Case Reports

THE CASE

A 21-year-old G3P2 mother gave birth to an African American girl via vaginal delivery. Labor had been induced due to gestational hypertension at term. She’d also had a stillborn at term at the age of 16 followed by a second live term birth 3 years ago. During this most recent pregnancy, she’d received adequate prenatal care and had been treated for chlamydia with a single dose of oral azithromycin 1 g.

The newborn had an Apgar score of 9 out of 9 and weighed 6.7 pounds at birth. During a physical examination in the nursery, the infant was found to have large areas of smooth depigmentation on her forehead, right forearm, lower abdomen, and left thigh, with surrounding areas of thickened skin that had mild scaling and hyperpigmentation (FIGURE). The depigmented areas involved approximately 15% of the newborn’s body. The father and paternal grandmother, who were present at the time of delivery, also had depigmented areas of their skin.

The newborn’s tongue was pink and her mucus membranes were moist. No macules or patches were noted on either the oral or vaginal mucosa. Cardiac, pulmonary, and ocular examinations (including evaluation of the retina by ophthalmoscopy) were normal. There was no nystagmus or strabismus. The newborn’s extremities were normal, symmetric, and moveable, and she was easily consoled.

COURTESY OF METRO HEALTH MEDICAL CENTER

THE DIAGNOSIS

We diagnosed the newborn with piebaldism based on her appearance. Piebaldism consists of hypopigmented/depigmented areas and is a clinical diagnosis; no testing is required.

Concerned about the areas of hyperpigmentation, we decided to get a dermatologist’s opinion. The dermatology team briefly considered the diagnosis of a large melanocytic nevus with sparing of some areas, but a skin biopsy of a hyperpigmented area on the left leg came back with a normal number of melanocytes.

DISCUSSION

Piebaldism is a rare autosomal dominant disorder characterized by the congenital absence of melanocytes in affected areas of the skin and hair due to mutations of the c-kit gene. The c-kit gene affects the differentiation and migration of melanoblasts from the neural crest during embryonic life.¹ The incidence of piebaldism is estimated to be less than one in 20,000.² Both males and females are equally affected, and no race is spared.^2,3

Affected individuals present with a white forelock and relatively stable, persistent depigmentation of skin with a characteristic distribution from birth.³ A white forelock arising from a triangular, elongated, or diamond-shaped midline or depigmented macule on the forehead may be the only manifestation in 80% to 90% of cases.³ The characteristic distribution of depigmented macules includes a central macule on the forehead, the anterior abdomen extending to the chest, the lateral trunk sparing the dorsal spine, and the mid-arms and legs sparing the hands and feet.²

Depigmented macules are rectangular, rhomboid, or irregular in shape and usually have a symmetrical distribution. Typically, islands of hyperpigmentation are present within and at the border of depigmented areas.⁴ Piebaldism is associated in rare instances with neurofibromatosis type 1, Hirschsprung’s disease, hearing loss, and Waardenburg syndrome.⁴

Histologically, melanocytes are absent or considerably reduced in the depigmented areas and are normal in number in the hyperpigmented areas.⁵

The differential diagnosis of piebaldism includes mosaicism, albinism, and vitiligo.

Cutaneous mosaicism stems from a gene mutation that occurs during embryogenesis and the lesions are distributed along certain patterns and forms. A chromosomal analysis of our patient showed a normal female karyotype that excluded mosaicism.

Albinism is a genetically inherited disorder characterized by partial or complete absence of melanin production in the skin, hair, and eyes.⁶ Eye and fundus examinations were normal in our patient, which excluded albinism.

Vitiligo is rarely present at birth but is usually acquired later in life. It results from an immune-mediated destruction of melanocytes and is not genetically inherited, although familial incidence has been reported.⁷

There are no effective therapies

A combination of dermabrasion and grafting of pigmented skin into depigmented areas, with or without phototherapy, has been used in select patients, although no solid data are available on its effectiveness.³ The lack of effective and safe therapies can make treatment challenging. Piebaldism is usually not medically harmful, but the emotional and psychological effects on the family and the patient as they grow up can be devastating. Therefore, supportive counseling is recommended.

Our patient. Supportive counseling and a follow-up appointment with a dermatologist was planned for our patient and her family.

The clinical diagnosis of piebaldism is straightforward based on the presence of a white forelock in the frontal region, the appearance of depigmented macules since birth that stay relatively stable, and the presence of a similar pattern of depigmented macules in other family members. Histologic or genetic testing is not necessary to establish the diagnosis. Rarely, cases of piebaldism are associated with hearing loss, necessitating a hearing assessment and an audiology exam. Unfortunately, there are no effective treatments for piebaldism.

THE CASE

A 21-year-old G3P2 mother gave birth to an African American girl via vaginal delivery. Labor had been induced due to gestational hypertension at term. She’d also had a stillborn at term at the age of 16 followed by a second live term birth 3 years ago. During this most recent pregnancy, she’d received adequate prenatal care and had been treated for chlamydia with a single dose of oral azithromycin 1 g.

The newborn had an Apgar score of 9 out of 9 and weighed 6.7 pounds at birth. During a physical examination in the nursery, the infant was found to have large areas of smooth depigmentation on her forehead, right forearm, lower abdomen, and left thigh, with surrounding areas of thickened skin that had mild scaling and hyperpigmentation (FIGURE). The depigmented areas involved approximately 15% of the newborn’s body. The father and paternal grandmother, who were present at the time of delivery, also had depigmented areas of their skin.

The newborn’s tongue was pink and her mucus membranes were moist. No macules or patches were noted on either the oral or vaginal mucosa. Cardiac, pulmonary, and ocular examinations (including evaluation of the retina by ophthalmoscopy) were normal. There was no nystagmus or strabismus. The newborn’s extremities were normal, symmetric, and moveable, and she was easily consoled.

COURTESY OF METRO HEALTH MEDICAL CENTER

THE DIAGNOSIS

We diagnosed the newborn with piebaldism based on her appearance. Piebaldism consists of hypopigmented/depigmented areas and is a clinical diagnosis; no testing is required.

Concerned about the areas of hyperpigmentation, we decided to get a dermatologist’s opinion. The dermatology team briefly considered the diagnosis of a large melanocytic nevus with sparing of some areas, but a skin biopsy of a hyperpigmented area on the left leg came back with a normal number of melanocytes.

DISCUSSION

Piebaldism is a rare autosomal dominant disorder characterized by the congenital absence of melanocytes in affected areas of the skin and hair due to mutations of the c-kit gene. The c-kit gene affects the differentiation and migration of melanoblasts from the neural crest during embryonic life.¹ The incidence of piebaldism is estimated to be less than one in 20,000.² Both males and females are equally affected, and no race is spared.^2,3

Affected individuals present with a white forelock and relatively stable, persistent depigmentation of skin with a characteristic distribution from birth.³ A white forelock arising from a triangular, elongated, or diamond-shaped midline or depigmented macule on the forehead may be the only manifestation in 80% to 90% of cases.³ The characteristic distribution of depigmented macules includes a central macule on the forehead, the anterior abdomen extending to the chest, the lateral trunk sparing the dorsal spine, and the mid-arms and legs sparing the hands and feet.²

Depigmented macules are rectangular, rhomboid, or irregular in shape and usually have a symmetrical distribution. Typically, islands of hyperpigmentation are present within and at the border of depigmented areas.⁴ Piebaldism is associated in rare instances with neurofibromatosis type 1, Hirschsprung’s disease, hearing loss, and Waardenburg syndrome.⁴

Histologically, melanocytes are absent or considerably reduced in the depigmented areas and are normal in number in the hyperpigmented areas.⁵

The differential diagnosis of piebaldism includes mosaicism, albinism, and vitiligo.

Cutaneous mosaicism stems from a gene mutation that occurs during embryogenesis and the lesions are distributed along certain patterns and forms. A chromosomal analysis of our patient showed a normal female karyotype that excluded mosaicism.

Albinism is a genetically inherited disorder characterized by partial or complete absence of melanin production in the skin, hair, and eyes.⁶ Eye and fundus examinations were normal in our patient, which excluded albinism.

Vitiligo is rarely present at birth but is usually acquired later in life. It results from an immune-mediated destruction of melanocytes and is not genetically inherited, although familial incidence has been reported.⁷

There are no effective therapies

A combination of dermabrasion and grafting of pigmented skin into depigmented areas, with or without phototherapy, has been used in select patients, although no solid data are available on its effectiveness.³ The lack of effective and safe therapies can make treatment challenging. Piebaldism is usually not medically harmful, but the emotional and psychological effects on the family and the patient as they grow up can be devastating. Therefore, supportive counseling is recommended.

Our patient. Supportive counseling and a follow-up appointment with a dermatologist was planned for our patient and her family.

The clinical diagnosis of piebaldism is straightforward based on the presence of a white forelock in the frontal region, the appearance of depigmented macules since birth that stay relatively stable, and the presence of a similar pattern of depigmented macules in other family members. Histologic or genetic testing is not necessary to establish the diagnosis. Rarely, cases of piebaldism are associated with hearing loss, necessitating a hearing assessment and an audiology exam. Unfortunately, there are no effective treatments for piebaldism.

THE CASE

A 21-year-old G3P2 mother gave birth to an African American girl via vaginal delivery. Labor had been induced due to gestational hypertension at term. She’d also had a stillborn at term at the age of 16 followed by a second live term birth 3 years ago. During this most recent pregnancy, she’d received adequate prenatal care and had been treated for chlamydia with a single dose of oral azithromycin 1 g.

The newborn had an Apgar score of 9 out of 9 and weighed 6.7 pounds at birth. During a physical examination in the nursery, the infant was found to have large areas of smooth depigmentation on her forehead, right forearm, lower abdomen, and left thigh, with surrounding areas of thickened skin that had mild scaling and hyperpigmentation (FIGURE). The depigmented areas involved approximately 15% of the newborn’s body. The father and paternal grandmother, who were present at the time of delivery, also had depigmented areas of their skin.

The newborn’s tongue was pink and her mucus membranes were moist. No macules or patches were noted on either the oral or vaginal mucosa. Cardiac, pulmonary, and ocular examinations (including evaluation of the retina by ophthalmoscopy) were normal. There was no nystagmus or strabismus. The newborn’s extremities were normal, symmetric, and moveable, and she was easily consoled.

COURTESY OF METRO HEALTH MEDICAL CENTER

THE DIAGNOSIS

We diagnosed the newborn with piebaldism based on her appearance. Piebaldism consists of hypopigmented/depigmented areas and is a clinical diagnosis; no testing is required.

Concerned about the areas of hyperpigmentation, we decided to get a dermatologist’s opinion. The dermatology team briefly considered the diagnosis of a large melanocytic nevus with sparing of some areas, but a skin biopsy of a hyperpigmented area on the left leg came back with a normal number of melanocytes.

DISCUSSION

Piebaldism is a rare autosomal dominant disorder characterized by the congenital absence of melanocytes in affected areas of the skin and hair due to mutations of the c-kit gene. The c-kit gene affects the differentiation and migration of melanoblasts from the neural crest during embryonic life.¹ The incidence of piebaldism is estimated to be less than one in 20,000.² Both males and females are equally affected, and no race is spared.^2,3

Affected individuals present with a white forelock and relatively stable, persistent depigmentation of skin with a characteristic distribution from birth.³ A white forelock arising from a triangular, elongated, or diamond-shaped midline or depigmented macule on the forehead may be the only manifestation in 80% to 90% of cases.³ The characteristic distribution of depigmented macules includes a central macule on the forehead, the anterior abdomen extending to the chest, the lateral trunk sparing the dorsal spine, and the mid-arms and legs sparing the hands and feet.²

Depigmented macules are rectangular, rhomboid, or irregular in shape and usually have a symmetrical distribution. Typically, islands of hyperpigmentation are present within and at the border of depigmented areas.⁴ Piebaldism is associated in rare instances with neurofibromatosis type 1, Hirschsprung’s disease, hearing loss, and Waardenburg syndrome.⁴

Histologically, melanocytes are absent or considerably reduced in the depigmented areas and are normal in number in the hyperpigmented areas.⁵

The differential diagnosis of piebaldism includes mosaicism, albinism, and vitiligo.

Cutaneous mosaicism stems from a gene mutation that occurs during embryogenesis and the lesions are distributed along certain patterns and forms. A chromosomal analysis of our patient showed a normal female karyotype that excluded mosaicism.

Albinism is a genetically inherited disorder characterized by partial or complete absence of melanin production in the skin, hair, and eyes.⁶ Eye and fundus examinations were normal in our patient, which excluded albinism.

Vitiligo is rarely present at birth but is usually acquired later in life. It results from an immune-mediated destruction of melanocytes and is not genetically inherited, although familial incidence has been reported.⁷

There are no effective therapies

A combination of dermabrasion and grafting of pigmented skin into depigmented areas, with or without phototherapy, has been used in select patients, although no solid data are available on its effectiveness.³ The lack of effective and safe therapies can make treatment challenging. Piebaldism is usually not medically harmful, but the emotional and psychological effects on the family and the patient as they grow up can be devastating. Therefore, supportive counseling is recommended.

Our patient. Supportive counseling and a follow-up appointment with a dermatologist was planned for our patient and her family.

The clinical diagnosis of piebaldism is straightforward based on the presence of a white forelock in the frontal region, the appearance of depigmented macules since birth that stay relatively stable, and the presence of a similar pattern of depigmented macules in other family members. Histologic or genetic testing is not necessary to establish the diagnosis. Rarely, cases of piebaldism are associated with hearing loss, necessitating a hearing assessment and an audiology exam. Unfortunately, there are no effective treatments for piebaldism.

Case Report

A 24-year-old man was referred to the dermatology department for evaluation of pustules, atrophic scars, and alopecia on the scalp of 6 years’ duration. Six years prior, erythema, scaling, and follicular keratotic papules had appeared on the superciliary arches, and he started to lose hair from the eyebrows. Three months later, he developed mildly pruritic and painful scaling and pustules on the scalp. These lesions resolved with atrophic scarring accompanied by alopecia. One year later, follicular keratotic papules developed on the cheeks, chest, abdomen, back, lateral upper arms, thighs, and axillae. Two years later, direct microscopy of the lesions on the scalp and fungal culture were negative. After 2 weeks of treatment with roxithromycin (0.15 g twice daily), the scalp pustules dried out and resolved; however, they recurred when the patient stopped taking the medication. Six months later, he was started on isotretinoin treatment (10 mg once daily) for half a year, but no improvement was seen. His parents were nonconsanguineous, and no other family members were affected.

Dermatologic examination revealed large areas of atrophic scarring and alopecia on the scalp. Only a few solitary hairs remained on the top of the head, with the follicles surrounded by keratotic papules, pustules, and black scabs. There was sparse hair on the forehead and temples and scattered hair clusters in the occipital region near the hairline. These follicles also were associated with keratotic papules (Figure 1A). Erythema, scales, and follicular keratotic papules of the superciliary arches with sparse eyebrows and axillary hairs were noted. Follicular keratotic papules also were observed on the cheeks, axillae, chest, abdomen, back, lateral upper arms, and thighs. Dental examination revealed a large space between the upper anterior teeth and the lower anterior teeth. The upper anterior teeth were anteverted, there was congenital absence of right lower central incisors, and the anterior teeth were in deep overbite and overjet (Figure 1B). There was gingival atrophy and calculus dentalis in the upper and lower teeth. He had a fissured tongue with atrophic filiform papillae (Figure 1C).

Comment

Folliculitis spinulosa decalvans, along with keratosis follicularis spinulosa decalvans (KFSD), keratosis pilaris atrophicans faciei, and atrophoderma vermiculatum, belongs to a group of diseases that includes keratosis pilaris atrophicans. In 1994, Oranje et al¹ suggested the term folliculitis spinulosa decalvans, with signs including persistent pustules, characteristic keratotic papules, and scarring alopecia of the scalp, which may be exacerbated at puberty. Staphylococcus aureus was isolated from the pustules in one study²; however, in another study, repeated cultures were negative.³ Although the main inheritance pattern of KFSD is X-linked, autosomal-dominant inheritance is more common in FSD. Furthermore, there are certain differences in the clinical manifestations of these 2 conditions. Therefore, it remains controversial if FSD is an independent disease or merely a subtype of KFSD.

Our patient’s symptoms manifested after puberty, primarily pustules as well as atrophic and scarring alopecia of the scalp and follicular keratotic papules on the head, face, trunk, lateral upper arms, and thighs. Pathologic examination showed massive infiltration of plasma cells, neutrophils, and multinucleated giant cells around the hair follicles. The clinical and histopathologic findings met the diagnostic criteria for FSD.

Folliculitis spinulosa decalvans is a rare clinical condition with few cases reported.^3-5 In addition to the aforementioned characteristic clinical manifestations, our patient also had dental anomalies, a fissured tongue, and atrophy of the tongue papillae, which are not known to be associated with FSD. Dental anomalies are characteristic of patients with Down syndrome, ectodermal dysplasia, Papillon-Lefèvre syndrome, and other conditions.⁶ Fissured tongue is a normal variant that occurs in 5% to 11% of individuals. It also is a classic but nonspecific feature of Melkersson-Rosenthal syndrome and may occur in psoriasis, Down syndrome, acromegaly, and Sjögren syndrome.⁷ Atrophy of the tongue papillae is associated with anemia, pellagra, Sjögren syndrome, candidiasis, and other conditions.⁸ Because there are no known reports of associations between FSD and any of these oral manifestations, it is possible that they were unrelated to FSD in our patient.

Folliculitis spinulosa decalvans usually is recurrent and there is no consistently effective treatment for it. Kunte et al⁴ reported that dapsone (100 mg/d) led to resolution of scalp inflammation and pustules within 1 month. Romine et al² reported that a 3-week course of dichloroxacillin (250 mg 4 times daily) induced disappearance of pustules around the hair follicles. However, Hallai et al⁵ reported a patient who was resistant to isotretinoin treatment. In our case, after 1 month of treatment with clarithromycin, metronidazole, viaminate, and fusidic acid cream, the pustules had resolved and the black scabs had fallen off, leaving atrophic scars. The long-term efficacy of this regimen is still under observation.

Conclusion

We report a case of FSD with dental anomalies, a fissured tongue, and atrophy of tongue papillae, none of which have previously been reported in association with FSD. We, therefore, believe that our patient’s oral manifestations are unrelated to FSD.

Case Report

A 24-year-old man was referred to the dermatology department for evaluation of pustules, atrophic scars, and alopecia on the scalp of 6 years’ duration. Six years prior, erythema, scaling, and follicular keratotic papules had appeared on the superciliary arches, and he started to lose hair from the eyebrows. Three months later, he developed mildly pruritic and painful scaling and pustules on the scalp. These lesions resolved with atrophic scarring accompanied by alopecia. One year later, follicular keratotic papules developed on the cheeks, chest, abdomen, back, lateral upper arms, thighs, and axillae. Two years later, direct microscopy of the lesions on the scalp and fungal culture were negative. After 2 weeks of treatment with roxithromycin (0.15 g twice daily), the scalp pustules dried out and resolved; however, they recurred when the patient stopped taking the medication. Six months later, he was started on isotretinoin treatment (10 mg once daily) for half a year, but no improvement was seen. His parents were nonconsanguineous, and no other family members were affected.

Dermatologic examination revealed large areas of atrophic scarring and alopecia on the scalp. Only a few solitary hairs remained on the top of the head, with the follicles surrounded by keratotic papules, pustules, and black scabs. There was sparse hair on the forehead and temples and scattered hair clusters in the occipital region near the hairline. These follicles also were associated with keratotic papules (Figure 1A). Erythema, scales, and follicular keratotic papules of the superciliary arches with sparse eyebrows and axillary hairs were noted. Follicular keratotic papules also were observed on the cheeks, axillae, chest, abdomen, back, lateral upper arms, and thighs. Dental examination revealed a large space between the upper anterior teeth and the lower anterior teeth. The upper anterior teeth were anteverted, there was congenital absence of right lower central incisors, and the anterior teeth were in deep overbite and overjet (Figure 1B). There was gingival atrophy and calculus dentalis in the upper and lower teeth. He had a fissured tongue with atrophic filiform papillae (Figure 1C).

Comment

Folliculitis spinulosa decalvans, along with keratosis follicularis spinulosa decalvans (KFSD), keratosis pilaris atrophicans faciei, and atrophoderma vermiculatum, belongs to a group of diseases that includes keratosis pilaris atrophicans. In 1994, Oranje et al¹ suggested the term folliculitis spinulosa decalvans, with signs including persistent pustules, characteristic keratotic papules, and scarring alopecia of the scalp, which may be exacerbated at puberty. Staphylococcus aureus was isolated from the pustules in one study²; however, in another study, repeated cultures were negative.³ Although the main inheritance pattern of KFSD is X-linked, autosomal-dominant inheritance is more common in FSD. Furthermore, there are certain differences in the clinical manifestations of these 2 conditions. Therefore, it remains controversial if FSD is an independent disease or merely a subtype of KFSD.

Our patient’s symptoms manifested after puberty, primarily pustules as well as atrophic and scarring alopecia of the scalp and follicular keratotic papules on the head, face, trunk, lateral upper arms, and thighs. Pathologic examination showed massive infiltration of plasma cells, neutrophils, and multinucleated giant cells around the hair follicles. The clinical and histopathologic findings met the diagnostic criteria for FSD.

Folliculitis spinulosa decalvans is a rare clinical condition with few cases reported.^3-5 In addition to the aforementioned characteristic clinical manifestations, our patient also had dental anomalies, a fissured tongue, and atrophy of the tongue papillae, which are not known to be associated with FSD. Dental anomalies are characteristic of patients with Down syndrome, ectodermal dysplasia, Papillon-Lefèvre syndrome, and other conditions.⁶ Fissured tongue is a normal variant that occurs in 5% to 11% of individuals. It also is a classic but nonspecific feature of Melkersson-Rosenthal syndrome and may occur in psoriasis, Down syndrome, acromegaly, and Sjögren syndrome.⁷ Atrophy of the tongue papillae is associated with anemia, pellagra, Sjögren syndrome, candidiasis, and other conditions.⁸ Because there are no known reports of associations between FSD and any of these oral manifestations, it is possible that they were unrelated to FSD in our patient.

Folliculitis spinulosa decalvans usually is recurrent and there is no consistently effective treatment for it. Kunte et al⁴ reported that dapsone (100 mg/d) led to resolution of scalp inflammation and pustules within 1 month. Romine et al² reported that a 3-week course of dichloroxacillin (250 mg 4 times daily) induced disappearance of pustules around the hair follicles. However, Hallai et al⁵ reported a patient who was resistant to isotretinoin treatment. In our case, after 1 month of treatment with clarithromycin, metronidazole, viaminate, and fusidic acid cream, the pustules had resolved and the black scabs had fallen off, leaving atrophic scars. The long-term efficacy of this regimen is still under observation.

Conclusion

We report a case of FSD with dental anomalies, a fissured tongue, and atrophy of tongue papillae, none of which have previously been reported in association with FSD. We, therefore, believe that our patient’s oral manifestations are unrelated to FSD.

Case Report

A 24-year-old man was referred to the dermatology department for evaluation of pustules, atrophic scars, and alopecia on the scalp of 6 years’ duration. Six years prior, erythema, scaling, and follicular keratotic papules had appeared on the superciliary arches, and he started to lose hair from the eyebrows. Three months later, he developed mildly pruritic and painful scaling and pustules on the scalp. These lesions resolved with atrophic scarring accompanied by alopecia. One year later, follicular keratotic papules developed on the cheeks, chest, abdomen, back, lateral upper arms, thighs, and axillae. Two years later, direct microscopy of the lesions on the scalp and fungal culture were negative. After 2 weeks of treatment with roxithromycin (0.15 g twice daily), the scalp pustules dried out and resolved; however, they recurred when the patient stopped taking the medication. Six months later, he was started on isotretinoin treatment (10 mg once daily) for half a year, but no improvement was seen. His parents were nonconsanguineous, and no other family members were affected.

Dermatologic examination revealed large areas of atrophic scarring and alopecia on the scalp. Only a few solitary hairs remained on the top of the head, with the follicles surrounded by keratotic papules, pustules, and black scabs. There was sparse hair on the forehead and temples and scattered hair clusters in the occipital region near the hairline. These follicles also were associated with keratotic papules (Figure 1A). Erythema, scales, and follicular keratotic papules of the superciliary arches with sparse eyebrows and axillary hairs were noted. Follicular keratotic papules also were observed on the cheeks, axillae, chest, abdomen, back, lateral upper arms, and thighs. Dental examination revealed a large space between the upper anterior teeth and the lower anterior teeth. The upper anterior teeth were anteverted, there was congenital absence of right lower central incisors, and the anterior teeth were in deep overbite and overjet (Figure 1B). There was gingival atrophy and calculus dentalis in the upper and lower teeth. He had a fissured tongue with atrophic filiform papillae (Figure 1C).

Comment

Folliculitis spinulosa decalvans, along with keratosis follicularis spinulosa decalvans (KFSD), keratosis pilaris atrophicans faciei, and atrophoderma vermiculatum, belongs to a group of diseases that includes keratosis pilaris atrophicans. In 1994, Oranje et al¹ suggested the term folliculitis spinulosa decalvans, with signs including persistent pustules, characteristic keratotic papules, and scarring alopecia of the scalp, which may be exacerbated at puberty. Staphylococcus aureus was isolated from the pustules in one study²; however, in another study, repeated cultures were negative.³ Although the main inheritance pattern of KFSD is X-linked, autosomal-dominant inheritance is more common in FSD. Furthermore, there are certain differences in the clinical manifestations of these 2 conditions. Therefore, it remains controversial if FSD is an independent disease or merely a subtype of KFSD.

Our patient’s symptoms manifested after puberty, primarily pustules as well as atrophic and scarring alopecia of the scalp and follicular keratotic papules on the head, face, trunk, lateral upper arms, and thighs. Pathologic examination showed massive infiltration of plasma cells, neutrophils, and multinucleated giant cells around the hair follicles. The clinical and histopathologic findings met the diagnostic criteria for FSD.

Folliculitis spinulosa decalvans is a rare clinical condition with few cases reported.^3-5 In addition to the aforementioned characteristic clinical manifestations, our patient also had dental anomalies, a fissured tongue, and atrophy of the tongue papillae, which are not known to be associated with FSD. Dental anomalies are characteristic of patients with Down syndrome, ectodermal dysplasia, Papillon-Lefèvre syndrome, and other conditions.⁶ Fissured tongue is a normal variant that occurs in 5% to 11% of individuals. It also is a classic but nonspecific feature of Melkersson-Rosenthal syndrome and may occur in psoriasis, Down syndrome, acromegaly, and Sjögren syndrome.⁷ Atrophy of the tongue papillae is associated with anemia, pellagra, Sjögren syndrome, candidiasis, and other conditions.⁸ Because there are no known reports of associations between FSD and any of these oral manifestations, it is possible that they were unrelated to FSD in our patient.

Folliculitis spinulosa decalvans usually is recurrent and there is no consistently effective treatment for it. Kunte et al⁴ reported that dapsone (100 mg/d) led to resolution of scalp inflammation and pustules within 1 month. Romine et al² reported that a 3-week course of dichloroxacillin (250 mg 4 times daily) induced disappearance of pustules around the hair follicles. However, Hallai et al⁵ reported a patient who was resistant to isotretinoin treatment. In our case, after 1 month of treatment with clarithromycin, metronidazole, viaminate, and fusidic acid cream, the pustules had resolved and the black scabs had fallen off, leaving atrophic scars. The long-term efficacy of this regimen is still under observation.

Conclusion

We report a case of FSD with dental anomalies, a fissured tongue, and atrophy of tongue papillae, none of which have previously been reported in association with FSD. We, therefore, believe that our patient’s oral manifestations are unrelated to FSD.

The term nevus spilus (NS), also known as speckled lentiginous nevus, was first used in the 19th century to describe lesions with background café au lait–like lentiginous melanocytic hyperplasia speckled with small, 1- to 3-mm, darker foci. The dark spots reflect lentigines; junctional, compound, and intradermal nevus cell nests; and more rarely Spitz and blue nevi. Both macular and papular subtypes have been described.¹ This birthmark is quite common, occurring in 1.3% to 2.3% of the adult population worldwide.² Hypertrichosis has been described in NS.^3-9 Two subsequent cases of malignant melanoma in hairy NS suggested that lesions may be particularly prone to malignant degeneration.^4,8 We report an additional case of hairy NS that was not associated with melanoma and consider whether dermatologists should warn their patients about this association.

Case Report

A 26-year-old woman presented with a stable 7×8-cm, tan-brown, macular, pigmented birthmark studded with darker 1- to 2-mm, irregular, brown-black and blue, confettilike macules on the left proximal lateral thigh that had been present since birth (Figure 1). Dark terminal hairs were present, arising from both the darker and lighter pigmented areas but not the surrounding normal skin.

A 4-mm punch biopsy from one of the dark blue macules demonstrated uniform lentiginous melanocytic hyperplasia and nevus cell nests adjacent to the sweat glands extending into the mid dermis (Figure 2). No clinical evidence of malignant degeneration was present.

Comment

The risk for melanoma is increased in classic nonspeckled congenital nevi and the risk correlates with the size of the lesion and most probably the number of nevus cells in the lesion that increase the risk for a random mutation.^8,10,11 It is likely that NS with or without hair presages a small increased risk for melanoma,^6,9,12 which is not surprising because NS is a subtype of congenital melanocytic nevus (CMN), a condition that is present at birth and results from a proliferation of melanocytes.⁶ Nevus spilus, however, appears to have a notably lower risk for malignant degeneration than other classic CMN of the same size. The following support for this hypothesis is offered: First, CMN have nevus cells broadly filling the dermis that extend more deeply into the dermis than NS (Figure 2A).¹⁰ In our estimation, CMN have at least 100 times the number of nevus cells per square centimeter compared to NS. The potential for malignant degeneration of any one melanocyte is greater when more are present. Second, although some NS lesions evolve, classic CMN are universally more proliferative than NS.^10,13 The involved skin in CMN thickens over time with increased numbers of melanocytes and marked overgrowth of adjacent tissue. Melanocytes in a proliferative phase may be more likely to undergo malignant degeneration.¹⁰

A PubMed search of articles indexed for MEDLINE using the search term nevus spilus and melanoma yielded 2 cases^4,8 of melanoma arising among 15 cases of hairy NS in the literature, which led to the suggestion that the presence of hair could be associated with an increased risk for malignant degeneration in NS (Table). This apparent high incidence of melanoma most likely reflects referral/publication bias rather than a statistically significant association. In fact, the clinical lesion most clinically similar to hairy NS is Becker nevus, with tan macules demonstrating lentiginous melanocytic hyperplasia associated with numerous coarse terminal hairs. There is no indication that Becker nevi have a considerable premalignant potential, though one case of melanoma arising in a Becker nevus has been reported.⁹ There is no evidence to suggest that classic CMN with hypertrichosis has a greater premalignant potential than similar lesions without hypertrichosis.

The term nevus spilus (NS), also known as speckled lentiginous nevus, was first used in the 19th century to describe lesions with background café au lait–like lentiginous melanocytic hyperplasia speckled with small, 1- to 3-mm, darker foci. The dark spots reflect lentigines; junctional, compound, and intradermal nevus cell nests; and more rarely Spitz and blue nevi. Both macular and papular subtypes have been described.¹ This birthmark is quite common, occurring in 1.3% to 2.3% of the adult population worldwide.² Hypertrichosis has been described in NS.^3-9 Two subsequent cases of malignant melanoma in hairy NS suggested that lesions may be particularly prone to malignant degeneration.^4,8 We report an additional case of hairy NS that was not associated with melanoma and consider whether dermatologists should warn their patients about this association.

Case Report

A 26-year-old woman presented with a stable 7×8-cm, tan-brown, macular, pigmented birthmark studded with darker 1- to 2-mm, irregular, brown-black and blue, confettilike macules on the left proximal lateral thigh that had been present since birth (Figure 1). Dark terminal hairs were present, arising from both the darker and lighter pigmented areas but not the surrounding normal skin.

A 4-mm punch biopsy from one of the dark blue macules demonstrated uniform lentiginous melanocytic hyperplasia and nevus cell nests adjacent to the sweat glands extending into the mid dermis (Figure 2). No clinical evidence of malignant degeneration was present.

Comment

The risk for melanoma is increased in classic nonspeckled congenital nevi and the risk correlates with the size of the lesion and most probably the number of nevus cells in the lesion that increase the risk for a random mutation.^8,10,11 It is likely that NS with or without hair presages a small increased risk for melanoma,^6,9,12 which is not surprising because NS is a subtype of congenital melanocytic nevus (CMN), a condition that is present at birth and results from a proliferation of melanocytes.⁶ Nevus spilus, however, appears to have a notably lower risk for malignant degeneration than other classic CMN of the same size. The following support for this hypothesis is offered: First, CMN have nevus cells broadly filling the dermis that extend more deeply into the dermis than NS (Figure 2A).¹⁰ In our estimation, CMN have at least 100 times the number of nevus cells per square centimeter compared to NS. The potential for malignant degeneration of any one melanocyte is greater when more are present. Second, although some NS lesions evolve, classic CMN are universally more proliferative than NS.^10,13 The involved skin in CMN thickens over time with increased numbers of melanocytes and marked overgrowth of adjacent tissue. Melanocytes in a proliferative phase may be more likely to undergo malignant degeneration.¹⁰

A PubMed search of articles indexed for MEDLINE using the search term nevus spilus and melanoma yielded 2 cases^4,8 of melanoma arising among 15 cases of hairy NS in the literature, which led to the suggestion that the presence of hair could be associated with an increased risk for malignant degeneration in NS (Table). This apparent high incidence of melanoma most likely reflects referral/publication bias rather than a statistically significant association. In fact, the clinical lesion most clinically similar to hairy NS is Becker nevus, with tan macules demonstrating lentiginous melanocytic hyperplasia associated with numerous coarse terminal hairs. There is no indication that Becker nevi have a considerable premalignant potential, though one case of melanoma arising in a Becker nevus has been reported.⁹ There is no evidence to suggest that classic CMN with hypertrichosis has a greater premalignant potential than similar lesions without hypertrichosis.

The term nevus spilus (NS), also known as speckled lentiginous nevus, was first used in the 19th century to describe lesions with background café au lait–like lentiginous melanocytic hyperplasia speckled with small, 1- to 3-mm, darker foci. The dark spots reflect lentigines; junctional, compound, and intradermal nevus cell nests; and more rarely Spitz and blue nevi. Both macular and papular subtypes have been described.¹ This birthmark is quite common, occurring in 1.3% to 2.3% of the adult population worldwide.² Hypertrichosis has been described in NS.^3-9 Two subsequent cases of malignant melanoma in hairy NS suggested that lesions may be particularly prone to malignant degeneration.^4,8 We report an additional case of hairy NS that was not associated with melanoma and consider whether dermatologists should warn their patients about this association.

Case Report

A 26-year-old woman presented with a stable 7×8-cm, tan-brown, macular, pigmented birthmark studded with darker 1- to 2-mm, irregular, brown-black and blue, confettilike macules on the left proximal lateral thigh that had been present since birth (Figure 1). Dark terminal hairs were present, arising from both the darker and lighter pigmented areas but not the surrounding normal skin.

A 4-mm punch biopsy from one of the dark blue macules demonstrated uniform lentiginous melanocytic hyperplasia and nevus cell nests adjacent to the sweat glands extending into the mid dermis (Figure 2). No clinical evidence of malignant degeneration was present.

Comment

The risk for melanoma is increased in classic nonspeckled congenital nevi and the risk correlates with the size of the lesion and most probably the number of nevus cells in the lesion that increase the risk for a random mutation.^8,10,11 It is likely that NS with or without hair presages a small increased risk for melanoma,^6,9,12 which is not surprising because NS is a subtype of congenital melanocytic nevus (CMN), a condition that is present at birth and results from a proliferation of melanocytes.⁶ Nevus spilus, however, appears to have a notably lower risk for malignant degeneration than other classic CMN of the same size. The following support for this hypothesis is offered: First, CMN have nevus cells broadly filling the dermis that extend more deeply into the dermis than NS (Figure 2A).¹⁰ In our estimation, CMN have at least 100 times the number of nevus cells per square centimeter compared to NS. The potential for malignant degeneration of any one melanocyte is greater when more are present. Second, although some NS lesions evolve, classic CMN are universally more proliferative than NS.^10,13 The involved skin in CMN thickens over time with increased numbers of melanocytes and marked overgrowth of adjacent tissue. Melanocytes in a proliferative phase may be more likely to undergo malignant degeneration.¹⁰

A PubMed search of articles indexed for MEDLINE using the search term nevus spilus and melanoma yielded 2 cases^4,8 of melanoma arising among 15 cases of hairy NS in the literature, which led to the suggestion that the presence of hair could be associated with an increased risk for malignant degeneration in NS (Table). This apparent high incidence of melanoma most likely reflects referral/publication bias rather than a statistically significant association. In fact, the clinical lesion most clinically similar to hairy NS is Becker nevus, with tan macules demonstrating lentiginous melanocytic hyperplasia associated with numerous coarse terminal hairs. There is no indication that Becker nevi have a considerable premalignant potential, though one case of melanoma arising in a Becker nevus has been reported.⁹ There is no evidence to suggest that classic CMN with hypertrichosis has a greater premalignant potential than similar lesions without hypertrichosis.

Click on the PDF icon at the top of this introduction to read the full article.

Click on the PDF icon at the top of this introduction to read the full article.

Click on the PDF icon at the top of this introduction to read the full article.

Stromal or mesenchymal tumors account for about 1% of gastrointestinal (GI) tract neoplasms and are divided into 2 main categories: the gastrointestinal stromal tumors (GISTs; 60%- 90% of mesencymal tumors), and the non-GIST neoplasms (10%-30% of mesencymal tumors).¹ The non-GIST neoplasms consist of a heterogenous group of soft-tissue tumors, identical to soft-tissue tumors elsewhere in the body.

Click on the PDF icon at the top of this introduction to read the full article.

Stromal or mesenchymal tumors account for about 1% of gastrointestinal (GI) tract neoplasms and are divided into 2 main categories: the gastrointestinal stromal tumors (GISTs; 60%- 90% of mesencymal tumors), and the non-GIST neoplasms (10%-30% of mesencymal tumors).¹ The non-GIST neoplasms consist of a heterogenous group of soft-tissue tumors, identical to soft-tissue tumors elsewhere in the body.

Click on the PDF icon at the top of this introduction to read the full article.

Stromal or mesenchymal tumors account for about 1% of gastrointestinal (GI) tract neoplasms and are divided into 2 main categories: the gastrointestinal stromal tumors (GISTs; 60%- 90% of mesencymal tumors), and the non-GIST neoplasms (10%-30% of mesencymal tumors).¹ The non-GIST neoplasms consist of a heterogenous group of soft-tissue tumors, identical to soft-tissue tumors elsewhere in the body.

Click on the PDF icon at the top of this introduction to read the full article.

Drug-induced subacute cutaneous lupus erythematosus (DI-SCLE) was first described in 1985 in 5 patients who had been taking hydrochlorothiazide.¹ The skin lesions in these patients were identical to those seen in idiopathic subacute cutaneous lupus erythematosus (SCLE) and were accompanied by the same autoantibodies (anti-Ro/Sjögren syndrome antigen A [SS-A] and anti-La/Sjögren syndrome antigen B [SS-B]) and HLA type (HLA-DR2/DR3) that are known to be associated with idiopathic SCLE. The skin lesions of SCLE in these 5 patients resolved spontaneously after discontinuing hydrochlorothiazide; however, anti-Ro/SS-A antibodies persisted in all except 1 patient.¹ Over the last decade, an increasing number of drugs from different classes have been implicated to be associated with DI-SCLE. Since the concept of DI-SCLE was introduced, it has been reported to look identical to idiopathic SCLE, both clinically and histopathologically; however, one report suggested that the 2 entities can be distinguished based on clinical variations.² In general, patients with DI-SCLE develop the same anti-Ro antibodies as seen in idiopathic SCLE. In addition, although the rash in DI-SCLE typically resolves with withdrawal of the offending drug, the antibodies tend to persist. Herein, we report a case of a patient being treated with an aromatase inhibitor who presented with clinical, serologic, and histopathologic evidence of DI-SCLE.

Case Report

A 69-year-old woman diagnosed with breast cancer 4 years prior to her presentation to dermatology initially underwent a lumpectomy and radiation treatment. She was subsequently started on anastrozole 2 years later. After 16 months of treatment with anastrozole, she developed an erythematous scaly rash on sun-exposed areas of the skin. The patient was seen by an outside dermatologist who treated her for a patient-perceived drug rash based on biopsy results that simply demonstrated interface dermatitis. She was treated with both topical and oral steroids with little improvement and therefore presented to our office approximately 6 months after starting treatment seeking a second opinion.

Physical examination revealed numerous erythematous scaly papules and plaques in a photodistributed pattern on the chest, back, legs, and arms (Figure 1). On further questioning, the patient noted that the rash became worse when she was at the beach or playing tennis outside as well as under indoor lights. A repeat biopsy was performed, revealing interface and perivascular dermatitis with an infiltrate composed of lymphocytes, histiocytes, and scattered pigment-laden macrophages (Figure 2). Given the appearance and distribution of the rash as well as the clinical scenario, drug-induced lupus was suspected. Anastrozole was the only medication being taken. Laboratory evaluation was performed and was negative for antinuclear antibodies, antihistone antibodies, and anti-La/SS-B antibodies but was positive for anti-Ro/SS-A antibodies (>8.0 U [reference range, <1.0 U]). Based on these findings, anastrozole-induced SCLE was the most likely explanation for this presentation. The patient was started on a sun-protective regimen (ie, wide-brimmed hat, daily sunscreen) and anastrozole was discontinued by her oncologist; the combination led to moderate improvement in symptoms. One week later, oral hydroxychloroquine 200 mg twice daily was started, which led to notable improvement (Figure 3). The patient was seen for 2 additional follow-up visits, each time with sustained resolution of the rash. The hydroxychloroquine was then stopped at her last visit 3 months after diagnosis. The patient was subsequently lost to follow-up.

Comment

Presentation of SCLE

Subacute cutaneous lupus erythematosus is a form of lupus erythematosus characterized by nonscarring, annular, scaly, erythematous plaques that occur on sun-exposed skin. The lesions are classically distributed on the upper back, chest, dorsal arms, and lateral neck but also can be found in other locations.^3,4 Subacute cutaneous lupus erythematosus may be idiopathic; may occur in patients with systemic lupus erythematosus, Sjögren syndrome, or deficiency of the second component of complement (C2d); or may be drug induced.⁵ On histology SCLE presents as a lichenoid tissue reaction with focal vacuolization of the epidermal basal layer and perivascular lymphocytic infiltrate. On direct immunofluorescence, both idiopathic and drug-induced SCLE present with granular deposition of IgM, IgG, and C3 in a bandlike array at the dermoepidermal junction and circulating anti-Ro/SS-A antibodies. Therefore, histopathologically and immunologically, DI-SCLE is indistinguishable from idiopathic cases.⁶

Differential Diagnosis

It was previously thought that the clinical presentation of DI-SCLE and idiopathic SCLE were indistinguishable; however, Marzano et al² described remarkable differences in the cutaneous manifestations of the 2 diseases. Drug-induced SCLE lesions are more widespread, occur more frequently on the legs, and may be bullous or erythema multiforme–like versus the idiopathic lesions, which tend to be more concentrated on the upper body and classically present as scaly erythematous plaques. Additionally, malar rash and vasculitic lesions, such as purpura and necrotic-ulcerative lesions, are seen more often in DI-SCLE.

Drug-induced systemic lupus erythematosus (DI-SLE) is a lupuslike syndrome that can be differentiated from DI-SCLE by virtue of its clinical and serological presentation. It differs from DI-SCLE in that DI-SLE typically does not present with skin symptoms; rather, systemic symptoms such as fever, weight loss, arthralgia, polyarthritis, pericarditis, and pleuritis are more commonly seen. Additionally, it has been associated with antihistone antibodies.⁴ More than 80 drugs have been reported to cause DI-SLE, including procainamide, hydralazine, and quinidine.⁷

To be classified as either DI-SCLE or DI-SLE, symptoms need to present after administration of the triggering drug and must resolve after the drug is discontinued.⁷ The drugs most commonly associated with DI-SCLE are thiazides, calcium channel blockers, tumor necrosis factor α inhibitors, angiotensin-converting enzyme inhibitors, and terbinafine, with few cases citing anastrozole as the inciting agent.^4,6,8,9 The incubation period for DI-SCLE varies substantially. Thiazide diuretics and calcium channel blockers typically have the longest incubation period, ranging from 6 months to 5 years for thiazides,^1,6,10,11 while calcium channel blockers have an average incubation period of 3 years.¹² Drug-induced SCLE associated with antifungals, however, usually is much more rapid in onset; the incubation period on average is 5 weeks for terbinafine and 2 weeks for griseofulvin.^13-15

Antiestrogen Drugs and SCLE

Anastrozole, the inciting agent in our case, is a third-generation, selective, nonsteroidal, aromatase inhibitor with no progestogenic, androgenic, or estrogenic activity. Anastrozole, when taken at its recommended dosage of 1 mg daily, will suppress estradiol. It is used as an adjuvant treatment of estrogen-sensitive breast cancer in postmenopausal women. In contrast to a prior case of DI-SCLE secondary to anastrozole in which the incubation period was approximately 1 month,⁸ our patient had an incubation period of approximately 16 months. Tamoxifen, another antiestrogen drug, also has been associated with DI-SCLE.⁹ In cases of tamoxifen-induced SCLE, the incubation period was several years, which is more similar to our patient.Although these drugs do not have the same mechanism of action, they both have antiestrogen properties.⁹ A systemic review of DI-SCLE reported that incubation periods between drug exposure and appearance of DI-SCLE varied greatly and were drug class dependent. It is possible that reactions associated with antiestrogen medications have a delayed presentation; however, given there are limited cases of anastrozole-induced DI-SCLE, we cannot make a clear statement on incubation periods.⁶

Reports of DI-SCLE caused by antiestrogen drugs are particularly interesting because sex hormones in relation to lupus disease activity have been the subject of debate for decades. Women are considerably more likely to develop autoimmune diseases than men, suggesting that steroid hormones, especially estrogen and progesterone, influence the immune system.¹⁶ Estrogen actions are proinflammatory, while the actions of progesterone, androgens, and glucocorticoids are anti-inflammatory.¹⁷ Studies in women with lupus revealed an increased rate of mild- to moderate-intensity disease flares associated with estrogen-containing hormone replace-ment therapy.^18-20

Over the years, several antiestrogen therapies have been used in murine models, which showed remarkable clinical improvement in the course of SLE. The precise mechanisms involved in disease immunomodulation by these therapies have not been elucidated.^21-23 It is thought that estrogen plays a role in the synthesis and expression of Ro antigens on the surface of keratinocytes, increasing the fixation of anti-Ro antibodies in keratinocytes and provoking the appearance of a cutaneous eruption in patients with a susceptible HLA profile.⁶

Conclusion

We report a rare case of SCLE induced by anastrozole use. Cases such as ours and others that implicate antiestrogen drugs in association with DI-SCLE are particularly noteworthy, considering many studies are looking at the potential usefulness of antiestrogen therapy in the treatment of SLE. Further research on this relationship is warranted.

Drug-induced subacute cutaneous lupus erythematosus (DI-SCLE) was first described in 1985 in 5 patients who had been taking hydrochlorothiazide.¹ The skin lesions in these patients were identical to those seen in idiopathic subacute cutaneous lupus erythematosus (SCLE) and were accompanied by the same autoantibodies (anti-Ro/Sjögren syndrome antigen A [SS-A] and anti-La/Sjögren syndrome antigen B [SS-B]) and HLA type (HLA-DR2/DR3) that are known to be associated with idiopathic SCLE. The skin lesions of SCLE in these 5 patients resolved spontaneously after discontinuing hydrochlorothiazide; however, anti-Ro/SS-A antibodies persisted in all except 1 patient.¹ Over the last decade, an increasing number of drugs from different classes have been implicated to be associated with DI-SCLE. Since the concept of DI-SCLE was introduced, it has been reported to look identical to idiopathic SCLE, both clinically and histopathologically; however, one report suggested that the 2 entities can be distinguished based on clinical variations.² In general, patients with DI-SCLE develop the same anti-Ro antibodies as seen in idiopathic SCLE. In addition, although the rash in DI-SCLE typically resolves with withdrawal of the offending drug, the antibodies tend to persist. Herein, we report a case of a patient being treated with an aromatase inhibitor who presented with clinical, serologic, and histopathologic evidence of DI-SCLE.

Case Report

A 69-year-old woman diagnosed with breast cancer 4 years prior to her presentation to dermatology initially underwent a lumpectomy and radiation treatment. She was subsequently started on anastrozole 2 years later. After 16 months of treatment with anastrozole, she developed an erythematous scaly rash on sun-exposed areas of the skin. The patient was seen by an outside dermatologist who treated her for a patient-perceived drug rash based on biopsy results that simply demonstrated interface dermatitis. She was treated with both topical and oral steroids with little improvement and therefore presented to our office approximately 6 months after starting treatment seeking a second opinion.

Physical examination revealed numerous erythematous scaly papules and plaques in a photodistributed pattern on the chest, back, legs, and arms (Figure 1). On further questioning, the patient noted that the rash became worse when she was at the beach or playing tennis outside as well as under indoor lights. A repeat biopsy was performed, revealing interface and perivascular dermatitis with an infiltrate composed of lymphocytes, histiocytes, and scattered pigment-laden macrophages (Figure 2). Given the appearance and distribution of the rash as well as the clinical scenario, drug-induced lupus was suspected. Anastrozole was the only medication being taken. Laboratory evaluation was performed and was negative for antinuclear antibodies, antihistone antibodies, and anti-La/SS-B antibodies but was positive for anti-Ro/SS-A antibodies (>8.0 U [reference range, <1.0 U]). Based on these findings, anastrozole-induced SCLE was the most likely explanation for this presentation. The patient was started on a sun-protective regimen (ie, wide-brimmed hat, daily sunscreen) and anastrozole was discontinued by her oncologist; the combination led to moderate improvement in symptoms. One week later, oral hydroxychloroquine 200 mg twice daily was started, which led to notable improvement (Figure 3). The patient was seen for 2 additional follow-up visits, each time with sustained resolution of the rash. The hydroxychloroquine was then stopped at her last visit 3 months after diagnosis. The patient was subsequently lost to follow-up.

Comment

Presentation of SCLE

Subacute cutaneous lupus erythematosus is a form of lupus erythematosus characterized by nonscarring, annular, scaly, erythematous plaques that occur on sun-exposed skin. The lesions are classically distributed on the upper back, chest, dorsal arms, and lateral neck but also can be found in other locations.^3,4 Subacute cutaneous lupus erythematosus may be idiopathic; may occur in patients with systemic lupus erythematosus, Sjögren syndrome, or deficiency of the second component of complement (C2d); or may be drug induced.⁵ On histology SCLE presents as a lichenoid tissue reaction with focal vacuolization of the epidermal basal layer and perivascular lymphocytic infiltrate. On direct immunofluorescence, both idiopathic and drug-induced SCLE present with granular deposition of IgM, IgG, and C3 in a bandlike array at the dermoepidermal junction and circulating anti-Ro/SS-A antibodies. Therefore, histopathologically and immunologically, DI-SCLE is indistinguishable from idiopathic cases.⁶

Differential Diagnosis

It was previously thought that the clinical presentation of DI-SCLE and idiopathic SCLE were indistinguishable; however, Marzano et al² described remarkable differences in the cutaneous manifestations of the 2 diseases. Drug-induced SCLE lesions are more widespread, occur more frequently on the legs, and may be bullous or erythema multiforme–like versus the idiopathic lesions, which tend to be more concentrated on the upper body and classically present as scaly erythematous plaques. Additionally, malar rash and vasculitic lesions, such as purpura and necrotic-ulcerative lesions, are seen more often in DI-SCLE.

Drug-induced systemic lupus erythematosus (DI-SLE) is a lupuslike syndrome that can be differentiated from DI-SCLE by virtue of its clinical and serological presentation. It differs from DI-SCLE in that DI-SLE typically does not present with skin symptoms; rather, systemic symptoms such as fever, weight loss, arthralgia, polyarthritis, pericarditis, and pleuritis are more commonly seen. Additionally, it has been associated with antihistone antibodies.⁴ More than 80 drugs have been reported to cause DI-SLE, including procainamide, hydralazine, and quinidine.⁷

To be classified as either DI-SCLE or DI-SLE, symptoms need to present after administration of the triggering drug and must resolve after the drug is discontinued.⁷ The drugs most commonly associated with DI-SCLE are thiazides, calcium channel blockers, tumor necrosis factor α inhibitors, angiotensin-converting enzyme inhibitors, and terbinafine, with few cases citing anastrozole as the inciting agent.^4,6,8,9 The incubation period for DI-SCLE varies substantially. Thiazide diuretics and calcium channel blockers typically have the longest incubation period, ranging from 6 months to 5 years for thiazides,^1,6,10,11 while calcium channel blockers have an average incubation period of 3 years.¹² Drug-induced SCLE associated with antifungals, however, usually is much more rapid in onset; the incubation period on average is 5 weeks for terbinafine and 2 weeks for griseofulvin.^13-15

Antiestrogen Drugs and SCLE

Anastrozole, the inciting agent in our case, is a third-generation, selective, nonsteroidal, aromatase inhibitor with no progestogenic, androgenic, or estrogenic activity. Anastrozole, when taken at its recommended dosage of 1 mg daily, will suppress estradiol. It is used as an adjuvant treatment of estrogen-sensitive breast cancer in postmenopausal women. In contrast to a prior case of DI-SCLE secondary to anastrozole in which the incubation period was approximately 1 month,⁸ our patient had an incubation period of approximately 16 months. Tamoxifen, another antiestrogen drug, also has been associated with DI-SCLE.⁹ In cases of tamoxifen-induced SCLE, the incubation period was several years, which is more similar to our patient.Although these drugs do not have the same mechanism of action, they both have antiestrogen properties.⁹ A systemic review of DI-SCLE reported that incubation periods between drug exposure and appearance of DI-SCLE varied greatly and were drug class dependent. It is possible that reactions associated with antiestrogen medications have a delayed presentation; however, given there are limited cases of anastrozole-induced DI-SCLE, we cannot make a clear statement on incubation periods.⁶

Reports of DI-SCLE caused by antiestrogen drugs are particularly interesting because sex hormones in relation to lupus disease activity have been the subject of debate for decades. Women are considerably more likely to develop autoimmune diseases than men, suggesting that steroid hormones, especially estrogen and progesterone, influence the immune system.¹⁶ Estrogen actions are proinflammatory, while the actions of progesterone, androgens, and glucocorticoids are anti-inflammatory.¹⁷ Studies in women with lupus revealed an increased rate of mild- to moderate-intensity disease flares associated with estrogen-containing hormone replace-ment therapy.^18-20

Over the years, several antiestrogen therapies have been used in murine models, which showed remarkable clinical improvement in the course of SLE. The precise mechanisms involved in disease immunomodulation by these therapies have not been elucidated.^21-23 It is thought that estrogen plays a role in the synthesis and expression of Ro antigens on the surface of keratinocytes, increasing the fixation of anti-Ro antibodies in keratinocytes and provoking the appearance of a cutaneous eruption in patients with a susceptible HLA profile.⁶

Conclusion

We report a rare case of SCLE induced by anastrozole use. Cases such as ours and others that implicate antiestrogen drugs in association with DI-SCLE are particularly noteworthy, considering many studies are looking at the potential usefulness of antiestrogen therapy in the treatment of SLE. Further research on this relationship is warranted.

Drug-induced subacute cutaneous lupus erythematosus (DI-SCLE) was first described in 1985 in 5 patients who had been taking hydrochlorothiazide.¹ The skin lesions in these patients were identical to those seen in idiopathic subacute cutaneous lupus erythematosus (SCLE) and were accompanied by the same autoantibodies (anti-Ro/Sjögren syndrome antigen A [SS-A] and anti-La/Sjögren syndrome antigen B [SS-B]) and HLA type (HLA-DR2/DR3) that are known to be associated with idiopathic SCLE. The skin lesions of SCLE in these 5 patients resolved spontaneously after discontinuing hydrochlorothiazide; however, anti-Ro/SS-A antibodies persisted in all except 1 patient.¹ Over the last decade, an increasing number of drugs from different classes have been implicated to be associated with DI-SCLE. Since the concept of DI-SCLE was introduced, it has been reported to look identical to idiopathic SCLE, both clinically and histopathologically; however, one report suggested that the 2 entities can be distinguished based on clinical variations.² In general, patients with DI-SCLE develop the same anti-Ro antibodies as seen in idiopathic SCLE. In addition, although the rash in DI-SCLE typically resolves with withdrawal of the offending drug, the antibodies tend to persist. Herein, we report a case of a patient being treated with an aromatase inhibitor who presented with clinical, serologic, and histopathologic evidence of DI-SCLE.

Case Report

A 69-year-old woman diagnosed with breast cancer 4 years prior to her presentation to dermatology initially underwent a lumpectomy and radiation treatment. She was subsequently started on anastrozole 2 years later. After 16 months of treatment with anastrozole, she developed an erythematous scaly rash on sun-exposed areas of the skin. The patient was seen by an outside dermatologist who treated her for a patient-perceived drug rash based on biopsy results that simply demonstrated interface dermatitis. She was treated with both topical and oral steroids with little improvement and therefore presented to our office approximately 6 months after starting treatment seeking a second opinion.

Physical examination revealed numerous erythematous scaly papules and plaques in a photodistributed pattern on the chest, back, legs, and arms (Figure 1). On further questioning, the patient noted that the rash became worse when she was at the beach or playing tennis outside as well as under indoor lights. A repeat biopsy was performed, revealing interface and perivascular dermatitis with an infiltrate composed of lymphocytes, histiocytes, and scattered pigment-laden macrophages (Figure 2). Given the appearance and distribution of the rash as well as the clinical scenario, drug-induced lupus was suspected. Anastrozole was the only medication being taken. Laboratory evaluation was performed and was negative for antinuclear antibodies, antihistone antibodies, and anti-La/SS-B antibodies but was positive for anti-Ro/SS-A antibodies (>8.0 U [reference range, <1.0 U]). Based on these findings, anastrozole-induced SCLE was the most likely explanation for this presentation. The patient was started on a sun-protective regimen (ie, wide-brimmed hat, daily sunscreen) and anastrozole was discontinued by her oncologist; the combination led to moderate improvement in symptoms. One week later, oral hydroxychloroquine 200 mg twice daily was started, which led to notable improvement (Figure 3). The patient was seen for 2 additional follow-up visits, each time with sustained resolution of the rash. The hydroxychloroquine was then stopped at her last visit 3 months after diagnosis. The patient was subsequently lost to follow-up.

Comment

Presentation of SCLE

Subacute cutaneous lupus erythematosus is a form of lupus erythematosus characterized by nonscarring, annular, scaly, erythematous plaques that occur on sun-exposed skin. The lesions are classically distributed on the upper back, chest, dorsal arms, and lateral neck but also can be found in other locations.^3,4 Subacute cutaneous lupus erythematosus may be idiopathic; may occur in patients with systemic lupus erythematosus, Sjögren syndrome, or deficiency of the second component of complement (C2d); or may be drug induced.⁵ On histology SCLE presents as a lichenoid tissue reaction with focal vacuolization of the epidermal basal layer and perivascular lymphocytic infiltrate. On direct immunofluorescence, both idiopathic and drug-induced SCLE present with granular deposition of IgM, IgG, and C3 in a bandlike array at the dermoepidermal junction and circulating anti-Ro/SS-A antibodies. Therefore, histopathologically and immunologically, DI-SCLE is indistinguishable from idiopathic cases.⁶

Differential Diagnosis

It was previously thought that the clinical presentation of DI-SCLE and idiopathic SCLE were indistinguishable; however, Marzano et al² described remarkable differences in the cutaneous manifestations of the 2 diseases. Drug-induced SCLE lesions are more widespread, occur more frequently on the legs, and may be bullous or erythema multiforme–like versus the idiopathic lesions, which tend to be more concentrated on the upper body and classically present as scaly erythematous plaques. Additionally, malar rash and vasculitic lesions, such as purpura and necrotic-ulcerative lesions, are seen more often in DI-SCLE.

Drug-induced systemic lupus erythematosus (DI-SLE) is a lupuslike syndrome that can be differentiated from DI-SCLE by virtue of its clinical and serological presentation. It differs from DI-SCLE in that DI-SLE typically does not present with skin symptoms; rather, systemic symptoms such as fever, weight loss, arthralgia, polyarthritis, pericarditis, and pleuritis are more commonly seen. Additionally, it has been associated with antihistone antibodies.⁴ More than 80 drugs have been reported to cause DI-SLE, including procainamide, hydralazine, and quinidine.⁷

To be classified as either DI-SCLE or DI-SLE, symptoms need to present after administration of the triggering drug and must resolve after the drug is discontinued.⁷ The drugs most commonly associated with DI-SCLE are thiazides, calcium channel blockers, tumor necrosis factor α inhibitors, angiotensin-converting enzyme inhibitors, and terbinafine, with few cases citing anastrozole as the inciting agent.^4,6,8,9 The incubation period for DI-SCLE varies substantially. Thiazide diuretics and calcium channel blockers typically have the longest incubation period, ranging from 6 months to 5 years for thiazides,^1,6,10,11 while calcium channel blockers have an average incubation period of 3 years.¹² Drug-induced SCLE associated with antifungals, however, usually is much more rapid in onset; the incubation period on average is 5 weeks for terbinafine and 2 weeks for griseofulvin.^13-15

Antiestrogen Drugs and SCLE

Anastrozole, the inciting agent in our case, is a third-generation, selective, nonsteroidal, aromatase inhibitor with no progestogenic, androgenic, or estrogenic activity. Anastrozole, when taken at its recommended dosage of 1 mg daily, will suppress estradiol. It is used as an adjuvant treatment of estrogen-sensitive breast cancer in postmenopausal women. In contrast to a prior case of DI-SCLE secondary to anastrozole in which the incubation period was approximately 1 month,⁸ our patient had an incubation period of approximately 16 months. Tamoxifen, another antiestrogen drug, also has been associated with DI-SCLE.⁹ In cases of tamoxifen-induced SCLE, the incubation period was several years, which is more similar to our patient.Although these drugs do not have the same mechanism of action, they both have antiestrogen properties.⁹ A systemic review of DI-SCLE reported that incubation periods between drug exposure and appearance of DI-SCLE varied greatly and were drug class dependent. It is possible that reactions associated with antiestrogen medications have a delayed presentation; however, given there are limited cases of anastrozole-induced DI-SCLE, we cannot make a clear statement on incubation periods.⁶

Reports of DI-SCLE caused by antiestrogen drugs are particularly interesting because sex hormones in relation to lupus disease activity have been the subject of debate for decades. Women are considerably more likely to develop autoimmune diseases than men, suggesting that steroid hormones, especially estrogen and progesterone, influence the immune system.¹⁶ Estrogen actions are proinflammatory, while the actions of progesterone, androgens, and glucocorticoids are anti-inflammatory.¹⁷ Studies in women with lupus revealed an increased rate of mild- to moderate-intensity disease flares associated with estrogen-containing hormone replace-ment therapy.^18-20

Over the years, several antiestrogen therapies have been used in murine models, which showed remarkable clinical improvement in the course of SLE. The precise mechanisms involved in disease immunomodulation by these therapies have not been elucidated.^21-23 It is thought that estrogen plays a role in the synthesis and expression of Ro antigens on the surface of keratinocytes, increasing the fixation of anti-Ro antibodies in keratinocytes and provoking the appearance of a cutaneous eruption in patients with a susceptible HLA profile.⁶

Conclusion

We report a rare case of SCLE induced by anastrozole use. Cases such as ours and others that implicate antiestrogen drugs in association with DI-SCLE are particularly noteworthy, considering many studies are looking at the potential usefulness of antiestrogen therapy in the treatment of SLE. Further research on this relationship is warranted.

Levamisole is an immunomodulatory drug that had been used to treat various medical conditions, including parasitic infections, nephrotic syndrome, and colorectal cancer,¹ before being withdrawn from the US market in 2000.The most common reasons for levamisole discontinuation were leukopenia and rashes (1%–2%),¹ many of which included leg ulcers and necrotizing purpura of the ears.^1,2 The drug is currently available only as a deworming agent in veterinary medicine.

Since 2007, increasing amounts of levamisole have been used as an adulterant in cocaine. In 2007, less than 10% of cocaine was contaminated with levamisole, with an increase to 77% by 2010.³ In addition, 78% of 249 urine toxicology screens that were positive for cocaine in an inner city hospital also tested positive for levamisole.⁴ Levamisole-cut cocaine has become a concern because it is associated with a life-threatening syndrome involving a necrotizing purpuric rash, autoantibody production, and leukopenia.⁵

Levamisole-induced vasculitis is an independent entity from cocaine-induced vasculitis, which is associated with skin findings ranging from palpable purpura and chronic ulcers to digital infarction secondary to its vasospastic activity.^6-8 Cocaine-induced vasculopathy has been related to cytoplasmic antineutrophil cytoplasmic antibody positivity and often resembles Wegener granulomatosis.⁶ Although both cocaine and levamisole have reportedly caused acrally distributed purpura and vasculopathy, levamisole is specifically associated with retiform purpura, ear involvement, and leukopenia.^6,9 In addition, levamisole-induced skin reactions have been linked to specific antibodies, including antinuclear, antiphospholipid, and perinuclear antineutrophil cytoplasmic antibody (p-ANCA).^2,5-7,9-14

We present a case of refractory levamisole-induced vasculitis and review its clinical presentation, diagnostic approach, laboratory findings, histology, and management. Furthermore, we discuss the possibility of a new treatment option for levamisole-induced vasculitis for patients with refractory disease or for patients who continue to use levamisole.

Case Report

A 49-year-old man with a history of polysubstance abuse presented with intermittent fevers and painful swollen ears as well as joint pain of 3 weeks’ duration. One week after the lesions developed on the ears, similar lesions were seen on the legs, arms, and trunk. He admitted to cocaine use 3 weeks prior to presentation when the symptoms began.

On physical examination, violaceous patches with necrotic bleeding edges and overlying black eschars were noted on the helices, antihelices, and ear lobules bilaterally (Figure 1). Retiform, purpuric to dark brown patches, some with signs of epidermal necrosis, were scattered on the arms, legs, and chest (Figure 2).

Laboratory examination revealed renal failure, anemia of chronic disease, and thrombocytosis (Table). The patient also screened positive for lupus anticoagulant and antinuclear antibodies and had elevated p-ANCA and anti–double-stranded DNA (Table). He also had an elevated sedimentation rate (109 mm/h [reference range, 0–20 mm/h]) and C-reactive protein level (11.3 mg/dL [reference range, 0–1.0 mg/dL])(Table). Urine toxicology was positive for cocaine.

A punch biopsy of the left thigh was performed on the edge of a retiform purpuric patch. Histopathologic examination revealed epidermal necrosis with subjacent intraluminal vascular thrombi along with extravasated red blood cells and neutrophilic debris (leukocytoclasis) and fibrin in and around vessel walls, consistent with vasculitis (Figure 3).

The patient was admitted to the hospital for pain management and wound care. Despite cocaine cessation and oral prednisone taper, the lesions on the legs worsened over the next several weeks. His condition was further complicated by wound infections, nonhealing ulcers, and subjective fevers and chills requiring frequent hospitalization. The patient was managed by the dermatology department as an outpatient and in clinic between hospital visits. He was treated with antibiotics, ulcer debridement, compression wraps, and aspirin (81 mg once daily) with moderate improvement.

Ten weeks after the first visit, the patient returned with worsening and recurrent leg and ear lesions. He denied any cocaine use since the initial hospital admission; however, a toxicology screen was never obtained. It was decided that the patient would need additional treatment along with traditional trigger (cocaine) avoidance and wound care. Combined treatment with aspirin (81 mg once daily), oral prednisone (40 mg once daily), and vardenafil hydrochloride (20 mg twice weekly) was initiated. At the end of week 1, the patient began to exhibit signs of improvement, which continued over the next 4 weeks. He was then lost to follow-up.

Comment

Our patient presented with severe necrotizing cutaneous vasculitis, likely secondary to levamisole exposure. Some of our patient’s cutaneous findings may be explained exclusively on the basis of cocaine exposure, but the characteristic lesion distribution and histopathologic findings along with the evidence of autoantibody positivity and concurrent arthralgias make the combination of levamisole and cocaine a more likely cause. Similar skin lesions were first described in children treated with levamisole for nephrotic syndrome.² The most common site of clinical involvement in these children was the ears, as seen in our patient. Our patient tested positive for p-ANCA, which is the most commonly reported autoantibody associated with this patient population. Sixty-one percent (20/33) of patients with levamisole-induced vasculitis from 2 separate reviews showed p-ANCA positivity.^7,10

On histopathology, our patient’s skin biopsy findings were consistent with those of prior reports of levamisole-induced vasculitis, which describe patterns of thrombotic vasculitis, leukocytoclasis, and fibrin deposition or occlusive disease.^2,6,7,9-14 Mixed histologic findings of vasculitis and thrombosis, usually with varying ages of thrombi, are characteristic of levamisole-induced purpura. In addition, the disease can present nonspecifically with pure microvascular thrombosis without vasculitis, especially later in the course.⁹

The recommended management of levamisole-induced vasculitis currently involves the withdrawal of the culprit adulterated cocaine along with supportive treatment. Spontaneous and complete clinical resolution of lesions has been reported within 2 to 3 weeks and serology normalization within 2 to 14 months of levamisole cessation.^2,6 A 2011 review of patients with levamisole-induced vasculitis reported 66% (19/29) of cases with either full cutaneous resolution after levamisole withdrawal or recurrence with resumed use, supporting a causal relationship.⁷ Walsh et al⁹ described 2 patients with recurrent and exacerbated retiform purpura following cocaine binges. Both of these patients had urine samples that tested positive for levamisole.⁹ In more severe cases, medications shown to be effective include colchicine, polidocanol, antibiotics, methotrexate, anticoagulants, and most commonly systemic corticosteroids.^7,10,11,15 Nonsteroidal anti-inflammatory drugs were successful in treating lesions in 2 patients with concurrent arthralgia.⁷ Rarely, patients have required surgical debridement or skin grafting due to advanced disease at initial presentation.^9,12-14 One of the most severe cases of levamisole-induced vasculitis reported in the literature involved 52% of the patient’s total body surface area with skin, soft tissue, and bony necrosis requiring nasal amputation, upper lip excision, skin grafting, and extremity amputation.¹⁴ Another severe case with widespread skin involvement was recently reported.¹⁶

For unclear reasons, our patient continued to develop cutaneous lesions despite self-reported cocaine cessation. Complete resolution required the combination of vardenafil, prednisone, and aspirin, along with debridement and wound care. Vardenafil, a selective phosphodiesterase 5 inhibitor, enhances the effect of nitrous oxide by increasing levels of cyclic guanosine monophosphate,¹⁷ which results in smooth muscle relaxation and vasodilatation. The primary indication for vardenafil is the treatment of erectile dysfunction, but it often is used off label in diseases that may benefit from vasodilatation. Because of its mechanism of action, it is understandable that a vasodilator such as vardenafil could be therapeutic in a condition associated with thrombosis. Moreover, the autoinflammatory nature of levamisole-induced vasculitis makes corticosteroid treatment effective. Given the 10-week delay in improvement, we suspect that it was the combination of treatment or an individual agent that led to our patient’s eventual recovery.

There are few reports in the literature focusing on optimal treatment of levamisole-induced vasculitis and none that mention alternative management for patients who continue to develop new lesions despite cocaine avoidance. Although the discontinuation of levamisole seems to be imperative for resolution of cutaneous lesions, it may not always be enough. It is possible that there is a subpopulation of patients that may not respond to the simple withdrawal of cocaine. It also should be mentioned that there was no urine toxicology screen obtained to support our patient’s reported cocaine cessation. Therefore, it is possible that his worsening condition was secondary to continued cocaine use. However, the patient successfully responded to the combination of vardenafil and prednisone, regardless of whether his condition persisted due to continued use of cocaine or not. This case suggests the possibility of a new treatment option for levamisole-induced vasculitis for patients who continue to use levamisole despite instruction for cessation or for patients with refractory disease.

Conclusion

A trial of prednisone and vardenafil should be considered for patients with refractory levamisole-induced vasculitis. Further studies and discussions of disease course are needed to identify the best treatment of this skin condition, especially for patients with refractory lesions.

Levamisole is an immunomodulatory drug that had been used to treat various medical conditions, including parasitic infections, nephrotic syndrome, and colorectal cancer,¹ before being withdrawn from the US market in 2000.The most common reasons for levamisole discontinuation were leukopenia and rashes (1%–2%),¹ many of which included leg ulcers and necrotizing purpura of the ears.^1,2 The drug is currently available only as a deworming agent in veterinary medicine.

Since 2007, increasing amounts of levamisole have been used as an adulterant in cocaine. In 2007, less than 10% of cocaine was contaminated with levamisole, with an increase to 77% by 2010.³ In addition, 78% of 249 urine toxicology screens that were positive for cocaine in an inner city hospital also tested positive for levamisole.⁴ Levamisole-cut cocaine has become a concern because it is associated with a life-threatening syndrome involving a necrotizing purpuric rash, autoantibody production, and leukopenia.⁵

Levamisole-induced vasculitis is an independent entity from cocaine-induced vasculitis, which is associated with skin findings ranging from palpable purpura and chronic ulcers to digital infarction secondary to its vasospastic activity.^6-8 Cocaine-induced vasculopathy has been related to cytoplasmic antineutrophil cytoplasmic antibody positivity and often resembles Wegener granulomatosis.⁶ Although both cocaine and levamisole have reportedly caused acrally distributed purpura and vasculopathy, levamisole is specifically associated with retiform purpura, ear involvement, and leukopenia.^6,9 In addition, levamisole-induced skin reactions have been linked to specific antibodies, including antinuclear, antiphospholipid, and perinuclear antineutrophil cytoplasmic antibody (p-ANCA).^2,5-7,9-14

We present a case of refractory levamisole-induced vasculitis and review its clinical presentation, diagnostic approach, laboratory findings, histology, and management. Furthermore, we discuss the possibility of a new treatment option for levamisole-induced vasculitis for patients with refractory disease or for patients who continue to use levamisole.

Case Report

A 49-year-old man with a history of polysubstance abuse presented with intermittent fevers and painful swollen ears as well as joint pain of 3 weeks’ duration. One week after the lesions developed on the ears, similar lesions were seen on the legs, arms, and trunk. He admitted to cocaine use 3 weeks prior to presentation when the symptoms began.

On physical examination, violaceous patches with necrotic bleeding edges and overlying black eschars were noted on the helices, antihelices, and ear lobules bilaterally (Figure 1). Retiform, purpuric to dark brown patches, some with signs of epidermal necrosis, were scattered on the arms, legs, and chest (Figure 2).

Laboratory examination revealed renal failure, anemia of chronic disease, and thrombocytosis (Table). The patient also screened positive for lupus anticoagulant and antinuclear antibodies and had elevated p-ANCA and anti–double-stranded DNA (Table). He also had an elevated sedimentation rate (109 mm/h [reference range, 0–20 mm/h]) and C-reactive protein level (11.3 mg/dL [reference range, 0–1.0 mg/dL])(Table). Urine toxicology was positive for cocaine.

A punch biopsy of the left thigh was performed on the edge of a retiform purpuric patch. Histopathologic examination revealed epidermal necrosis with subjacent intraluminal vascular thrombi along with extravasated red blood cells and neutrophilic debris (leukocytoclasis) and fibrin in and around vessel walls, consistent with vasculitis (Figure 3).

The patient was admitted to the hospital for pain management and wound care. Despite cocaine cessation and oral prednisone taper, the lesions on the legs worsened over the next several weeks. His condition was further complicated by wound infections, nonhealing ulcers, and subjective fevers and chills requiring frequent hospitalization. The patient was managed by the dermatology department as an outpatient and in clinic between hospital visits. He was treated with antibiotics, ulcer debridement, compression wraps, and aspirin (81 mg once daily) with moderate improvement.

Ten weeks after the first visit, the patient returned with worsening and recurrent leg and ear lesions. He denied any cocaine use since the initial hospital admission; however, a toxicology screen was never obtained. It was decided that the patient would need additional treatment along with traditional trigger (cocaine) avoidance and wound care. Combined treatment with aspirin (81 mg once daily), oral prednisone (40 mg once daily), and vardenafil hydrochloride (20 mg twice weekly) was initiated. At the end of week 1, the patient began to exhibit signs of improvement, which continued over the next 4 weeks. He was then lost to follow-up.

Comment

Our patient presented with severe necrotizing cutaneous vasculitis, likely secondary to levamisole exposure. Some of our patient’s cutaneous findings may be explained exclusively on the basis of cocaine exposure, but the characteristic lesion distribution and histopathologic findings along with the evidence of autoantibody positivity and concurrent arthralgias make the combination of levamisole and cocaine a more likely cause. Similar skin lesions were first described in children treated with levamisole for nephrotic syndrome.² The most common site of clinical involvement in these children was the ears, as seen in our patient. Our patient tested positive for p-ANCA, which is the most commonly reported autoantibody associated with this patient population. Sixty-one percent (20/33) of patients with levamisole-induced vasculitis from 2 separate reviews showed p-ANCA positivity.^7,10

On histopathology, our patient’s skin biopsy findings were consistent with those of prior reports of levamisole-induced vasculitis, which describe patterns of thrombotic vasculitis, leukocytoclasis, and fibrin deposition or occlusive disease.^2,6,7,9-14 Mixed histologic findings of vasculitis and thrombosis, usually with varying ages of thrombi, are characteristic of levamisole-induced purpura. In addition, the disease can present nonspecifically with pure microvascular thrombosis without vasculitis, especially later in the course.⁹

The recommended management of levamisole-induced vasculitis currently involves the withdrawal of the culprit adulterated cocaine along with supportive treatment. Spontaneous and complete clinical resolution of lesions has been reported within 2 to 3 weeks and serology normalization within 2 to 14 months of levamisole cessation.^2,6 A 2011 review of patients with levamisole-induced vasculitis reported 66% (19/29) of cases with either full cutaneous resolution after levamisole withdrawal or recurrence with resumed use, supporting a causal relationship.⁷ Walsh et al⁹ described 2 patients with recurrent and exacerbated retiform purpura following cocaine binges. Both of these patients had urine samples that tested positive for levamisole.⁹ In more severe cases, medications shown to be effective include colchicine, polidocanol, antibiotics, methotrexate, anticoagulants, and most commonly systemic corticosteroids.^7,10,11,15 Nonsteroidal anti-inflammatory drugs were successful in treating lesions in 2 patients with concurrent arthralgia.⁷ Rarely, patients have required surgical debridement or skin grafting due to advanced disease at initial presentation.^9,12-14 One of the most severe cases of levamisole-induced vasculitis reported in the literature involved 52% of the patient’s total body surface area with skin, soft tissue, and bony necrosis requiring nasal amputation, upper lip excision, skin grafting, and extremity amputation.¹⁴ Another severe case with widespread skin involvement was recently reported.¹⁶

For unclear reasons, our patient continued to develop cutaneous lesions despite self-reported cocaine cessation. Complete resolution required the combination of vardenafil, prednisone, and aspirin, along with debridement and wound care. Vardenafil, a selective phosphodiesterase 5 inhibitor, enhances the effect of nitrous oxide by increasing levels of cyclic guanosine monophosphate,¹⁷ which results in smooth muscle relaxation and vasodilatation. The primary indication for vardenafil is the treatment of erectile dysfunction, but it often is used off label in diseases that may benefit from vasodilatation. Because of its mechanism of action, it is understandable that a vasodilator such as vardenafil could be therapeutic in a condition associated with thrombosis. Moreover, the autoinflammatory nature of levamisole-induced vasculitis makes corticosteroid treatment effective. Given the 10-week delay in improvement, we suspect that it was the combination of treatment or an individual agent that led to our patient’s eventual recovery.

There are few reports in the literature focusing on optimal treatment of levamisole-induced vasculitis and none that mention alternative management for patients who continue to develop new lesions despite cocaine avoidance. Although the discontinuation of levamisole seems to be imperative for resolution of cutaneous lesions, it may not always be enough. It is possible that there is a subpopulation of patients that may not respond to the simple withdrawal of cocaine. It also should be mentioned that there was no urine toxicology screen obtained to support our patient’s reported cocaine cessation. Therefore, it is possible that his worsening condition was secondary to continued cocaine use. However, the patient successfully responded to the combination of vardenafil and prednisone, regardless of whether his condition persisted due to continued use of cocaine or not. This case suggests the possibility of a new treatment option for levamisole-induced vasculitis for patients who continue to use levamisole despite instruction for cessation or for patients with refractory disease.

Conclusion

A trial of prednisone and vardenafil should be considered for patients with refractory levamisole-induced vasculitis. Further studies and discussions of disease course are needed to identify the best treatment of this skin condition, especially for patients with refractory lesions.

Levamisole is an immunomodulatory drug that had been used to treat various medical conditions, including parasitic infections, nephrotic syndrome, and colorectal cancer,¹ before being withdrawn from the US market in 2000.The most common reasons for levamisole discontinuation were leukopenia and rashes (1%–2%),¹ many of which included leg ulcers and necrotizing purpura of the ears.^1,2 The drug is currently available only as a deworming agent in veterinary medicine.

Since 2007, increasing amounts of levamisole have been used as an adulterant in cocaine. In 2007, less than 10% of cocaine was contaminated with levamisole, with an increase to 77% by 2010.³ In addition, 78% of 249 urine toxicology screens that were positive for cocaine in an inner city hospital also tested positive for levamisole.⁴ Levamisole-cut cocaine has become a concern because it is associated with a life-threatening syndrome involving a necrotizing purpuric rash, autoantibody production, and leukopenia.⁵

Levamisole-induced vasculitis is an independent entity from cocaine-induced vasculitis, which is associated with skin findings ranging from palpable purpura and chronic ulcers to digital infarction secondary to its vasospastic activity.^6-8 Cocaine-induced vasculopathy has been related to cytoplasmic antineutrophil cytoplasmic antibody positivity and often resembles Wegener granulomatosis.⁶ Although both cocaine and levamisole have reportedly caused acrally distributed purpura and vasculopathy, levamisole is specifically associated with retiform purpura, ear involvement, and leukopenia.^6,9 In addition, levamisole-induced skin reactions have been linked to specific antibodies, including antinuclear, antiphospholipid, and perinuclear antineutrophil cytoplasmic antibody (p-ANCA).^2,5-7,9-14

We present a case of refractory levamisole-induced vasculitis and review its clinical presentation, diagnostic approach, laboratory findings, histology, and management. Furthermore, we discuss the possibility of a new treatment option for levamisole-induced vasculitis for patients with refractory disease or for patients who continue to use levamisole.

Case Report

A 49-year-old man with a history of polysubstance abuse presented with intermittent fevers and painful swollen ears as well as joint pain of 3 weeks’ duration. One week after the lesions developed on the ears, similar lesions were seen on the legs, arms, and trunk. He admitted to cocaine use 3 weeks prior to presentation when the symptoms began.

On physical examination, violaceous patches with necrotic bleeding edges and overlying black eschars were noted on the helices, antihelices, and ear lobules bilaterally (Figure 1). Retiform, purpuric to dark brown patches, some with signs of epidermal necrosis, were scattered on the arms, legs, and chest (Figure 2).

Laboratory examination revealed renal failure, anemia of chronic disease, and thrombocytosis (Table). The patient also screened positive for lupus anticoagulant and antinuclear antibodies and had elevated p-ANCA and anti–double-stranded DNA (Table). He also had an elevated sedimentation rate (109 mm/h [reference range, 0–20 mm/h]) and C-reactive protein level (11.3 mg/dL [reference range, 0–1.0 mg/dL])(Table). Urine toxicology was positive for cocaine.

A punch biopsy of the left thigh was performed on the edge of a retiform purpuric patch. Histopathologic examination revealed epidermal necrosis with subjacent intraluminal vascular thrombi along with extravasated red blood cells and neutrophilic debris (leukocytoclasis) and fibrin in and around vessel walls, consistent with vasculitis (Figure 3).

The patient was admitted to the hospital for pain management and wound care. Despite cocaine cessation and oral prednisone taper, the lesions on the legs worsened over the next several weeks. His condition was further complicated by wound infections, nonhealing ulcers, and subjective fevers and chills requiring frequent hospitalization. The patient was managed by the dermatology department as an outpatient and in clinic between hospital visits. He was treated with antibiotics, ulcer debridement, compression wraps, and aspirin (81 mg once daily) with moderate improvement.

Ten weeks after the first visit, the patient returned with worsening and recurrent leg and ear lesions. He denied any cocaine use since the initial hospital admission; however, a toxicology screen was never obtained. It was decided that the patient would need additional treatment along with traditional trigger (cocaine) avoidance and wound care. Combined treatment with aspirin (81 mg once daily), oral prednisone (40 mg once daily), and vardenafil hydrochloride (20 mg twice weekly) was initiated. At the end of week 1, the patient began to exhibit signs of improvement, which continued over the next 4 weeks. He was then lost to follow-up.

Comment

Our patient presented with severe necrotizing cutaneous vasculitis, likely secondary to levamisole exposure. Some of our patient’s cutaneous findings may be explained exclusively on the basis of cocaine exposure, but the characteristic lesion distribution and histopathologic findings along with the evidence of autoantibody positivity and concurrent arthralgias make the combination of levamisole and cocaine a more likely cause. Similar skin lesions were first described in children treated with levamisole for nephrotic syndrome.² The most common site of clinical involvement in these children was the ears, as seen in our patient. Our patient tested positive for p-ANCA, which is the most commonly reported autoantibody associated with this patient population. Sixty-one percent (20/33) of patients with levamisole-induced vasculitis from 2 separate reviews showed p-ANCA positivity.^7,10

On histopathology, our patient’s skin biopsy findings were consistent with those of prior reports of levamisole-induced vasculitis, which describe patterns of thrombotic vasculitis, leukocytoclasis, and fibrin deposition or occlusive disease.^2,6,7,9-14 Mixed histologic findings of vasculitis and thrombosis, usually with varying ages of thrombi, are characteristic of levamisole-induced purpura. In addition, the disease can present nonspecifically with pure microvascular thrombosis without vasculitis, especially later in the course.⁹

The recommended management of levamisole-induced vasculitis currently involves the withdrawal of the culprit adulterated cocaine along with supportive treatment. Spontaneous and complete clinical resolution of lesions has been reported within 2 to 3 weeks and serology normalization within 2 to 14 months of levamisole cessation.^2,6 A 2011 review of patients with levamisole-induced vasculitis reported 66% (19/29) of cases with either full cutaneous resolution after levamisole withdrawal or recurrence with resumed use, supporting a causal relationship.⁷ Walsh et al⁹ described 2 patients with recurrent and exacerbated retiform purpura following cocaine binges. Both of these patients had urine samples that tested positive for levamisole.⁹ In more severe cases, medications shown to be effective include colchicine, polidocanol, antibiotics, methotrexate, anticoagulants, and most commonly systemic corticosteroids.^7,10,11,15 Nonsteroidal anti-inflammatory drugs were successful in treating lesions in 2 patients with concurrent arthralgia.⁷ Rarely, patients have required surgical debridement or skin grafting due to advanced disease at initial presentation.^9,12-14 One of the most severe cases of levamisole-induced vasculitis reported in the literature involved 52% of the patient’s total body surface area with skin, soft tissue, and bony necrosis requiring nasal amputation, upper lip excision, skin grafting, and extremity amputation.¹⁴ Another severe case with widespread skin involvement was recently reported.¹⁶

For unclear reasons, our patient continued to develop cutaneous lesions despite self-reported cocaine cessation. Complete resolution required the combination of vardenafil, prednisone, and aspirin, along with debridement and wound care. Vardenafil, a selective phosphodiesterase 5 inhibitor, enhances the effect of nitrous oxide by increasing levels of cyclic guanosine monophosphate,¹⁷ which results in smooth muscle relaxation and vasodilatation. The primary indication for vardenafil is the treatment of erectile dysfunction, but it often is used off label in diseases that may benefit from vasodilatation. Because of its mechanism of action, it is understandable that a vasodilator such as vardenafil could be therapeutic in a condition associated with thrombosis. Moreover, the autoinflammatory nature of levamisole-induced vasculitis makes corticosteroid treatment effective. Given the 10-week delay in improvement, we suspect that it was the combination of treatment or an individual agent that led to our patient’s eventual recovery.

There are few reports in the literature focusing on optimal treatment of levamisole-induced vasculitis and none that mention alternative management for patients who continue to develop new lesions despite cocaine avoidance. Although the discontinuation of levamisole seems to be imperative for resolution of cutaneous lesions, it may not always be enough. It is possible that there is a subpopulation of patients that may not respond to the simple withdrawal of cocaine. It also should be mentioned that there was no urine toxicology screen obtained to support our patient’s reported cocaine cessation. Therefore, it is possible that his worsening condition was secondary to continued cocaine use. However, the patient successfully responded to the combination of vardenafil and prednisone, regardless of whether his condition persisted due to continued use of cocaine or not. This case suggests the possibility of a new treatment option for levamisole-induced vasculitis for patients who continue to use levamisole despite instruction for cessation or for patients with refractory disease.

Conclusion

A trial of prednisone and vardenafil should be considered for patients with refractory levamisole-induced vasculitis. Further studies and discussions of disease course are needed to identify the best treatment of this skin condition, especially for patients with refractory lesions.

Case Report

A 23-year-old woman presented with a horizontal split along the midline of the right great toenail associated with some tenderness of 2 to 3 months’ duration. Approximately 5 years prior, she noticed a bluish-colored area under the nail that had been steadily increasing in size. She denied a history of trauma, drainage, or bleeding. There was no history of other nail abnormalities. Her medications and personal, family, and social history were noncontributory.

Physical examination of the right great toenail revealed a horizontal split of the nail plate with a bluish hue visible under the nail plate (Figure 1A). The remaining toenails and fingernails were normal. A punch biopsy of the nail bed was performed with a presumptive clinical diagnosis of subungual melanoma versus melanocytic nevus versus cyst (Figure 1B). Nail plate avulsion revealed a blackened nail bed dotted with areas of bluish color and a red friable nodule present focally. Upon further inspection, extension was apparent into the distal matrix.

Histopathologic examination revealed a cystic structure with an epithelial lining mostly reminiscent of an isthmus catagen cyst admixed with the presence of both an intermittent focal granular layer and an eosinophilic cuticle surrounding pink laminated keratin, most consistent with a diagnosis of subungual onycholemmal cyst (SOC)(Figure 2). A reexcision was performed with removal of half of the nail bed, including a portion of the distal matrix extending inferiorly to the bone. Variably sized, epithelium-lined, keratin-filled cystic structures emanated from the nail bed epithelium. There were foci of hemorrhage and granulation tissue secondary to cyst rupture (Figure 3). The defect healed by secondary intention. No clinical evidence of recurrence was seen at 6-month follow-up.

Subungual onycholemmal cysts, also known as subungual epidermoid cysts or subungual epidermoid inclusions, are rare and distinctive nail abnormalities occurring in the dermis of the nail bed. We present a case of an SOC in a toenail mimicking subungual malignant melanoma.

Originally described by Samman¹ in 1959, SOCs were attributed to trauma to the nail with resultant implantation of the epidermis into the deeper tissue. Lewin^2,3 examined 90 postmortem fingernail and nail bed samples and found 8 subungual epidermoid cysts associated with clubbing of the fingernails. He postulated that the early pathogenesis of clubbing involved dermal fibroblast proliferation in the nail bed, leading to sequestration of nail bed epithelium into the dermis with resultant cyst formation. Microscopic subungual cysts also were identified in normal-appearing nails without evidence of trauma, thought to have arisen from the tips of the nail bed rete ridges by a process of bulbous proliferation rather than sequestration. These findings in normal nails suggest that SOCs may represent a more common entity than previously recognized.

It is imperative to recognize the presence of nail unit tumors early because of the risk for permanent nail plate dystrophy and the possibility of a malignant tumor.^4,5 Subungual onycholemmal cysts may present with a wide spectrum of clinical findings including marked subungual hyperkeratosis, onychodystrophy, ridging, nail bed pigmentation, clubbing, thickening, or less often a normal-appearing nail. Based on reported cases, several trends are evident. Although nail dystrophy is most often asymptomatic, pain is not uncommon.^5,6 It most commonly involves single digits, predominantly thumbs and great toenails.^7,8 This predilection suggests that trauma or other local factors may be involved in its pathogenesis. Of note, trauma to the nail may occur years before the development of the lesions or it may not be recalled at all.

Diagnosis requires a degree of clinical suspicion and a nail bed biopsy with partial or total nail plate avulsion to visualize the pathologic portion of the nail bed. Because surgical intervention may lead to the implantation of epithelium, recurrences after nail biopsy or excision may occur.

In contrast to epidermal inclusion cysts arising in the skin, most SOCs do not have a granular layer.⁹ Hair and nails represent analogous differentiation products of the ectoderm. The nail matrix is homologous to portions of the hair matrix, while the nail bed epithelium is comparable to the outer root sheath of the hair follicle.⁷ Subungual onycholemmal cysts originate from the nail bed epithelium, which keratinizes in the absence of a granular layer, similar to the follicular isthmus outer root sheath. Thus, SOCs are comparable to the outer root sheath–derived isthmus-catagen cysts because of their abrupt central keratinization.⁸

Subungual onycholemmal cysts also must be distinguished from slowly growing malignant tumors of the nail bed epithelium, referred to as onycholemmal carcinomas by Alessi et al.¹⁰ This entity characteristically presents in elderly patients as a slowly growing, circumscribed, subungual discoloration that may ulcerate, destroying the nail apparatus and penetrating the phalangeal bone. On histopathology, it is characterized by small cysts filled with eosinophilic keratin devoid of a granular layer and lined by atypical squamous epithelium accompanied by solid nests and strands of atypical keratinocytes within the dermis.¹¹ When a cystic component and clear cells predominate, the designation of malignant proliferating onycholemmal cyst has been applied. Its infiltrative growth pattern with destruction of the underlying bone makes it an important entity to exclude when considering the differential diagnosis of tumors of the nail bed.

Subungual melanomas comprise only 1% to 3% of malignant melanomas and 85% are initially misdiagnosed due to their rarity and nonspecific variable presentation. Aside from clinical evidence of Hutchinson sign in the early stages in almost all cases, accurate diagnosis of subungual melanoma and differentiation from SOCs relies on histopathology. A biopsy is necessary to make the diagnosis, but even microscopic findings may be nonspecific during the early stages.

Conclusion

We report a case of a 23-year-old woman with horizontal ridging and tenderness of the right great toenail associated with pigmentation of 5 years’ duration due to an SOC. The etiology of these subungual cysts, with or without nail abnormalities, still remains unclear. Its predilection for the thumbs and great toenails suggests that trauma or other local factors may be involved in its pathogenesis. Because of the rarity of this entity, there are no guidelines for surgical treatment. Subungual onycholemmal cysts may be an underrecognized and more common entity that must be considered when discussing tumors of the nail unit.

Case Report

A 23-year-old woman presented with a horizontal split along the midline of the right great toenail associated with some tenderness of 2 to 3 months’ duration. Approximately 5 years prior, she noticed a bluish-colored area under the nail that had been steadily increasing in size. She denied a history of trauma, drainage, or bleeding. There was no history of other nail abnormalities. Her medications and personal, family, and social history were noncontributory.

Physical examination of the right great toenail revealed a horizontal split of the nail plate with a bluish hue visible under the nail plate (Figure 1A). The remaining toenails and fingernails were normal. A punch biopsy of the nail bed was performed with a presumptive clinical diagnosis of subungual melanoma versus melanocytic nevus versus cyst (Figure 1B). Nail plate avulsion revealed a blackened nail bed dotted with areas of bluish color and a red friable nodule present focally. Upon further inspection, extension was apparent into the distal matrix.

Histopathologic examination revealed a cystic structure with an epithelial lining mostly reminiscent of an isthmus catagen cyst admixed with the presence of both an intermittent focal granular layer and an eosinophilic cuticle surrounding pink laminated keratin, most consistent with a diagnosis of subungual onycholemmal cyst (SOC)(Figure 2). A reexcision was performed with removal of half of the nail bed, including a portion of the distal matrix extending inferiorly to the bone. Variably sized, epithelium-lined, keratin-filled cystic structures emanated from the nail bed epithelium. There were foci of hemorrhage and granulation tissue secondary to cyst rupture (Figure 3). The defect healed by secondary intention. No clinical evidence of recurrence was seen at 6-month follow-up.

Subungual onycholemmal cysts, also known as subungual epidermoid cysts or subungual epidermoid inclusions, are rare and distinctive nail abnormalities occurring in the dermis of the nail bed. We present a case of an SOC in a toenail mimicking subungual malignant melanoma.

Originally described by Samman¹ in 1959, SOCs were attributed to trauma to the nail with resultant implantation of the epidermis into the deeper tissue. Lewin^2,3 examined 90 postmortem fingernail and nail bed samples and found 8 subungual epidermoid cysts associated with clubbing of the fingernails. He postulated that the early pathogenesis of clubbing involved dermal fibroblast proliferation in the nail bed, leading to sequestration of nail bed epithelium into the dermis with resultant cyst formation. Microscopic subungual cysts also were identified in normal-appearing nails without evidence of trauma, thought to have arisen from the tips of the nail bed rete ridges by a process of bulbous proliferation rather than sequestration. These findings in normal nails suggest that SOCs may represent a more common entity than previously recognized.

It is imperative to recognize the presence of nail unit tumors early because of the risk for permanent nail plate dystrophy and the possibility of a malignant tumor.^4,5 Subungual onycholemmal cysts may present with a wide spectrum of clinical findings including marked subungual hyperkeratosis, onychodystrophy, ridging, nail bed pigmentation, clubbing, thickening, or less often a normal-appearing nail. Based on reported cases, several trends are evident. Although nail dystrophy is most often asymptomatic, pain is not uncommon.^5,6 It most commonly involves single digits, predominantly thumbs and great toenails.^7,8 This predilection suggests that trauma or other local factors may be involved in its pathogenesis. Of note, trauma to the nail may occur years before the development of the lesions or it may not be recalled at all.

Diagnosis requires a degree of clinical suspicion and a nail bed biopsy with partial or total nail plate avulsion to visualize the pathologic portion of the nail bed. Because surgical intervention may lead to the implantation of epithelium, recurrences after nail biopsy or excision may occur.

In contrast to epidermal inclusion cysts arising in the skin, most SOCs do not have a granular layer.⁹ Hair and nails represent analogous differentiation products of the ectoderm. The nail matrix is homologous to portions of the hair matrix, while the nail bed epithelium is comparable to the outer root sheath of the hair follicle.⁷ Subungual onycholemmal cysts originate from the nail bed epithelium, which keratinizes in the absence of a granular layer, similar to the follicular isthmus outer root sheath. Thus, SOCs are comparable to the outer root sheath–derived isthmus-catagen cysts because of their abrupt central keratinization.⁸

Subungual onycholemmal cysts also must be distinguished from slowly growing malignant tumors of the nail bed epithelium, referred to as onycholemmal carcinomas by Alessi et al.¹⁰ This entity characteristically presents in elderly patients as a slowly growing, circumscribed, subungual discoloration that may ulcerate, destroying the nail apparatus and penetrating the phalangeal bone. On histopathology, it is characterized by small cysts filled with eosinophilic keratin devoid of a granular layer and lined by atypical squamous epithelium accompanied by solid nests and strands of atypical keratinocytes within the dermis.¹¹ When a cystic component and clear cells predominate, the designation of malignant proliferating onycholemmal cyst has been applied. Its infiltrative growth pattern with destruction of the underlying bone makes it an important entity to exclude when considering the differential diagnosis of tumors of the nail bed.

Subungual melanomas comprise only 1% to 3% of malignant melanomas and 85% are initially misdiagnosed due to their rarity and nonspecific variable presentation. Aside from clinical evidence of Hutchinson sign in the early stages in almost all cases, accurate diagnosis of subungual melanoma and differentiation from SOCs relies on histopathology. A biopsy is necessary to make the diagnosis, but even microscopic findings may be nonspecific during the early stages.

Conclusion

We report a case of a 23-year-old woman with horizontal ridging and tenderness of the right great toenail associated with pigmentation of 5 years’ duration due to an SOC. The etiology of these subungual cysts, with or without nail abnormalities, still remains unclear. Its predilection for the thumbs and great toenails suggests that trauma or other local factors may be involved in its pathogenesis. Because of the rarity of this entity, there are no guidelines for surgical treatment. Subungual onycholemmal cysts may be an underrecognized and more common entity that must be considered when discussing tumors of the nail unit.

Case Report

A 23-year-old woman presented with a horizontal split along the midline of the right great toenail associated with some tenderness of 2 to 3 months’ duration. Approximately 5 years prior, she noticed a bluish-colored area under the nail that had been steadily increasing in size. She denied a history of trauma, drainage, or bleeding. There was no history of other nail abnormalities. Her medications and personal, family, and social history were noncontributory.

Physical examination of the right great toenail revealed a horizontal split of the nail plate with a bluish hue visible under the nail plate (Figure 1A). The remaining toenails and fingernails were normal. A punch biopsy of the nail bed was performed with a presumptive clinical diagnosis of subungual melanoma versus melanocytic nevus versus cyst (Figure 1B). Nail plate avulsion revealed a blackened nail bed dotted with areas of bluish color and a red friable nodule present focally. Upon further inspection, extension was apparent into the distal matrix.

Histopathologic examination revealed a cystic structure with an epithelial lining mostly reminiscent of an isthmus catagen cyst admixed with the presence of both an intermittent focal granular layer and an eosinophilic cuticle surrounding pink laminated keratin, most consistent with a diagnosis of subungual onycholemmal cyst (SOC)(Figure 2). A reexcision was performed with removal of half of the nail bed, including a portion of the distal matrix extending inferiorly to the bone. Variably sized, epithelium-lined, keratin-filled cystic structures emanated from the nail bed epithelium. There were foci of hemorrhage and granulation tissue secondary to cyst rupture (Figure 3). The defect healed by secondary intention. No clinical evidence of recurrence was seen at 6-month follow-up.

Subungual onycholemmal cysts, also known as subungual epidermoid cysts or subungual epidermoid inclusions, are rare and distinctive nail abnormalities occurring in the dermis of the nail bed. We present a case of an SOC in a toenail mimicking subungual malignant melanoma.

Originally described by Samman¹ in 1959, SOCs were attributed to trauma to the nail with resultant implantation of the epidermis into the deeper tissue. Lewin^2,3 examined 90 postmortem fingernail and nail bed samples and found 8 subungual epidermoid cysts associated with clubbing of the fingernails. He postulated that the early pathogenesis of clubbing involved dermal fibroblast proliferation in the nail bed, leading to sequestration of nail bed epithelium into the dermis with resultant cyst formation. Microscopic subungual cysts also were identified in normal-appearing nails without evidence of trauma, thought to have arisen from the tips of the nail bed rete ridges by a process of bulbous proliferation rather than sequestration. These findings in normal nails suggest that SOCs may represent a more common entity than previously recognized.

It is imperative to recognize the presence of nail unit tumors early because of the risk for permanent nail plate dystrophy and the possibility of a malignant tumor.^4,5 Subungual onycholemmal cysts may present with a wide spectrum of clinical findings including marked subungual hyperkeratosis, onychodystrophy, ridging, nail bed pigmentation, clubbing, thickening, or less often a normal-appearing nail. Based on reported cases, several trends are evident. Although nail dystrophy is most often asymptomatic, pain is not uncommon.^5,6 It most commonly involves single digits, predominantly thumbs and great toenails.^7,8 This predilection suggests that trauma or other local factors may be involved in its pathogenesis. Of note, trauma to the nail may occur years before the development of the lesions or it may not be recalled at all.

Diagnosis requires a degree of clinical suspicion and a nail bed biopsy with partial or total nail plate avulsion to visualize the pathologic portion of the nail bed. Because surgical intervention may lead to the implantation of epithelium, recurrences after nail biopsy or excision may occur.

In contrast to epidermal inclusion cysts arising in the skin, most SOCs do not have a granular layer.⁹ Hair and nails represent analogous differentiation products of the ectoderm. The nail matrix is homologous to portions of the hair matrix, while the nail bed epithelium is comparable to the outer root sheath of the hair follicle.⁷ Subungual onycholemmal cysts originate from the nail bed epithelium, which keratinizes in the absence of a granular layer, similar to the follicular isthmus outer root sheath. Thus, SOCs are comparable to the outer root sheath–derived isthmus-catagen cysts because of their abrupt central keratinization.⁸

Subungual onycholemmal cysts also must be distinguished from slowly growing malignant tumors of the nail bed epithelium, referred to as onycholemmal carcinomas by Alessi et al.¹⁰ This entity characteristically presents in elderly patients as a slowly growing, circumscribed, subungual discoloration that may ulcerate, destroying the nail apparatus and penetrating the phalangeal bone. On histopathology, it is characterized by small cysts filled with eosinophilic keratin devoid of a granular layer and lined by atypical squamous epithelium accompanied by solid nests and strands of atypical keratinocytes within the dermis.¹¹ When a cystic component and clear cells predominate, the designation of malignant proliferating onycholemmal cyst has been applied. Its infiltrative growth pattern with destruction of the underlying bone makes it an important entity to exclude when considering the differential diagnosis of tumors of the nail bed.

Subungual melanomas comprise only 1% to 3% of malignant melanomas and 85% are initially misdiagnosed due to their rarity and nonspecific variable presentation. Aside from clinical evidence of Hutchinson sign in the early stages in almost all cases, accurate diagnosis of subungual melanoma and differentiation from SOCs relies on histopathology. A biopsy is necessary to make the diagnosis, but even microscopic findings may be nonspecific during the early stages.

Conclusion

We report a case of a 23-year-old woman with horizontal ridging and tenderness of the right great toenail associated with pigmentation of 5 years’ duration due to an SOC. The etiology of these subungual cysts, with or without nail abnormalities, still remains unclear. Its predilection for the thumbs and great toenails suggests that trauma or other local factors may be involved in its pathogenesis. Because of the rarity of this entity, there are no guidelines for surgical treatment. Subungual onycholemmal cysts may be an underrecognized and more common entity that must be considered when discussing tumors of the nail unit.