolor, seborrheic dermatitis), inflammatory skin disorders (eg, pityriasis alba, postinflammatory dyschromia), and mycosis fungoides (MF) as well as leprosy.

The hypopigmented macules of PMH have nonspecific histopathologic findings; lesional skin often shows minimal alterations as compared to normal skin. A sparse perivascular lymphocytic infiltrate often is observed,^4,5 and at times, a decrease in epidermal melanin content can be detected.^1-3,6,7

We report 4 cases with considerable facial involvement of hypopigmented macules that were determined to be consistent with PMH. We propose that characteristic macules that are not clinically or histopathologically consistent with other disease entities are compatible with a diagnosis of PMH, regardless of the distribution. A diagnosis of PMH should be considered in the differential when there are suggestive facial lesions in addition to truncal lesions.

Case Reports

Patient 1
A 40-year-old man presented with hypopigmented macules on the face (Figure 1), trunk, chest, arms, and legs of 2 years’ duration. The lesions were asymptomatic and had started on the forehead as hypopigmented macules, then progressed to the trunk, arms, and legs. The patient denied any prior rash, injury, or hyperpigmentation associated with the distribution of the lesions.

A rapid plasma reagin (RPR) test was conducted to rule out secondary syphilis and was nonreactive. During a series of clinical encounters over several months, a total of 5 biopsies of lesions on the face and back were performed. All specimens contained mild mononuclear perivascular inflammation (Figure 2). In some foci, staining for Melan-A revealed a decrease in epidermal melanocytes (Figure 3). Periodic acid–Schiff staining performed on one section revealed a few pityriasis spores but no hyphal elements, suggesting colonization rather than infection.

The patient initially was started on tacrolimus ointment 0.1% once daily and narrowband UVB phototherapy twice weekly for 3 months without benefit. A diagnosis of tinea versicolor was revisited and the patient was switched to ketoconazole shampoo 1% two to 3 times weekly on the face, trunk, arms, and legs for 10 to 15 minutes prior to rinsing, and ketoconazole cream 2% was applied twice daily to the affected areas for 2 months without notable improvement. Once-weekly 150-mg pulse doses of oral fluconazole for 8 weeks were started but proved equally ineffective. Antibiotic therapy aimed at eradicating Propionibacterium acnes was considered following a provisional diagnosis of PMH after the patient failed 5 months of therapy for tinea versicolor.

Patient 2
A 54-year-old man presented with hypopigmented to depigmented nonscaly macules on the face, trunk, chest, and arms of several months’ duration. The patient initially noted hypopigmentation on the face that gradually spread to the rest of the body. The patient denied any prior rash or hyperpigmentation in the affected areas. At the initial visit to our clinic, a potassium hydroxide (KOH) preparation of the face and back was positive for tinea versicolor. The patient was treated with ketoconazole shampoo 1% two to 3 times weekly for several weeks on the scalp, face, trunk, arms, and legs for 10 to 15 minutes prior to rinsing and 2 total doses of oral fluconazole 150 mg taken 1 week apart.

Three months later the patient returned with no improvement of the existing lesions and with progression of the disease to previously uninvolved areas of the trunk, arms, and legs. Biopsy of a facial lesion was performed, and laboratory studies including RPR, thyroid-stimulating hormone, and antinuclear antibody tests were conducted to screen for possible systemic disease. Microscopic analysis of the biopsied facial lesion revealed a sparse perivascular infiltrate of lymphocytes and plasma cells but no evidence of yeast or hyphal elements. Melan-A staining did not reveal a decreased number of epidermal melanocytes. All laboratory studies were negative or within normal limits. Desonide ointment 0.05% was prescribed to relieve the patient’s occasional pruritus. Although the patient’s symptoms resolved, the hypopigmented macules continued to progress, making a diagnosis of PMH more likely given the lack of improvement on treatment for tinea versicolor. Pimecrolimus cream 1% was started with discontinuation of desonide for steroid-sparing therapy.

Patient 3
A 63-year-old man presented with progressive nonscaly and asymptomatic hypopigmented macules on the face, trunk, abdomen, and back of 5 years’ duration. He first noted lesions on the abdomen and they subsequently spread to the rest of the body. The patient denied any prior rash, hyperpigmentation, or other lesions in the involved areas.

One year prior to the current presentation, KOH scrapings from the lesions performed by an outside physician were negative. During his initial visit to our clinic, an abdominal biopsy was performed, and histopathologic analysis showed postinflammatory pigmentary alteration; however, the patient denied any prior history of rash or injury in the distribution of the lesions that would correlate with the histopathologic findings of postinflammatory pigmentation. Because the histopathologic findings showed postinflammatory pigmentary alteration, additional stains including Melan-A were not performed.

The patient was provisionally treated with ketoconazole shampoo 1% two to 3 times weekly on the face, trunk, arms, and legs for 10 to 15 minutes prior to rinsing and ketoconazole cream 2% twice daily to the affected areas. After several months on this regimen, the patient did not report any improvement. An abdominal skin biopsy was again performed and revealed similar histopathology. Periodic acid–Schiff staining was negative for fungus. A diagnosis of PMH was made, and the patient was started on benzoyl peroxide wash 5% and clindamycin lotion.

Patient 4
A 45-year-old woman presented with hypopigmented, nonscaly macules on the face, neck, chest, trunk, and back. She first noted the lesions on the face and trunk more than 8 years prior, and they subsequently progressed. Potassium hydroxide scrapings performed on the lesions at the current presentation were negative, and a skin biopsy from the neck revealed postinflammatory pigmentary alteration, although the patient had no history of rash or injury in the areas in which the lesions were distributed.

Fontana-Masson and Melan-A staining of the skin biopsy of the neck revealed a normal distribution of melanocytes and pigment at the dermoepidermal junction. An RPR test was nonreactive. A diagnosis of PMH was made, and the patient was started on benzoyl peroxide wash 5% and clindamycin phosphate lotion 1%.

Comment

The 4 cases of PMH reported here showed extensive facial involvement in addition to the characteristic hypopigmented lesions on the trunk, arms, and legs. It is unclear why the lesions in these patients had a predominantly facial distribution. Involvement of the face in PMH has not been commonly reported in the literature. Martínez-Martínez et al³ reported 12 PMH patients with lesions only presenting in lumbar and abdominal distributions. Kim et al⁸ presented a series of 23 PMH patients treated with narrowband UVB in whom 56% (9/16) saw repigmentation in 90% of the lesions following treatment. The most commonly affected area was the lower back, followed by the abdomen, upper back, chest, sacral region, flank, and shoulders, respectively.⁸ In a review by Relyveld et al,¹ PMH is described as a predominantly truncal disease that can occasionally extend to the neck, face, and proximal arms and legs; however, no specific cases were reported.

Previous case series have reported PMH primarily in adolescents and young adults, with mean ages ranging from 26 to 30 years.^1,3 The 4 patients reported here were older, ranging in age from 40 to 65 years. This discrepancy in age may contribute to the facial distribution encountered in this patient population; however, given the small number of patients in our case series, such extrapolation is premature. Most recently, Westerhof et al⁶ demonstrated a relationship between the presence of P acnes, a common skin commensal of the face, and the hypopigmented macules of PMH. The investigators suggested that some strains of P acnes produce a factor that is yet to be identified that interferes with melanogenesis. The response of PMH lesions to topical treatments such as benzoyl peroxide, clindamycin, and phototherapy has lent credence to the potential etiologic role of P acnes in this condition.^9,10 The interplay between age, PMH distribution, and P acnes requires further investigation.

The biopsies in our 4 patients were consistent with the nonspecific histopathologic characteristics of PMH lesions. Biopsies in all 4 patients revealed a sparse perivascular lymphocytic infiltrate, and in 2 of the cases, postinflammatory pigmentary alteration was noted. Such changes often are described in PMH lesions.^4,5 In other cases detailed in the literature, lesional and nonlesional skin often are indistinguishable on hematoxylin and eosin staining.¹¹ In the 3 patients for whom we performed additional immunohistochemical studies, results were mixed: Melan-A staining revealed a decreased number of melanocytes in Patient 1 but not in Patients 2 or 4. Many reported cases in the literature have not demonstrated a decrease in melanocyte density but instead show a decrease in melanin content in lesional skin.^1-3,6,7 Although additional stains performed in Patient 4 revealed neither a decrease in the number of melanocytes nor a decrease in the melanin content, such histopathologic findings of PMH often are subtle. Additional stains were not performed in Patient 3. More studies are needed to characterize the immunohistochemical staining patterns of lesional skin in patients with PMH.

Tinea versicolor, pityriasis alba, mycosis fungoides, sarcoidosis, leprosy, and syphilis typically are included in the differential diagnosis for PMH. Tinea versicolor traditionally is diagnosed based on the combination of irregular hypopigmented or hyperpigmented scaly macules and a KOH preparation that is positive for hyphae and spores. Similar to PMH, tinea versicolor is most often found on the trunk, but unusual cases have been reported involving the face.¹²

Patient 2 reflected how it can be difficult diagnostically to distinguish between tinea versicolor and PMH. Although this patient initially had a KOH scraping suggestive for tinea versicolor, adequate treatment with oral fluconazole and ketoconazole shampoo did not result in improvement. The hypopigmented lesions in this patient continued to progress despite therapy. Additionally, his hypopigmented to depigmented nonscaly macules were more clinically consistent with the characteristic description of lesion configuration in PMH than with the irregular, more sharply defined, asymmetric, and scaly spots of tinea versicolor. Furthermore, the inflammatory findings on biopsy favored a diagnosis of PMH.

Pityriasis alba, most frequently presents on the face in the form of hypopigmented, sometimes slightly scaly macules but also can occur on the body. It usually occurs in younger patients who often have an atopic diathesis. Histologic findings generally are nonspecific, but discrete eczematous changes can sometimes be appreciated in the epidermis and dermis. None of our patients had histories suggestive of an atopic diathesis or lesion distributions typical of pityriasis alba. Histologic findings also were more consistent with PMH than pityriasis alba.

A diagnosis of patch-stage hypopigmented MF should also be entertained in patients with hypopigmented macules, as it can appear similar to the lesions of PMH. Hypopigmented MF often is associated with subtle atrophy, scaling, poikiloderma, and erythema. These features were not present in the 4 cases presented here. Histologically, atypical lymphocytes with prominent epidermotropism and tagging of the epidermis by large lymphocytic infiltrates are seen in cases of hypopigmented MF. These findings were not present in biopsies from our patients.

Hypopigmented sarcoidosis, leprosy, and syphilis are other systemic diseases associated with hypopigmented lesions. Histologically, noncaseasting granulomas in the dermis or subcutaneous tissue would favor a diagnosis of sarcoidosis over PMH. In patients who live in endemic areas, a diagnosis of leprosy for an anesthetic hypopigmented lesion would be higher in the differential. Finally, it is important to rule out secondary syphilis when diagnosing PMH. Known as the great imitator, secondary syphilis may present in a patient in the form of hypopigmented macules. Patients 1, 2, and 4 had nonreactive RPR tests; unfortunately, RPR was not checked in Patient 3. He denied all risk factors for syphilis.

Various topical and oral treatments were prescribed for each patient, but so far none have been unequivocally effective. In the literature, there are reports supporting the efficacy of topical antimicrobial agents targeting P acnes.^9,10 One case report noted improvement in a patient with PMH after isotretinoin use.¹³ Phototherapy also has been reported to improve PMH in several case reports^4-8; however, consistent response to these therapies has not been documented. Unfortunately for patients with a diagnosis of PMH, a lack of effective treatment options often exists.

This series of 4 cases highlights the importance of considering PMH in the differential of hypopigmented macules, even when they appear predominantly on the face.

Progressive macular hypomelanosis (PMH) is a noninflammatory skin disorder characterized by ill-defined, nummular, hypopigmented, and nonscaly macules. Historically, various names have been used to describe this entity. Several of these terms, including cutis trunci variata and nummular and confluent hypomelanosis of the trunk, reflected its predominantly truncal distribution.^1,2 Less frequently, involvement on the neck, buttocks, and arms and legs has been noted.^1,2 A lack of facial involvement previously has been highlighted as a key clinical feature of PMH.³

Progressive macular hypomelanosis is a diagnosis of exclusion. Hypopigmented diseases commonly considered in the differential include those caused by fungi and yeasts (eg, tinea versicolor, seborrheic dermatitis), inflammatory skin disorders (eg, pityriasis alba, postinflammatory dyschromia), and mycosis fungoides (MF) as well as leprosy.

The hypopigmented macules of PMH have nonspecific histopathologic findings; lesional skin often shows minimal alterations as compared to normal skin. A sparse perivascular lymphocytic infiltrate often is observed,^4,5 and at times, a decrease in epidermal melanin content can be detected.^1-3,6,7

We report 4 cases with considerable facial involvement of hypopigmented macules that were determined to be consistent with PMH. We propose that characteristic macules that are not clinically or histopathologically consistent with other disease entities are compatible with a diagnosis of PMH, regardless of the distribution. A diagnosis of PMH should be considered in the differential when there are suggestive facial lesions in addition to truncal lesions.

Case Reports

Patient 1
A 40-year-old man presented with hypopigmented macules on the face (Figure 1), trunk, chest, arms, and legs of 2 years’ duration. The lesions were asymptomatic and had started on the forehead as hypopigmented macules, then progressed to the trunk, arms, and legs. The patient denied any prior rash, injury, or hyperpigmentation associated with the distribution of the lesions.

A rapid plasma reagin (RPR) test was conducted to rule out secondary syphilis and was nonreactive. During a series of clinical encounters over several months, a total of 5 biopsies of lesions on the face and back were performed. All specimens contained mild mononuclear perivascular inflammation (Figure 2). In some foci, staining for Melan-A revealed a decrease in epidermal melanocytes (Figure 3). Periodic acid–Schiff staining performed on one section revealed a few pityriasis spores but no hyphal elements, suggesting colonization rather than infection.

The patient initially was started on tacrolimus ointment 0.1% once daily and narrowband UVB phototherapy twice weekly for 3 months without benefit. A diagnosis of tinea versicolor was revisited and the patient was switched to ketoconazole shampoo 1% two to 3 times weekly on the face, trunk, arms, and legs for 10 to 15 minutes prior to rinsing, and ketoconazole cream 2% was applied twice daily to the affected areas for 2 months without notable improvement. Once-weekly 150-mg pulse doses of oral fluconazole for 8 weeks were started but proved equally ineffective. Antibiotic therapy aimed at eradicating Propionibacterium acnes was considered following a provisional diagnosis of PMH after the patient failed 5 months of therapy for tinea versicolor.

Patient 2
A 54-year-old man presented with hypopigmented to depigmented nonscaly macules on the face, trunk, chest, and arms of several months’ duration. The patient initially noted hypopigmentation on the face that gradually spread to the rest of the body. The patient denied any prior rash or hyperpigmentation in the affected areas. At the initial visit to our clinic, a potassium hydroxide (KOH) preparation of the face and back was positive for tinea versicolor. The patient was treated with ketoconazole shampoo 1% two to 3 times weekly for several weeks on the scalp, face, trunk, arms, and legs for 10 to 15 minutes prior to rinsing and 2 total doses of oral fluconazole 150 mg taken 1 week apart.

Three months later the patient returned with no improvement of the existing lesions and with progression of the disease to previously uninvolved areas of the trunk, arms, and legs. Biopsy of a facial lesion was performed, and laboratory studies including RPR, thyroid-stimulating hormone, and antinuclear antibody tests were conducted to screen for possible systemic disease. Microscopic analysis of the biopsied facial lesion revealed a sparse perivascular infiltrate of lymphocytes and plasma cells but no evidence of yeast or hyphal elements. Melan-A staining did not reveal a decreased number of epidermal melanocytes. All laboratory studies were negative or within normal limits. Desonide ointment 0.05% was prescribed to relieve the patient’s occasional pruritus. Although the patient’s symptoms resolved, the hypopigmented macules continued to progress, making a diagnosis of PMH more likely given the lack of improvement on treatment for tinea versicolor. Pimecrolimus cream 1% was started with discontinuation of desonide for steroid-sparing therapy.

Patient 3
A 63-year-old man presented with progressive nonscaly and asymptomatic hypopigmented macules on the face, trunk, abdomen, and back of 5 years’ duration. He first noted lesions on the abdomen and they subsequently spread to the rest of the body. The patient denied any prior rash, hyperpigmentation, or other lesions in the involved areas.

One year prior to the current presentation, KOH scrapings from the lesions performed by an outside physician were negative. During his initial visit to our clinic, an abdominal biopsy was performed, and histopathologic analysis showed postinflammatory pigmentary alteration; however, the patient denied any prior history of rash or injury in the distribution of the lesions that would correlate with the histopathologic findings of postinflammatory pigmentation. Because the histopathologic findings showed postinflammatory pigmentary alteration, additional stains including Melan-A were not performed.

The patient was provisionally treated with ketoconazole shampoo 1% two to 3 times weekly on the face, trunk, arms, and legs for 10 to 15 minutes prior to rinsing and ketoconazole cream 2% twice daily to the affected areas. After several months on this regimen, the patient did not report any improvement. An abdominal skin biopsy was again performed and revealed similar histopathology. Periodic acid–Schiff staining was negative for fungus. A diagnosis of PMH was made, and the patient was started on benzoyl peroxide wash 5% and clindamycin lotion.

Patient 4
A 45-year-old woman presented with hypopigmented, nonscaly macules on the face, neck, chest, trunk, and back. She first noted the lesions on the face and trunk more than 8 years prior, and they subsequently progressed. Potassium hydroxide scrapings performed on the lesions at the current presentation were negative, and a skin biopsy from the neck revealed postinflammatory pigmentary alteration, although the patient had no history of rash or injury in the areas in which the lesions were distributed.

Fontana-Masson and Melan-A staining of the skin biopsy of the neck revealed a normal distribution of melanocytes and pigment at the dermoepidermal junction. An RPR test was nonreactive. A diagnosis of PMH was made, and the patient was started on benzoyl peroxide wash 5% and clindamycin phosphate lotion 1%.

Comment

The 4 cases of PMH reported here showed extensive facial involvement in addition to the characteristic hypopigmented lesions on the trunk, arms, and legs. It is unclear why the lesions in these patients had a predominantly facial distribution. Involvement of the face in PMH has not been commonly reported in the literature. Martínez-Martínez et al³ reported 12 PMH patients with lesions only presenting in lumbar and abdominal distributions. Kim et al⁸ presented a series of 23 PMH patients treated with narrowband UVB in whom 56% (9/16) saw repigmentation in 90% of the lesions following treatment. The most commonly affected area was the lower back, followed by the abdomen, upper back, chest, sacral region, flank, and shoulders, respectively.⁸ In a review by Relyveld et al,¹ PMH is described as a predominantly truncal disease that can occasionally extend to the neck, face, and proximal arms and legs; however, no specific cases were reported.

Previous case series have reported PMH primarily in adolescents and young adults, with mean ages ranging from 26 to 30 years.^1,3 The 4 patients reported here were older, ranging in age from 40 to 65 years. This discrepancy in age may contribute to the facial distribution encountered in this patient population; however, given the small number of patients in our case series, such extrapolation is premature. Most recently, Westerhof et al⁶ demonstrated a relationship between the presence of P acnes, a common skin commensal of the face, and the hypopigmented macules of PMH. The investigators suggested that some strains of P acnes produce a factor that is yet to be identified that interferes with melanogenesis. The response of PMH lesions to topical treatments such as benzoyl peroxide, clindamycin, and phototherapy has lent credence to the potential etiologic role of P acnes in this condition.^9,10 The interplay between age, PMH distribution, and P acnes requires further investigation.

The biopsies in our 4 patients were consistent with the nonspecific histopathologic characteristics of PMH lesions. Biopsies in all 4 patients revealed a sparse perivascular lymphocytic infiltrate, and in 2 of the cases, postinflammatory pigmentary alteration was noted. Such changes often are described in PMH lesions.^4,5 In other cases detailed in the literature, lesional and nonlesional skin often are indistinguishable on hematoxylin and eosin staining.¹¹ In the 3 patients for whom we performed additional immunohistochemical studies, results were mixed: Melan-A staining revealed a decreased number of melanocytes in Patient 1 but not in Patients 2 or 4. Many reported cases in the literature have not demonstrated a decrease in melanocyte density but instead show a decrease in melanin content in lesional skin.^1-3,6,7 Although additional stains performed in Patient 4 revealed neither a decrease in the number of melanocytes nor a decrease in the melanin content, such histopathologic findings of PMH often are subtle. Additional stains were not performed in Patient 3. More studies are needed to characterize the immunohistochemical staining patterns of lesional skin in patients with PMH.

Tinea versicolor, pityriasis alba, mycosis fungoides, sarcoidosis, leprosy, and syphilis typically are included in the differential diagnosis for PMH. Tinea versicolor traditionally is diagnosed based on the combination of irregular hypopigmented or hyperpigmented scaly macules and a KOH preparation that is positive for hyphae and spores. Similar to PMH, tinea versicolor is most often found on the trunk, but unusual cases have been reported involving the face.¹²

Patient 2 reflected how it can be difficult diagnostically to distinguish between tinea versicolor and PMH. Although this patient initially had a KOH scraping suggestive for tinea versicolor, adequate treatment with oral fluconazole and ketoconazole shampoo did not result in improvement. The hypopigmented lesions in this patient continued to progress despite therapy. Additionally, his hypopigmented to depigmented nonscaly macules were more clinically consistent with the characteristic description of lesion configuration in PMH than with the irregular, more sharply defined, asymmetric, and scaly spots of tinea versicolor. Furthermore, the inflammatory findings on biopsy favored a diagnosis of PMH.

Pityriasis alba, most frequently presents on the face in the form of hypopigmented, sometimes slightly scaly macules but also can occur on the body. It usually occurs in younger patients who often have an atopic diathesis. Histologic findings generally are nonspecific, but discrete eczematous changes can sometimes be appreciated in the epidermis and dermis. None of our patients had histories suggestive of an atopic diathesis or lesion distributions typical of pityriasis alba. Histologic findings also were more consistent with PMH than pityriasis alba.

A diagnosis of patch-stage hypopigmented MF should also be entertained in patients with hypopigmented macules, as it can appear similar to the lesions of PMH. Hypopigmented MF often is associated with subtle atrophy, scaling, poikiloderma, and erythema. These features were not present in the 4 cases presented here. Histologically, atypical lymphocytes with prominent epidermotropism and tagging of the epidermis by large lymphocytic infiltrates are seen in cases of hypopigmented MF. These findings were not present in biopsies from our patients.

Hypopigmented sarcoidosis, leprosy, and syphilis are other systemic diseases associated with hypopigmented lesions. Histologically, noncaseasting granulomas in the dermis or subcutaneous tissue would favor a diagnosis of sarcoidosis over PMH. In patients who live in endemic areas, a diagnosis of leprosy for an anesthetic hypopigmented lesion would be higher in the differential. Finally, it is important to rule out secondary syphilis when diagnosing PMH. Known as the great imitator, secondary syphilis may present in a patient in the form of hypopigmented macules. Patients 1, 2, and 4 had nonreactive RPR tests; unfortunately, RPR was not checked in Patient 3. He denied all risk factors for syphilis.

Various topical and oral treatments were prescribed for each patient, but so far none have been unequivocally effective. In the literature, there are reports supporting the efficacy of topical antimicrobial agents targeting P acnes.^9,10 One case report noted improvement in a patient with PMH after isotretinoin use.¹³ Phototherapy also has been reported to improve PMH in several case reports^4-8; however, consistent response to these therapies has not been documented. Unfortunately for patients with a diagnosis of PMH, a lack of effective treatment options often exists.

This series of 4 cases highlights the importance of considering PMH in the differential of hypopigmented macules, even when they appear predominantly on the face.

Case Report

A 77-year-old man was admitted to the general medicine service at our institution for treatment of a diffuse macular eruption and hemorrhagic bullae 12 days after undergoing left-knee revision arthroplasty during which a cement spacer impregnated with vancomycin and tobramycin was placed. At the time of the surgery, the patient also received intravenous (IV) vancomycin and oral ciprofloxacin, which were continued postoperatively until his hospital presentation. The patient was recovering well until postoperative day 7, when he developed painful swelling and erythema surrounding the surgical wound on the left knee. Concerned that his symptoms indicated a flare of gout, he restarted a former allopurinol prescription from an outside physician after 2 years of nonuse. The skin changes progressed distally on the left leg over the next 48 hours. By postoperative day 10, he had developed serosanguinous blisters on the left knee (Figure 1A) and oral mucosa (Figure 1B), as well as erythematous nodules on the bilateral palms. He presented to our institution for emergent care on postoperative day 12 following progression of the eruption to the inguinal region (Figure 2A), buttocks (Figure 2B), and abdominal region.

Due to concerns about a potential drug reaction, the IV vancomycin, oral ciprofloxacin, and oral allopurinol were discontinued on hospital admission. A dermatology consultation (D.A.D., J.A.Z., E.T.) was obtained, and a punch biopsy from a lesion on the left thigh revealed a neutrophil-rich subepidermal bulla with scattered eosinophils (Figure 3A). Direct immunofluorescence demonstrated linear IgA (Figure 3B) and C3 deposition along the dermoepidermal junction, which confirmed a diagnosis of drug-induced linear IgA bullous dermatosis (LABD). Vancomycin was suspected as the causative agent.¹ An initial vancomycin trough level drawn 48 hours after discontinuation (postoperative day 13) was still therapeutic at 14 µg/mL (reference range, 10–20 µg/mL in adults). This was substantially higher than the predicted value of 3 µg/mL based on renal excretion. Similarly, 5 additional serum levels obtained during the patient’s hospital course were greater than those predicted, and follow-up trough levels remained detectable at 1 µg/mL 2 weeks after discontinuation.

Oral prednisone 60 mg once daily and oral dapsone 25 mg once daily were initiated on hospital days 4 and 6 (postoperative days 15 and 17), respectively. A 6-week course of oral ciprofloxacin 750 mg twice daily and daptomycin 8 mg/kg once daily was initiated for bacterial coverage on hospital day 5 (postoperative day 16). Topical triamcinolone and an anesthetic mouthwash also were used to treat the mucosal involvement. The lesions stabilized on the third day of steroid therapy, and the patient was discharged 7 days after hospital admission (postoperative day 18). Dapsone was rapidly increased to 100 mg once daily over the next week for Pneumocystis jirovecii pneumonia prophylaxis. An increase in prednisone to 80 mg once daily was required 3 days after the patient was discharged due to worsening oral lesions. Five days after discharge, the patient was readmitted to the hospital for 3 days due to acute kidney injury (AKI) in which his baseline creatinine level tripled. The cause of renal impairment was unknown, resulting in empiric discontinuation of dapsone on postoperative day 27. Prophylaxis for P jirovecii pneumonia was replaced with once-monthly inhaled pentamidine. Prednisone was tapered 20 days after the original presentation (postoperative day 32) following gradual improvement of both the skin and oral lesions. At dermatology follow-up 2 weeks later, doxycycline 100 mg twice daily was added for residual inflammation of the left leg. A deep vein thrombosis was discovered in the left leg 10 days later, and 3 months of anticoagulation therapy was initiated with discontinuation of the doxycycline. The patient continued to have renal insufficiency several weeks after dapsone discontinuation and developed prominent peripheral motor neuropathy with bilateral thenar atrophy. He did not experience any skin eruptions or relapses in the weeks following prednisone cessation and underwent successful removal of the cement spacer with full left-knee reconstruction 4 months after his initial presentation to our institution. At 9-month dermatology follow-up, the LABD remained in remission.

Comment

Linear IgA bullous dermatosis is a well-documented autoimmune mucocutaneous disorder characterized by linear IgA deposits at the dermoepidermal junction. The development of autoantibodies to antigens within the basement membrane zone leads to both cellular and humoral immune responses that facilitate the subepidermal blistering rash in LABD.^2,3 Linear IgA bullous dermatosis affects all ages and races with a bimodal epidemiology. The adult form typically appears after 60 years of age, whereas the childhood form (chronic bullous disease of childhood) appears between 6 months and 6 years of age.³ Medications—particularly vancomycin—are responsible for a substantial portion of cases.^1-4 In one review, vancomycin was implicated in almost half (22/52 [42.3%]) of drug-related cases of LABD.⁴ Other associated medications include captopril, trimethoprim-sulfamethoxazole, phenytoin, and diclo-fenac.^3,4 Vancomycin-associated LABD has a substantially shorter time to onset of symptoms, with a mean of 8.6 days compared to 63.8 days for other causative agents.⁴Resolution of symptoms also occurs more quickly, with remission occurring in 66.7% (16/24) of cases at a mean time of 13 days compared to a 39.2% (11/28) resolution rate with a mean time of 18.9 days following discontinuation of other implicated medications.⁴ While idiopathic LABD involves the mucous membranes in up to 80% of cases, drug-induced LABD is less commonly associated with mucosal lesions. In an earlier systematic review from 1966 to 2002, 32% (7/22) of reported cases of vancomycin-induced LABD were reported to have mucosal involvement.^5,6 In 2012, one group found that most published cases of drug-induced LABD do not use standardized algorithms, such as the Naranjo algorithm, to definitively tie LABD onset to medication use.⁴ The Naranjo algorithm, devised in 1981, consists of 10 questions that determine the probability of adverse drug reactions.⁷ In our case, a Naranjo score of 5 suggested a probable adverse drug reaction due to vancomycin use; however, we cannot completely exclude ciprofloxacin in our case in light of a case report of LABD in the setting of IV vancomycin and ciprofloxacin use.⁸ In our patient, ciprofloxacin had a Naranjo score of 2, which suggested a possible adverse drug reaction. Allopurinol, which does not have any published association with LABD, also had a Naranjo score of 2 in our patient.

The initial treatment of drug-induced LABD is immediate discontinuation of the suspected agent(s) and supportive care.⁹ Although future avoidance of vancomycin is recommended in patients with a history of LABD, there are reported cases of successful rechallenges.^4,10 The early removal of our patient’s cement spacer was discouraged by both the orthopedics and infectious disease consultation services due to potential complications as well as the patient’s gradual improvement during his hospital course.

Dapsone is considered the standard systemic treatment for LABD. Sulfapyridine is an alternative to dapsone, or a combination of these 2 drugs may be used. Corticosteroids can be added to each of these regimens to achieve remission, as in our case.² Although dapsone was discontinued in the setting of the patient’s AKI, the vancomycin in the dual-eluting spacer was more likely the culprit. A review of 544 postoperative outcomes following the use of an antibiotic-impregnated cement spacer (AICS) during 2-stage arthroplasty displayed an 8- to 10-fold increase in the development of AKIs compared to the rate of AKIs following primary joint arthroplasty.¹⁰ While our patient’s AKI was not attributed to dapsone, his prominent peripheral motor neuropathy with resultant bilateral thenar atrophy was a rare complication of dapsone use. While dapsone-associated neuropathy has been reported in daily dosages of as low as 75 mg, it typically is seen in doses of at least 300 mg per day and in larger cumulative dosages.¹¹

Despite having a well-characterized vancomycin-induced LABD in the setting of known vancomycin exposure, our patient’s case was particularly challenging given the continued presence of the vancomycin-impregnated cement spacer (VICS) in the left knee, resulting in vancomycin levels at admission and during subsequent measurements over 2 weeks that were all several-fold higher than the renal clearance predicted.

Vancomycin-associated LABD does not appear to be dose dependent and has been reported at both subtherapeutic^1-3 and supratherapeutic levels,^5-9 whereas toxicity reactions are more common at supratherapeutic levels.⁹ The literature on AICS use suggests that drug elution occurs at relatively unpredictable rates based on a variety of factors, including the type of cement used and the initial antibiotic concentration.^12,13 Furthermore, the addition of tobramycin to VICSs has been found to increase the rate of vancomycin delivery through a phenomenon known as passive opportunism.¹⁴

As AICS devices allow for the delivery of higher concentrations of antibiotics to a localized area, systemic complications are considered rare but have been reported.¹³ Our report describes a rare case of LABD in the setting of a VICS. One clinical aspect of our case that supports the implication of VICS as the cause of the patient’s LABD is the concentration of bullae overlying the incision site on the left knee. A case of a desquamating rash in a patient with an implanted VICS has been documented in which the early lesions were localized to the surgical leg, as in our case.¹⁵ Unlike our case, there was a history of Stevens-Johnson syndrome following previous vancomycin exposure. A case of a gentamicin-impregnated cement spacer causing allergic dermatitis that was most prominent in the surgical leg also has been reported.¹⁶ An isomorphic phenomenon (Köbner phenomenon) has been suggested in the setting of vancomycin-induced LABD lesions that intensified at a site of adhesive tape application,¹⁷ but the Köbner phenomenon did not appear to be a major factor in our patient. The removal of the patient’s cement spacer was performed to prevent development of a chronic autoimmune response or autoreactivity state against the skin basement membrane zone structural antigen.

Case Report

A 77-year-old man was admitted to the general medicine service at our institution for treatment of a diffuse macular eruption and hemorrhagic bullae 12 days after undergoing left-knee revision arthroplasty during which a cement spacer impregnated with vancomycin and tobramycin was placed. At the time of the surgery, the patient also received intravenous (IV) vancomycin and oral ciprofloxacin, which were continued postoperatively until his hospital presentation. The patient was recovering well until postoperative day 7, when he developed painful swelling and erythema surrounding the surgical wound on the left knee. Concerned that his symptoms indicated a flare of gout, he restarted a former allopurinol prescription from an outside physician after 2 years of nonuse. The skin changes progressed distally on the left leg over the next 48 hours. By postoperative day 10, he had developed serosanguinous blisters on the left knee (Figure 1A) and oral mucosa (Figure 1B), as well as erythematous nodules on the bilateral palms. He presented to our institution for emergent care on postoperative day 12 following progression of the eruption to the inguinal region (Figure 2A), buttocks (Figure 2B), and abdominal region.

Due to concerns about a potential drug reaction, the IV vancomycin, oral ciprofloxacin, and oral allopurinol were discontinued on hospital admission. A dermatology consultation (D.A.D., J.A.Z., E.T.) was obtained, and a punch biopsy from a lesion on the left thigh revealed a neutrophil-rich subepidermal bulla with scattered eosinophils (Figure 3A). Direct immunofluorescence demonstrated linear IgA (Figure 3B) and C3 deposition along the dermoepidermal junction, which confirmed a diagnosis of drug-induced linear IgA bullous dermatosis (LABD). Vancomycin was suspected as the causative agent.¹ An initial vancomycin trough level drawn 48 hours after discontinuation (postoperative day 13) was still therapeutic at 14 µg/mL (reference range, 10–20 µg/mL in adults). This was substantially higher than the predicted value of 3 µg/mL based on renal excretion. Similarly, 5 additional serum levels obtained during the patient’s hospital course were greater than those predicted, and follow-up trough levels remained detectable at 1 µg/mL 2 weeks after discontinuation.

Oral prednisone 60 mg once daily and oral dapsone 25 mg once daily were initiated on hospital days 4 and 6 (postoperative days 15 and 17), respectively. A 6-week course of oral ciprofloxacin 750 mg twice daily and daptomycin 8 mg/kg once daily was initiated for bacterial coverage on hospital day 5 (postoperative day 16). Topical triamcinolone and an anesthetic mouthwash also were used to treat the mucosal involvement. The lesions stabilized on the third day of steroid therapy, and the patient was discharged 7 days after hospital admission (postoperative day 18). Dapsone was rapidly increased to 100 mg once daily over the next week for Pneumocystis jirovecii pneumonia prophylaxis. An increase in prednisone to 80 mg once daily was required 3 days after the patient was discharged due to worsening oral lesions. Five days after discharge, the patient was readmitted to the hospital for 3 days due to acute kidney injury (AKI) in which his baseline creatinine level tripled. The cause of renal impairment was unknown, resulting in empiric discontinuation of dapsone on postoperative day 27. Prophylaxis for P jirovecii pneumonia was replaced with once-monthly inhaled pentamidine. Prednisone was tapered 20 days after the original presentation (postoperative day 32) following gradual improvement of both the skin and oral lesions. At dermatology follow-up 2 weeks later, doxycycline 100 mg twice daily was added for residual inflammation of the left leg. A deep vein thrombosis was discovered in the left leg 10 days later, and 3 months of anticoagulation therapy was initiated with discontinuation of the doxycycline. The patient continued to have renal insufficiency several weeks after dapsone discontinuation and developed prominent peripheral motor neuropathy with bilateral thenar atrophy. He did not experience any skin eruptions or relapses in the weeks following prednisone cessation and underwent successful removal of the cement spacer with full left-knee reconstruction 4 months after his initial presentation to our institution. At 9-month dermatology follow-up, the LABD remained in remission.

Comment

Linear IgA bullous dermatosis is a well-documented autoimmune mucocutaneous disorder characterized by linear IgA deposits at the dermoepidermal junction. The development of autoantibodies to antigens within the basement membrane zone leads to both cellular and humoral immune responses that facilitate the subepidermal blistering rash in LABD.^2,3 Linear IgA bullous dermatosis affects all ages and races with a bimodal epidemiology. The adult form typically appears after 60 years of age, whereas the childhood form (chronic bullous disease of childhood) appears between 6 months and 6 years of age.³ Medications—particularly vancomycin—are responsible for a substantial portion of cases.^1-4 In one review, vancomycin was implicated in almost half (22/52 [42.3%]) of drug-related cases of LABD.⁴ Other associated medications include captopril, trimethoprim-sulfamethoxazole, phenytoin, and diclo-fenac.^3,4 Vancomycin-associated LABD has a substantially shorter time to onset of symptoms, with a mean of 8.6 days compared to 63.8 days for other causative agents.⁴Resolution of symptoms also occurs more quickly, with remission occurring in 66.7% (16/24) of cases at a mean time of 13 days compared to a 39.2% (11/28) resolution rate with a mean time of 18.9 days following discontinuation of other implicated medications.⁴ While idiopathic LABD involves the mucous membranes in up to 80% of cases, drug-induced LABD is less commonly associated with mucosal lesions. In an earlier systematic review from 1966 to 2002, 32% (7/22) of reported cases of vancomycin-induced LABD were reported to have mucosal involvement.^5,6 In 2012, one group found that most published cases of drug-induced LABD do not use standardized algorithms, such as the Naranjo algorithm, to definitively tie LABD onset to medication use.⁴ The Naranjo algorithm, devised in 1981, consists of 10 questions that determine the probability of adverse drug reactions.⁷ In our case, a Naranjo score of 5 suggested a probable adverse drug reaction due to vancomycin use; however, we cannot completely exclude ciprofloxacin in our case in light of a case report of LABD in the setting of IV vancomycin and ciprofloxacin use.⁸ In our patient, ciprofloxacin had a Naranjo score of 2, which suggested a possible adverse drug reaction. Allopurinol, which does not have any published association with LABD, also had a Naranjo score of 2 in our patient.

The initial treatment of drug-induced LABD is immediate discontinuation of the suspected agent(s) and supportive care.⁹ Although future avoidance of vancomycin is recommended in patients with a history of LABD, there are reported cases of successful rechallenges.^4,10 The early removal of our patient’s cement spacer was discouraged by both the orthopedics and infectious disease consultation services due to potential complications as well as the patient’s gradual improvement during his hospital course.

Dapsone is considered the standard systemic treatment for LABD. Sulfapyridine is an alternative to dapsone, or a combination of these 2 drugs may be used. Corticosteroids can be added to each of these regimens to achieve remission, as in our case.² Although dapsone was discontinued in the setting of the patient’s AKI, the vancomycin in the dual-eluting spacer was more likely the culprit. A review of 544 postoperative outcomes following the use of an antibiotic-impregnated cement spacer (AICS) during 2-stage arthroplasty displayed an 8- to 10-fold increase in the development of AKIs compared to the rate of AKIs following primary joint arthroplasty.¹⁰ While our patient’s AKI was not attributed to dapsone, his prominent peripheral motor neuropathy with resultant bilateral thenar atrophy was a rare complication of dapsone use. While dapsone-associated neuropathy has been reported in daily dosages of as low as 75 mg, it typically is seen in doses of at least 300 mg per day and in larger cumulative dosages.¹¹

Despite having a well-characterized vancomycin-induced LABD in the setting of known vancomycin exposure, our patient’s case was particularly challenging given the continued presence of the vancomycin-impregnated cement spacer (VICS) in the left knee, resulting in vancomycin levels at admission and during subsequent measurements over 2 weeks that were all several-fold higher than the renal clearance predicted.

Vancomycin-associated LABD does not appear to be dose dependent and has been reported at both subtherapeutic^1-3 and supratherapeutic levels,^5-9 whereas toxicity reactions are more common at supratherapeutic levels.⁹ The literature on AICS use suggests that drug elution occurs at relatively unpredictable rates based on a variety of factors, including the type of cement used and the initial antibiotic concentration.^12,13 Furthermore, the addition of tobramycin to VICSs has been found to increase the rate of vancomycin delivery through a phenomenon known as passive opportunism.¹⁴

As AICS devices allow for the delivery of higher concentrations of antibiotics to a localized area, systemic complications are considered rare but have been reported.¹³ Our report describes a rare case of LABD in the setting of a VICS. One clinical aspect of our case that supports the implication of VICS as the cause of the patient’s LABD is the concentration of bullae overlying the incision site on the left knee. A case of a desquamating rash in a patient with an implanted VICS has been documented in which the early lesions were localized to the surgical leg, as in our case.¹⁵ Unlike our case, there was a history of Stevens-Johnson syndrome following previous vancomycin exposure. A case of a gentamicin-impregnated cement spacer causing allergic dermatitis that was most prominent in the surgical leg also has been reported.¹⁶ An isomorphic phenomenon (Köbner phenomenon) has been suggested in the setting of vancomycin-induced LABD lesions that intensified at a site of adhesive tape application,¹⁷ but the Köbner phenomenon did not appear to be a major factor in our patient. The removal of the patient’s cement spacer was performed to prevent development of a chronic autoimmune response or autoreactivity state against the skin basement membrane zone structural antigen.

Case Report

A 77-year-old man was admitted to the general medicine service at our institution for treatment of a diffuse macular eruption and hemorrhagic bullae 12 days after undergoing left-knee revision arthroplasty during which a cement spacer impregnated with vancomycin and tobramycin was placed. At the time of the surgery, the patient also received intravenous (IV) vancomycin and oral ciprofloxacin, which were continued postoperatively until his hospital presentation. The patient was recovering well until postoperative day 7, when he developed painful swelling and erythema surrounding the surgical wound on the left knee. Concerned that his symptoms indicated a flare of gout, he restarted a former allopurinol prescription from an outside physician after 2 years of nonuse. The skin changes progressed distally on the left leg over the next 48 hours. By postoperative day 10, he had developed serosanguinous blisters on the left knee (Figure 1A) and oral mucosa (Figure 1B), as well as erythematous nodules on the bilateral palms. He presented to our institution for emergent care on postoperative day 12 following progression of the eruption to the inguinal region (Figure 2A), buttocks (Figure 2B), and abdominal region.

Due to concerns about a potential drug reaction, the IV vancomycin, oral ciprofloxacin, and oral allopurinol were discontinued on hospital admission. A dermatology consultation (D.A.D., J.A.Z., E.T.) was obtained, and a punch biopsy from a lesion on the left thigh revealed a neutrophil-rich subepidermal bulla with scattered eosinophils (Figure 3A). Direct immunofluorescence demonstrated linear IgA (Figure 3B) and C3 deposition along the dermoepidermal junction, which confirmed a diagnosis of drug-induced linear IgA bullous dermatosis (LABD). Vancomycin was suspected as the causative agent.¹ An initial vancomycin trough level drawn 48 hours after discontinuation (postoperative day 13) was still therapeutic at 14 µg/mL (reference range, 10–20 µg/mL in adults). This was substantially higher than the predicted value of 3 µg/mL based on renal excretion. Similarly, 5 additional serum levels obtained during the patient’s hospital course were greater than those predicted, and follow-up trough levels remained detectable at 1 µg/mL 2 weeks after discontinuation.

Oral prednisone 60 mg once daily and oral dapsone 25 mg once daily were initiated on hospital days 4 and 6 (postoperative days 15 and 17), respectively. A 6-week course of oral ciprofloxacin 750 mg twice daily and daptomycin 8 mg/kg once daily was initiated for bacterial coverage on hospital day 5 (postoperative day 16). Topical triamcinolone and an anesthetic mouthwash also were used to treat the mucosal involvement. The lesions stabilized on the third day of steroid therapy, and the patient was discharged 7 days after hospital admission (postoperative day 18). Dapsone was rapidly increased to 100 mg once daily over the next week for Pneumocystis jirovecii pneumonia prophylaxis. An increase in prednisone to 80 mg once daily was required 3 days after the patient was discharged due to worsening oral lesions. Five days after discharge, the patient was readmitted to the hospital for 3 days due to acute kidney injury (AKI) in which his baseline creatinine level tripled. The cause of renal impairment was unknown, resulting in empiric discontinuation of dapsone on postoperative day 27. Prophylaxis for P jirovecii pneumonia was replaced with once-monthly inhaled pentamidine. Prednisone was tapered 20 days after the original presentation (postoperative day 32) following gradual improvement of both the skin and oral lesions. At dermatology follow-up 2 weeks later, doxycycline 100 mg twice daily was added for residual inflammation of the left leg. A deep vein thrombosis was discovered in the left leg 10 days later, and 3 months of anticoagulation therapy was initiated with discontinuation of the doxycycline. The patient continued to have renal insufficiency several weeks after dapsone discontinuation and developed prominent peripheral motor neuropathy with bilateral thenar atrophy. He did not experience any skin eruptions or relapses in the weeks following prednisone cessation and underwent successful removal of the cement spacer with full left-knee reconstruction 4 months after his initial presentation to our institution. At 9-month dermatology follow-up, the LABD remained in remission.

Comment

Linear IgA bullous dermatosis is a well-documented autoimmune mucocutaneous disorder characterized by linear IgA deposits at the dermoepidermal junction. The development of autoantibodies to antigens within the basement membrane zone leads to both cellular and humoral immune responses that facilitate the subepidermal blistering rash in LABD.^2,3 Linear IgA bullous dermatosis affects all ages and races with a bimodal epidemiology. The adult form typically appears after 60 years of age, whereas the childhood form (chronic bullous disease of childhood) appears between 6 months and 6 years of age.³ Medications—particularly vancomycin—are responsible for a substantial portion of cases.^1-4 In one review, vancomycin was implicated in almost half (22/52 [42.3%]) of drug-related cases of LABD.⁴ Other associated medications include captopril, trimethoprim-sulfamethoxazole, phenytoin, and diclo-fenac.^3,4 Vancomycin-associated LABD has a substantially shorter time to onset of symptoms, with a mean of 8.6 days compared to 63.8 days for other causative agents.⁴Resolution of symptoms also occurs more quickly, with remission occurring in 66.7% (16/24) of cases at a mean time of 13 days compared to a 39.2% (11/28) resolution rate with a mean time of 18.9 days following discontinuation of other implicated medications.⁴ While idiopathic LABD involves the mucous membranes in up to 80% of cases, drug-induced LABD is less commonly associated with mucosal lesions. In an earlier systematic review from 1966 to 2002, 32% (7/22) of reported cases of vancomycin-induced LABD were reported to have mucosal involvement.^5,6 In 2012, one group found that most published cases of drug-induced LABD do not use standardized algorithms, such as the Naranjo algorithm, to definitively tie LABD onset to medication use.⁴ The Naranjo algorithm, devised in 1981, consists of 10 questions that determine the probability of adverse drug reactions.⁷ In our case, a Naranjo score of 5 suggested a probable adverse drug reaction due to vancomycin use; however, we cannot completely exclude ciprofloxacin in our case in light of a case report of LABD in the setting of IV vancomycin and ciprofloxacin use.⁸ In our patient, ciprofloxacin had a Naranjo score of 2, which suggested a possible adverse drug reaction. Allopurinol, which does not have any published association with LABD, also had a Naranjo score of 2 in our patient.

The initial treatment of drug-induced LABD is immediate discontinuation of the suspected agent(s) and supportive care.⁹ Although future avoidance of vancomycin is recommended in patients with a history of LABD, there are reported cases of successful rechallenges.^4,10 The early removal of our patient’s cement spacer was discouraged by both the orthopedics and infectious disease consultation services due to potential complications as well as the patient’s gradual improvement during his hospital course.

Dapsone is considered the standard systemic treatment for LABD. Sulfapyridine is an alternative to dapsone, or a combination of these 2 drugs may be used. Corticosteroids can be added to each of these regimens to achieve remission, as in our case.² Although dapsone was discontinued in the setting of the patient’s AKI, the vancomycin in the dual-eluting spacer was more likely the culprit. A review of 544 postoperative outcomes following the use of an antibiotic-impregnated cement spacer (AICS) during 2-stage arthroplasty displayed an 8- to 10-fold increase in the development of AKIs compared to the rate of AKIs following primary joint arthroplasty.¹⁰ While our patient’s AKI was not attributed to dapsone, his prominent peripheral motor neuropathy with resultant bilateral thenar atrophy was a rare complication of dapsone use. While dapsone-associated neuropathy has been reported in daily dosages of as low as 75 mg, it typically is seen in doses of at least 300 mg per day and in larger cumulative dosages.¹¹

Despite having a well-characterized vancomycin-induced LABD in the setting of known vancomycin exposure, our patient’s case was particularly challenging given the continued presence of the vancomycin-impregnated cement spacer (VICS) in the left knee, resulting in vancomycin levels at admission and during subsequent measurements over 2 weeks that were all several-fold higher than the renal clearance predicted.

Vancomycin-associated LABD does not appear to be dose dependent and has been reported at both subtherapeutic^1-3 and supratherapeutic levels,^5-9 whereas toxicity reactions are more common at supratherapeutic levels.⁹ The literature on AICS use suggests that drug elution occurs at relatively unpredictable rates based on a variety of factors, including the type of cement used and the initial antibiotic concentration.^12,13 Furthermore, the addition of tobramycin to VICSs has been found to increase the rate of vancomycin delivery through a phenomenon known as passive opportunism.¹⁴

As AICS devices allow for the delivery of higher concentrations of antibiotics to a localized area, systemic complications are considered rare but have been reported.¹³ Our report describes a rare case of LABD in the setting of a VICS. One clinical aspect of our case that supports the implication of VICS as the cause of the patient’s LABD is the concentration of bullae overlying the incision site on the left knee. A case of a desquamating rash in a patient with an implanted VICS has been documented in which the early lesions were localized to the surgical leg, as in our case.¹⁵ Unlike our case, there was a history of Stevens-Johnson syndrome following previous vancomycin exposure. A case of a gentamicin-impregnated cement spacer causing allergic dermatitis that was most prominent in the surgical leg also has been reported.¹⁶ An isomorphic phenomenon (Köbner phenomenon) has been suggested in the setting of vancomycin-induced LABD lesions that intensified at a site of adhesive tape application,¹⁷ but the Köbner phenomenon did not appear to be a major factor in our patient. The removal of the patient’s cement spacer was performed to prevent development of a chronic autoimmune response or autoreactivity state against the skin basement membrane zone structural antigen.

In today’s society there is a ubiquitous pressure to lose weight, reduce fat, and rejuvenate the skin that stems not only from images of idealized bodies in the media but also from our growing knowledge of the detrimental effects of obesity. Along with diet and exercise, it has become popular to use noninvasive devices to attain these goals by means of body contouring—the optimization of the definition, smoothness, and shape of the human physique.¹ In fact, body contouring currently is the fastest-growing area of cosmetic dermatology.²

Previously, body contouring primarily involved invasive procedures (eg, liposuction) that are associated with various adverse effects, financial costs, and lengthy downtime.³ More recently, a growing demand for safer and less painful procedures for adipose tissue reduction and skin tightening have led to the development of several novel modalities for noninvasive body contouring. Although the results achieved using these new technologies may be less dramatic than invasive techniques and are not immediate, they do not carry the risks and adverse effects that are associated with surgical procedures and therefore are increasingly requested by cosmetic patients.^4,5 New noninvasive techniques primarily target the physical properties of fat, resulting in an efflux of triglycerides from fat cells, causing either reduced size, necrosis, or apoptosis of adipocytes.^3,6 Of these modalities, cold-induced adipocyte apoptosis has been commercially available the longest and has been the most researched; however, other noninvasive body contouring techniques have been increasingly explored by researchers since the first reports of human adipose tissue explants exhibiting features of apoptosis after heat injury became available.^7,8

There currently are 4 leading modalities used for noninvasive body contouring: cryolipolysis, radiofrequency (RF), high-intensity focused ultrasound (HIFU), and laser therapy (Table). Although no procedure has yet been accepted as the gold standard, investigators are working to determine which technique is the most effective.⁹ In this article, we provide an overview of these techniques to help dermatologists choose appropriate modalities for their cosmetic patients.

Cryolipolysis

Cryolipolysis is unique in that it employs the principle that lipid-rich adipocytes are more susceptible to freezing than surrounding water-rich cells, allowing selective apoptosis while preserving the adjacent structures. As macrophages digest the apoptotic adipocytes, patients experience a decrease in subcutaneous fat volume over the subsequent 2 to 3 months.^10-13 Cryolipolysis has been gaining popularity since 2010, when it was first approved by the US Food and Drug Administration (FDA) for fat reduction in the flank areas; it was later approved for the abdomen in 2012, thighs in 2014, and submental area in 2015.¹⁴ Most recently, cryolipolysis was approved for fat reduction in the arms, back, and buttocks in 2016.

The most popular cryolipolysis device applies suction to the treatment area and vacuums the tissue between 2 cooling panels for 30 to 60 minutes.⁹ Clinical studies investigating the safety and efficacy of cryolipolysis have reported a high degree of patient satisfaction with the procedure and only minimal side effects.^4,6,15,16 Common complications of cryolipolysis include erythema, swelling, and sensitivity at the treatment site followed by a lesser incidence of pain, tingling, and bruising, all of which generally resolve within a few weeks of treatment.⁶ With the removal of adipocytes, there has been concern regarding elevations in blood lipid levels and liver enzymes; however, these laboratory values have been reported to remain within normal limits during and after cryolipolysis.^17,18 Of note, patients should be advised of the risk of paradoxical adipose hyperplasia, a rare side effect of cryolipolysis in which a large, demarcated, tender fat mass develops at the treatment site 2 to 3 months after treatment, with an estimated incidence of 1 in 20,000.¹⁹ However, the incidence of paradoxical adipose hyperplasia may be underestimated, as a single practice reported an incidence of 0.47% in 422 cryolipolysis treatments.²⁰ This complication has not been associated with any of the heat-induced fat reduction modalities.

Cryolipolysis has been found to be safe for all skin types with no reported pigmentary changes.¹⁶ It should not be performed in patients with cold-induced conditions (eg, cryoglobulinemia, cold urticaria) or in those with severe varicose veins or atopic dermatitis.^21,22 Patients benefitting most from this procedure are those who require only small or moderate amounts of adipose tissue and cellulite removal with separate fat bulges.^12,17 Interestingly, cryolipolysis also has been used off label to treat pseudogynecomastia in male patients.²³

Radiofrequency

Radiofrequency has become an important and frequently used modality in cosmetic dermatology.²⁴ This modality differs from cryolipolysis in that it relies on exploiting the difference in water content and impedance between tissues: the skin has low impedance, whereas fat tissue has high impedance. Radiofrequency induces thermal injury to targeted tissue layers, rather than the cold-induced damage seen in cryolipolysis, through devices that focus thermal energy on tissues with high impedance, inducing apoptosis of cells in the subcutaneous adipose tissue with minimal risk of damaging the epidermis, dermis, and muscle.^9,25 Ultimately, thermal exposure to 43°C to 45°C over several minutes results in a delayed adipocyte death response.⁴ In addition to adipocyte death, RF has been shown to cause denaturation of collagen fibrils, leading to subsequent remodeling, neocollagenesis, and skin tightening.²⁶

Radiofrequency devices can be broadly classified as monopolar or bipolar.^24,27 Bipolar devices generally require more frequent treatments, whereas monopolar devices tend to require fewer treatment sessions with superior circumference and fat reduction.²⁸

Overall, RF devices have a favorable side effect profile. The most common side effects are erythema and edema at the treatment site lasting less than 24 hours after the procedure.²⁵ The absence of complications such as abdominal discomfort, erythema, and burning during treatment have been reported,²⁷ with the exception of 1 case of hyperesthesia on the abdomen that lasted for 3 days after a treatment session.⁵ Although RF has beneficial effects on circumference reduction in the abdomen and thighs and can improve the appearance of cellulite, an increase in body weight may occur during treatment. When a localized area of fat such as the thigh is targeted for treatment but the remaining fat cells in the body are not affected, the remaining cells can continue to grow and expand; for instance, although fat cells destroyed with RF will not continue to expand, fat cells in untreated areas may continue to grow due to continued weight gain (eg, from excessive eating), leading to overall weight gain. Thus, patients must understand that weight gain is not an indication of treatment failure after RF or any other method of irreversible fat destruction.⁵

High-intensity Focused Ultrasound

High-intensity focused ultrasound recently was introduced as a new treatment modality for body contouring, specifically for skin tightening and rejuvenation.⁵ The mechanism of HIFU is similar to that of RF in that it also relies on heat to cause adipocyte apoptosis; however, it utilizes acoustic energy rather than electric energy. High-intensity focused ultrasound devices can deliver energy to the deep dermis, subdermal connective tissue, and fibromuscular layers in precise microcoagulation zones without damage to the epidermis. The focused energy induces a high temperature (>65°C) within 1 to 3 seconds, causing cell protein coagulation in the targeted area. In addition to its thermal effects, HIFU induces a mechanical effect that disrupts cell membranes immediately, which contributes to the coagulation necrosis process, further promoting necrosis and apoptosis. The effects of these devices can be visualized, as there always is a sharp demarcation between the targeted and untargeted tissue.²⁹ Additionally, microcoagulation is thought to cause gradual skin tightening through collagen contraction and remodeling.³⁰

High-intensity focused ultrasound first received FDA approval for eyebrow lifting and has been used safely and effectively to treat facial and neck skin in a variety of skin types as well as to improve the clinical appearance of the abdomen and thighs.³¹ This technique is best suited for patients with mild to moderate laxity of the skin or soft tissue who have a body mass index less than 30 kg/m² and are seeking mild body contouring.³² The ideal patient is young with normal wound healing, since the clinical response to treatment is partly dependent on new collagen synthesis.³³ Older patients with extensive photoaging or severe skin laxity are not good candidates for HIFU.

There are a variety of available HIFU devices,³⁴ which utilize special transducers that direct ultrasound energy to a small focal point in the subcutaneous tissues that harmlessly passes through the skin.³⁵ By using newly developed transducers with different energy outputs and focal depths, dermatologists can tailor HIFU treatment to meet the unique physical characteristics of each patient.³¹

Adverse effects of HIFU are limited to transient pain in most patients and occasional erythema and ecchymosis in some cases.³¹ In general, most adverse effects resolve spontaneously within 4 weeks and all by 12 weeks posttreatment. Studies also have reported hard subcutaneous nodules, discomfort, burning sensation, mild blisters, and one case of purpuric lesions, all at the treatment site.^36-39 There is no evidence that HIFU can cause abnormalities in serum lipids or liver function tests.

Lasers

Laser technology is a rapidly growing modality in noninvasive body contouring. A novel device recently emerged as the first and only FDA-cleared hyperthermic laser for fat reduction and noninvasive body contouring of the abdomen, flanks, back, inner and outer thighs, and submental area.^40,41 The device is a 1060-nm diode laser that uses thermal energy to destroy adipose tissue, leading to permanent reduction in stubborn fat without surgery or downtime through the use of a flat, nonsuction applicator that is designed for consistent, natural-looking results. The device includes a contact cooling system that helps to limit thermal discomfort and prevent damage to the surface of the skin during the procedure. Initial improvement can be seen as quickly as 6 weeks posttreatment, and optimal results usually occur in as few as 12 weeks. This device was found to have an excellent safety profile and was well tolerated among patients, with only mild pain reported.^42,43

Prior to the development of this new 1060-nm diode laser, the initial application of lasers for noninvasive body contouring involved low-level laser therapy (LLLT), also known as cold laser therapy.⁴⁰ One device has 5 rotating diode laser heads that work at a wavelength of 635 nm. Treatment sessions last up to 30 minutes, and 6 to 8 sessions are required to obtain optimal results. Low-level laser therapy is a unique modality that is not based on thermal tissue damage, but rather on producing transient microscopic pores in adipocytes that allow lipids to leak out, leading to fat reduction.³⁴ Because LLLT causes immediate emptying of targeted adipocytes, results are noticeable as soon as treatment is completed; however, there is no necrosis or apoptosis of adipocytes, so the recurrence of fat deposition is believed to be greater when compared to the other modalities. Because the results are temporary, long-term or permanent results should not be expected with LLLT. Depending on the patient’s goals, the temporary nature of the results can be either an advantage or disadvantage: some may prefer immediate results despite gradual diminishment over subsequent months, whereas others may prefer results that progressively increase over time and are more permanent, as seen with cryolipolysis, HIFU, and RF.³

Complications of LLLT generally are fewer and more mild than with all other body contouring procedures, with several studies reporting no adverse effects.^44-48 Others reported swelling or erythema at the treatment area, pain or tingling during treatment, and increased urination, all of which were temporary and resolved spontaneously.⁴⁹ Additionally, although the lipids released from treatment are cleared through the lymphatic system, LLLT has not been shown to increase serum lipid levels.⁵⁰

Conclusion

The field of noninvasive body contouring is undoubtedly growing and will likely continue to rise in popularity as the efficacy and safety of these treatments improve. Although the available technologies vary by mechanism and side effect profiles, several devices have been revealed to be safe and effective in reducing subcutaneous fat tissue and improving skin laxity.¹ However, additional studies are needed to evaluate these devices in a standardized manner, especially considering the high costs associated with treatment.³² Current studies investigating these devices vary in treatment protocol, treatment area, number and timing of follow-up sessions, and outcome measures, making it challenging to compare the results objectively.³ Dermatologists offering body contouring treatments need to be intimately familiar with the available devices and determine which treatment is appropriate for each patient in order to provide the highest quality care. Most importantly, patients and physicians must discuss individual goals when choosing a body-contouring method in order to maximize patient satisfaction.

In today’s society there is a ubiquitous pressure to lose weight, reduce fat, and rejuvenate the skin that stems not only from images of idealized bodies in the media but also from our growing knowledge of the detrimental effects of obesity. Along with diet and exercise, it has become popular to use noninvasive devices to attain these goals by means of body contouring—the optimization of the definition, smoothness, and shape of the human physique.¹ In fact, body contouring currently is the fastest-growing area of cosmetic dermatology.²

Previously, body contouring primarily involved invasive procedures (eg, liposuction) that are associated with various adverse effects, financial costs, and lengthy downtime.³ More recently, a growing demand for safer and less painful procedures for adipose tissue reduction and skin tightening have led to the development of several novel modalities for noninvasive body contouring. Although the results achieved using these new technologies may be less dramatic than invasive techniques and are not immediate, they do not carry the risks and adverse effects that are associated with surgical procedures and therefore are increasingly requested by cosmetic patients.^4,5 New noninvasive techniques primarily target the physical properties of fat, resulting in an efflux of triglycerides from fat cells, causing either reduced size, necrosis, or apoptosis of adipocytes.^3,6 Of these modalities, cold-induced adipocyte apoptosis has been commercially available the longest and has been the most researched; however, other noninvasive body contouring techniques have been increasingly explored by researchers since the first reports of human adipose tissue explants exhibiting features of apoptosis after heat injury became available.^7,8

There currently are 4 leading modalities used for noninvasive body contouring: cryolipolysis, radiofrequency (RF), high-intensity focused ultrasound (HIFU), and laser therapy (Table). Although no procedure has yet been accepted as the gold standard, investigators are working to determine which technique is the most effective.⁹ In this article, we provide an overview of these techniques to help dermatologists choose appropriate modalities for their cosmetic patients.

Cryolipolysis

Cryolipolysis is unique in that it employs the principle that lipid-rich adipocytes are more susceptible to freezing than surrounding water-rich cells, allowing selective apoptosis while preserving the adjacent structures. As macrophages digest the apoptotic adipocytes, patients experience a decrease in subcutaneous fat volume over the subsequent 2 to 3 months.^10-13 Cryolipolysis has been gaining popularity since 2010, when it was first approved by the US Food and Drug Administration (FDA) for fat reduction in the flank areas; it was later approved for the abdomen in 2012, thighs in 2014, and submental area in 2015.¹⁴ Most recently, cryolipolysis was approved for fat reduction in the arms, back, and buttocks in 2016.

The most popular cryolipolysis device applies suction to the treatment area and vacuums the tissue between 2 cooling panels for 30 to 60 minutes.⁹ Clinical studies investigating the safety and efficacy of cryolipolysis have reported a high degree of patient satisfaction with the procedure and only minimal side effects.^4,6,15,16 Common complications of cryolipolysis include erythema, swelling, and sensitivity at the treatment site followed by a lesser incidence of pain, tingling, and bruising, all of which generally resolve within a few weeks of treatment.⁶ With the removal of adipocytes, there has been concern regarding elevations in blood lipid levels and liver enzymes; however, these laboratory values have been reported to remain within normal limits during and after cryolipolysis.^17,18 Of note, patients should be advised of the risk of paradoxical adipose hyperplasia, a rare side effect of cryolipolysis in which a large, demarcated, tender fat mass develops at the treatment site 2 to 3 months after treatment, with an estimated incidence of 1 in 20,000.¹⁹ However, the incidence of paradoxical adipose hyperplasia may be underestimated, as a single practice reported an incidence of 0.47% in 422 cryolipolysis treatments.²⁰ This complication has not been associated with any of the heat-induced fat reduction modalities.

Cryolipolysis has been found to be safe for all skin types with no reported pigmentary changes.¹⁶ It should not be performed in patients with cold-induced conditions (eg, cryoglobulinemia, cold urticaria) or in those with severe varicose veins or atopic dermatitis.^21,22 Patients benefitting most from this procedure are those who require only small or moderate amounts of adipose tissue and cellulite removal with separate fat bulges.^12,17 Interestingly, cryolipolysis also has been used off label to treat pseudogynecomastia in male patients.²³

Radiofrequency

Radiofrequency has become an important and frequently used modality in cosmetic dermatology.²⁴ This modality differs from cryolipolysis in that it relies on exploiting the difference in water content and impedance between tissues: the skin has low impedance, whereas fat tissue has high impedance. Radiofrequency induces thermal injury to targeted tissue layers, rather than the cold-induced damage seen in cryolipolysis, through devices that focus thermal energy on tissues with high impedance, inducing apoptosis of cells in the subcutaneous adipose tissue with minimal risk of damaging the epidermis, dermis, and muscle.^9,25 Ultimately, thermal exposure to 43°C to 45°C over several minutes results in a delayed adipocyte death response.⁴ In addition to adipocyte death, RF has been shown to cause denaturation of collagen fibrils, leading to subsequent remodeling, neocollagenesis, and skin tightening.²⁶

Radiofrequency devices can be broadly classified as monopolar or bipolar.^24,27 Bipolar devices generally require more frequent treatments, whereas monopolar devices tend to require fewer treatment sessions with superior circumference and fat reduction.²⁸

Overall, RF devices have a favorable side effect profile. The most common side effects are erythema and edema at the treatment site lasting less than 24 hours after the procedure.²⁵ The absence of complications such as abdominal discomfort, erythema, and burning during treatment have been reported,²⁷ with the exception of 1 case of hyperesthesia on the abdomen that lasted for 3 days after a treatment session.⁵ Although RF has beneficial effects on circumference reduction in the abdomen and thighs and can improve the appearance of cellulite, an increase in body weight may occur during treatment. When a localized area of fat such as the thigh is targeted for treatment but the remaining fat cells in the body are not affected, the remaining cells can continue to grow and expand; for instance, although fat cells destroyed with RF will not continue to expand, fat cells in untreated areas may continue to grow due to continued weight gain (eg, from excessive eating), leading to overall weight gain. Thus, patients must understand that weight gain is not an indication of treatment failure after RF or any other method of irreversible fat destruction.⁵

High-intensity Focused Ultrasound

High-intensity focused ultrasound recently was introduced as a new treatment modality for body contouring, specifically for skin tightening and rejuvenation.⁵ The mechanism of HIFU is similar to that of RF in that it also relies on heat to cause adipocyte apoptosis; however, it utilizes acoustic energy rather than electric energy. High-intensity focused ultrasound devices can deliver energy to the deep dermis, subdermal connective tissue, and fibromuscular layers in precise microcoagulation zones without damage to the epidermis. The focused energy induces a high temperature (>65°C) within 1 to 3 seconds, causing cell protein coagulation in the targeted area. In addition to its thermal effects, HIFU induces a mechanical effect that disrupts cell membranes immediately, which contributes to the coagulation necrosis process, further promoting necrosis and apoptosis. The effects of these devices can be visualized, as there always is a sharp demarcation between the targeted and untargeted tissue.²⁹ Additionally, microcoagulation is thought to cause gradual skin tightening through collagen contraction and remodeling.³⁰

High-intensity focused ultrasound first received FDA approval for eyebrow lifting and has been used safely and effectively to treat facial and neck skin in a variety of skin types as well as to improve the clinical appearance of the abdomen and thighs.³¹ This technique is best suited for patients with mild to moderate laxity of the skin or soft tissue who have a body mass index less than 30 kg/m² and are seeking mild body contouring.³² The ideal patient is young with normal wound healing, since the clinical response to treatment is partly dependent on new collagen synthesis.³³ Older patients with extensive photoaging or severe skin laxity are not good candidates for HIFU.

There are a variety of available HIFU devices,³⁴ which utilize special transducers that direct ultrasound energy to a small focal point in the subcutaneous tissues that harmlessly passes through the skin.³⁵ By using newly developed transducers with different energy outputs and focal depths, dermatologists can tailor HIFU treatment to meet the unique physical characteristics of each patient.³¹

Adverse effects of HIFU are limited to transient pain in most patients and occasional erythema and ecchymosis in some cases.³¹ In general, most adverse effects resolve spontaneously within 4 weeks and all by 12 weeks posttreatment. Studies also have reported hard subcutaneous nodules, discomfort, burning sensation, mild blisters, and one case of purpuric lesions, all at the treatment site.^36-39 There is no evidence that HIFU can cause abnormalities in serum lipids or liver function tests.

Lasers

Laser technology is a rapidly growing modality in noninvasive body contouring. A novel device recently emerged as the first and only FDA-cleared hyperthermic laser for fat reduction and noninvasive body contouring of the abdomen, flanks, back, inner and outer thighs, and submental area.^40,41 The device is a 1060-nm diode laser that uses thermal energy to destroy adipose tissue, leading to permanent reduction in stubborn fat without surgery or downtime through the use of a flat, nonsuction applicator that is designed for consistent, natural-looking results. The device includes a contact cooling system that helps to limit thermal discomfort and prevent damage to the surface of the skin during the procedure. Initial improvement can be seen as quickly as 6 weeks posttreatment, and optimal results usually occur in as few as 12 weeks. This device was found to have an excellent safety profile and was well tolerated among patients, with only mild pain reported.^42,43

Prior to the development of this new 1060-nm diode laser, the initial application of lasers for noninvasive body contouring involved low-level laser therapy (LLLT), also known as cold laser therapy.⁴⁰ One device has 5 rotating diode laser heads that work at a wavelength of 635 nm. Treatment sessions last up to 30 minutes, and 6 to 8 sessions are required to obtain optimal results. Low-level laser therapy is a unique modality that is not based on thermal tissue damage, but rather on producing transient microscopic pores in adipocytes that allow lipids to leak out, leading to fat reduction.³⁴ Because LLLT causes immediate emptying of targeted adipocytes, results are noticeable as soon as treatment is completed; however, there is no necrosis or apoptosis of adipocytes, so the recurrence of fat deposition is believed to be greater when compared to the other modalities. Because the results are temporary, long-term or permanent results should not be expected with LLLT. Depending on the patient’s goals, the temporary nature of the results can be either an advantage or disadvantage: some may prefer immediate results despite gradual diminishment over subsequent months, whereas others may prefer results that progressively increase over time and are more permanent, as seen with cryolipolysis, HIFU, and RF.³

Complications of LLLT generally are fewer and more mild than with all other body contouring procedures, with several studies reporting no adverse effects.^44-48 Others reported swelling or erythema at the treatment area, pain or tingling during treatment, and increased urination, all of which were temporary and resolved spontaneously.⁴⁹ Additionally, although the lipids released from treatment are cleared through the lymphatic system, LLLT has not been shown to increase serum lipid levels.⁵⁰

Conclusion

The field of noninvasive body contouring is undoubtedly growing and will likely continue to rise in popularity as the efficacy and safety of these treatments improve. Although the available technologies vary by mechanism and side effect profiles, several devices have been revealed to be safe and effective in reducing subcutaneous fat tissue and improving skin laxity.¹ However, additional studies are needed to evaluate these devices in a standardized manner, especially considering the high costs associated with treatment.³² Current studies investigating these devices vary in treatment protocol, treatment area, number and timing of follow-up sessions, and outcome measures, making it challenging to compare the results objectively.³ Dermatologists offering body contouring treatments need to be intimately familiar with the available devices and determine which treatment is appropriate for each patient in order to provide the highest quality care. Most importantly, patients and physicians must discuss individual goals when choosing a body-contouring method in order to maximize patient satisfaction.

In today’s society there is a ubiquitous pressure to lose weight, reduce fat, and rejuvenate the skin that stems not only from images of idealized bodies in the media but also from our growing knowledge of the detrimental effects of obesity. Along with diet and exercise, it has become popular to use noninvasive devices to attain these goals by means of body contouring—the optimization of the definition, smoothness, and shape of the human physique.¹ In fact, body contouring currently is the fastest-growing area of cosmetic dermatology.²

Previously, body contouring primarily involved invasive procedures (eg, liposuction) that are associated with various adverse effects, financial costs, and lengthy downtime.³ More recently, a growing demand for safer and less painful procedures for adipose tissue reduction and skin tightening have led to the development of several novel modalities for noninvasive body contouring. Although the results achieved using these new technologies may be less dramatic than invasive techniques and are not immediate, they do not carry the risks and adverse effects that are associated with surgical procedures and therefore are increasingly requested by cosmetic patients.^4,5 New noninvasive techniques primarily target the physical properties of fat, resulting in an efflux of triglycerides from fat cells, causing either reduced size, necrosis, or apoptosis of adipocytes.^3,6 Of these modalities, cold-induced adipocyte apoptosis has been commercially available the longest and has been the most researched; however, other noninvasive body contouring techniques have been increasingly explored by researchers since the first reports of human adipose tissue explants exhibiting features of apoptosis after heat injury became available.^7,8

There currently are 4 leading modalities used for noninvasive body contouring: cryolipolysis, radiofrequency (RF), high-intensity focused ultrasound (HIFU), and laser therapy (Table). Although no procedure has yet been accepted as the gold standard, investigators are working to determine which technique is the most effective.⁹ In this article, we provide an overview of these techniques to help dermatologists choose appropriate modalities for their cosmetic patients.

Cryolipolysis

Cryolipolysis is unique in that it employs the principle that lipid-rich adipocytes are more susceptible to freezing than surrounding water-rich cells, allowing selective apoptosis while preserving the adjacent structures. As macrophages digest the apoptotic adipocytes, patients experience a decrease in subcutaneous fat volume over the subsequent 2 to 3 months.^10-13 Cryolipolysis has been gaining popularity since 2010, when it was first approved by the US Food and Drug Administration (FDA) for fat reduction in the flank areas; it was later approved for the abdomen in 2012, thighs in 2014, and submental area in 2015.¹⁴ Most recently, cryolipolysis was approved for fat reduction in the arms, back, and buttocks in 2016.

The most popular cryolipolysis device applies suction to the treatment area and vacuums the tissue between 2 cooling panels for 30 to 60 minutes.⁹ Clinical studies investigating the safety and efficacy of cryolipolysis have reported a high degree of patient satisfaction with the procedure and only minimal side effects.^4,6,15,16 Common complications of cryolipolysis include erythema, swelling, and sensitivity at the treatment site followed by a lesser incidence of pain, tingling, and bruising, all of which generally resolve within a few weeks of treatment.⁶ With the removal of adipocytes, there has been concern regarding elevations in blood lipid levels and liver enzymes; however, these laboratory values have been reported to remain within normal limits during and after cryolipolysis.^17,18 Of note, patients should be advised of the risk of paradoxical adipose hyperplasia, a rare side effect of cryolipolysis in which a large, demarcated, tender fat mass develops at the treatment site 2 to 3 months after treatment, with an estimated incidence of 1 in 20,000.¹⁹ However, the incidence of paradoxical adipose hyperplasia may be underestimated, as a single practice reported an incidence of 0.47% in 422 cryolipolysis treatments.²⁰ This complication has not been associated with any of the heat-induced fat reduction modalities.

Cryolipolysis has been found to be safe for all skin types with no reported pigmentary changes.¹⁶ It should not be performed in patients with cold-induced conditions (eg, cryoglobulinemia, cold urticaria) or in those with severe varicose veins or atopic dermatitis.^21,22 Patients benefitting most from this procedure are those who require only small or moderate amounts of adipose tissue and cellulite removal with separate fat bulges.^12,17 Interestingly, cryolipolysis also has been used off label to treat pseudogynecomastia in male patients.²³

Radiofrequency

Radiofrequency has become an important and frequently used modality in cosmetic dermatology.²⁴ This modality differs from cryolipolysis in that it relies on exploiting the difference in water content and impedance between tissues: the skin has low impedance, whereas fat tissue has high impedance. Radiofrequency induces thermal injury to targeted tissue layers, rather than the cold-induced damage seen in cryolipolysis, through devices that focus thermal energy on tissues with high impedance, inducing apoptosis of cells in the subcutaneous adipose tissue with minimal risk of damaging the epidermis, dermis, and muscle.^9,25 Ultimately, thermal exposure to 43°C to 45°C over several minutes results in a delayed adipocyte death response.⁴ In addition to adipocyte death, RF has been shown to cause denaturation of collagen fibrils, leading to subsequent remodeling, neocollagenesis, and skin tightening.²⁶

Radiofrequency devices can be broadly classified as monopolar or bipolar.^24,27 Bipolar devices generally require more frequent treatments, whereas monopolar devices tend to require fewer treatment sessions with superior circumference and fat reduction.²⁸

Overall, RF devices have a favorable side effect profile. The most common side effects are erythema and edema at the treatment site lasting less than 24 hours after the procedure.²⁵ The absence of complications such as abdominal discomfort, erythema, and burning during treatment have been reported,²⁷ with the exception of 1 case of hyperesthesia on the abdomen that lasted for 3 days after a treatment session.⁵ Although RF has beneficial effects on circumference reduction in the abdomen and thighs and can improve the appearance of cellulite, an increase in body weight may occur during treatment. When a localized area of fat such as the thigh is targeted for treatment but the remaining fat cells in the body are not affected, the remaining cells can continue to grow and expand; for instance, although fat cells destroyed with RF will not continue to expand, fat cells in untreated areas may continue to grow due to continued weight gain (eg, from excessive eating), leading to overall weight gain. Thus, patients must understand that weight gain is not an indication of treatment failure after RF or any other method of irreversible fat destruction.⁵

High-intensity Focused Ultrasound

High-intensity focused ultrasound recently was introduced as a new treatment modality for body contouring, specifically for skin tightening and rejuvenation.⁵ The mechanism of HIFU is similar to that of RF in that it also relies on heat to cause adipocyte apoptosis; however, it utilizes acoustic energy rather than electric energy. High-intensity focused ultrasound devices can deliver energy to the deep dermis, subdermal connective tissue, and fibromuscular layers in precise microcoagulation zones without damage to the epidermis. The focused energy induces a high temperature (>65°C) within 1 to 3 seconds, causing cell protein coagulation in the targeted area. In addition to its thermal effects, HIFU induces a mechanical effect that disrupts cell membranes immediately, which contributes to the coagulation necrosis process, further promoting necrosis and apoptosis. The effects of these devices can be visualized, as there always is a sharp demarcation between the targeted and untargeted tissue.²⁹ Additionally, microcoagulation is thought to cause gradual skin tightening through collagen contraction and remodeling.³⁰

High-intensity focused ultrasound first received FDA approval for eyebrow lifting and has been used safely and effectively to treat facial and neck skin in a variety of skin types as well as to improve the clinical appearance of the abdomen and thighs.³¹ This technique is best suited for patients with mild to moderate laxity of the skin or soft tissue who have a body mass index less than 30 kg/m² and are seeking mild body contouring.³² The ideal patient is young with normal wound healing, since the clinical response to treatment is partly dependent on new collagen synthesis.³³ Older patients with extensive photoaging or severe skin laxity are not good candidates for HIFU.

There are a variety of available HIFU devices,³⁴ which utilize special transducers that direct ultrasound energy to a small focal point in the subcutaneous tissues that harmlessly passes through the skin.³⁵ By using newly developed transducers with different energy outputs and focal depths, dermatologists can tailor HIFU treatment to meet the unique physical characteristics of each patient.³¹

Adverse effects of HIFU are limited to transient pain in most patients and occasional erythema and ecchymosis in some cases.³¹ In general, most adverse effects resolve spontaneously within 4 weeks and all by 12 weeks posttreatment. Studies also have reported hard subcutaneous nodules, discomfort, burning sensation, mild blisters, and one case of purpuric lesions, all at the treatment site.^36-39 There is no evidence that HIFU can cause abnormalities in serum lipids or liver function tests.

Lasers

Laser technology is a rapidly growing modality in noninvasive body contouring. A novel device recently emerged as the first and only FDA-cleared hyperthermic laser for fat reduction and noninvasive body contouring of the abdomen, flanks, back, inner and outer thighs, and submental area.^40,41 The device is a 1060-nm diode laser that uses thermal energy to destroy adipose tissue, leading to permanent reduction in stubborn fat without surgery or downtime through the use of a flat, nonsuction applicator that is designed for consistent, natural-looking results. The device includes a contact cooling system that helps to limit thermal discomfort and prevent damage to the surface of the skin during the procedure. Initial improvement can be seen as quickly as 6 weeks posttreatment, and optimal results usually occur in as few as 12 weeks. This device was found to have an excellent safety profile and was well tolerated among patients, with only mild pain reported.^42,43

Prior to the development of this new 1060-nm diode laser, the initial application of lasers for noninvasive body contouring involved low-level laser therapy (LLLT), also known as cold laser therapy.⁴⁰ One device has 5 rotating diode laser heads that work at a wavelength of 635 nm. Treatment sessions last up to 30 minutes, and 6 to 8 sessions are required to obtain optimal results. Low-level laser therapy is a unique modality that is not based on thermal tissue damage, but rather on producing transient microscopic pores in adipocytes that allow lipids to leak out, leading to fat reduction.³⁴ Because LLLT causes immediate emptying of targeted adipocytes, results are noticeable as soon as treatment is completed; however, there is no necrosis or apoptosis of adipocytes, so the recurrence of fat deposition is believed to be greater when compared to the other modalities. Because the results are temporary, long-term or permanent results should not be expected with LLLT. Depending on the patient’s goals, the temporary nature of the results can be either an advantage or disadvantage: some may prefer immediate results despite gradual diminishment over subsequent months, whereas others may prefer results that progressively increase over time and are more permanent, as seen with cryolipolysis, HIFU, and RF.³

Complications of LLLT generally are fewer and more mild than with all other body contouring procedures, with several studies reporting no adverse effects.^44-48 Others reported swelling or erythema at the treatment area, pain or tingling during treatment, and increased urination, all of which were temporary and resolved spontaneously.⁴⁹ Additionally, although the lipids released from treatment are cleared through the lymphatic system, LLLT has not been shown to increase serum lipid levels.⁵⁰

Conclusion

The field of noninvasive body contouring is undoubtedly growing and will likely continue to rise in popularity as the efficacy and safety of these treatments improve. Although the available technologies vary by mechanism and side effect profiles, several devices have been revealed to be safe and effective in reducing subcutaneous fat tissue and improving skin laxity.¹ However, additional studies are needed to evaluate these devices in a standardized manner, especially considering the high costs associated with treatment.³² Current studies investigating these devices vary in treatment protocol, treatment area, number and timing of follow-up sessions, and outcome measures, making it challenging to compare the results objectively.³ Dermatologists offering body contouring treatments need to be intimately familiar with the available devices and determine which treatment is appropriate for each patient in order to provide the highest quality care. Most importantly, patients and physicians must discuss individual goals when choosing a body-contouring method in order to maximize patient satisfaction.