Case Letter

To the Editor:

A 55-year-old man with a history of Graves disease treated with radioactive iodine and Graves ophthalmopathy was referred to our dermatology clinic by his endocrinologist with a 2-year history of severe pretibial myxedema (PM) that had failed treatment with systemic immunosuppressants after diagnosis by an outside dermatologist in the United Kingdom approximately 2 years prior. In addition to burning pain and difficulty walking associated with progressive “enlarging” of the lower legs and feet (Figure, A and B), the patient reported that he consistently had to find larger shoes (size 13 at the current presentation). His medications included gabapentin for foot pain and levothyroxine for hypothyroidism.

Physical examination revealed diffuse, waxy, indurated, flesh-colored and erythematous plaques and nodules with a peau d’orange appearance on the dorsal feet, ankles, and lower legs. Laboratory evaluation revealed a thyroid stimulating immunoglobulin level of 617% (reference range, <140%) and mild anemia. His thyroid stimulating hormone and free T4 levels, a comprehensive metabolic panel, and lipid panel were all within reference range.

Treatment with oral, intravenous, and intralesional steroids; cyclosporine; and azathioprine were tried prior to presentation to our clinic with no improvement. The patient was started on pentoxifylline (400 mg 3 times daily), intralesional triamcinolone acetonide (5 mg/mL every 3–4 weeks), clobetasol propionate ointment 0.05% under occlusion twice daily, short-stretch bandages, and compression stockings (20–30 mm Hg). The baseline circumference of the extremities also were measured (right ankle, 12 in; left ankle, 11.5 in; right and left mid-plantar feet, 12 in).

At 3-week follow-up, the lesions had flattened with softening of the skin. The patient reported his legs were smaller and he had bought a new pair of shoes at size 8.5 (Figure, C). He noted less pain and difficulty with walking. The circumference of the extremities was measured again (right ankle, 10.2 in; left ankle, 10 in; right and left mid-plantar feet, 10.5 in). The patient continued treatment and was followed for 3 months. At each visit, clinical improvement was noted as well as report of decreased pain while walking (Figure, D).

Pretibial myxedema is a known manifestation of Graves disease that almost always occurs in the presence of Graves ophthalmopathy. Pretibial myxedema occurs in 0.5% to 4.3% of patients with Graves disease and variably manifests as diffuse nonpitting edema or localized, waxy, indurated plaques or nodules.^1,2

The proposed pathogenesis of PM is that autoantibodies directed against the thyroid receptors cross-react with the fibroblasts of the skin,^2,3 which stimulates the fibroblasts to produce high amounts of glycosaminoglycans, especially hyaluronic acid, in the dermis and subcutis of the pretibial area. It is not known why there is a predilection for the anterior shins, but mechanical factors and dependent position (ie, leg position is lower than the level of the heart) may be involved.⁴

The mainstay of treatment for PM is topical and intralesional corticosteroids, which may have a benefit in mild to moderate disease; however, in cases of severe disease that is refractory to intralesional and topical corticosteroids under occlusion, more aggressive treatment is required. Systemic immunosuppressants such as cyclosporine, azathioprine, and corticosteroids have proven useful in some but not all cases.^5,6

Our patient did not respond to treatment with systemic and intralesional corticosteroids, cyclosporine, or azathioprine before he presented to our clinic; however, the lesions were dramatically improved after 3 weeks of treatment with pentoxifylline, intralesional and topical corticosteroids under occlusion, short-stretch bandages, and compression stockings.

Pentoxifylline inhibits the proliferation and glycosaminoglycan synthesis of cultured fibroblasts derived from patients with Graves ophthalmology and PM.⁷ It has been shown to reduce thickness of skin lesions when used in combination with topical or intralesional steroids.^3,8 Corticosteroids are thought to block fibroblast-mediated glycosaminoglycan production.^3,9 The deposition of mucin, which is comprised of glycosaminoglycans, expands the dermal tissue and causes fluid to accumulate; it also causes compression of dermal lymphatics, worsening the dermal edema. Because fluid accumulates, the use of short-stretch bandages and compression stockings may provide additional benefit, as was seen in our patient, whose shoe size decreased from a 13 to an 8.5 within 3 weeks of treatment.

In conclusion, the combination of pentoxifylline, intralesional and topical corticosteroids under occlusion, short-stretch bandages, and compression garments can cause substantial improvement in severe PM refractory to systemic immunosuppressants.

To the Editor:

A 55-year-old man with a history of Graves disease treated with radioactive iodine and Graves ophthalmopathy was referred to our dermatology clinic by his endocrinologist with a 2-year history of severe pretibial myxedema (PM) that had failed treatment with systemic immunosuppressants after diagnosis by an outside dermatologist in the United Kingdom approximately 2 years prior. In addition to burning pain and difficulty walking associated with progressive “enlarging” of the lower legs and feet (Figure, A and B), the patient reported that he consistently had to find larger shoes (size 13 at the current presentation). His medications included gabapentin for foot pain and levothyroxine for hypothyroidism.

Physical examination revealed diffuse, waxy, indurated, flesh-colored and erythematous plaques and nodules with a peau d’orange appearance on the dorsal feet, ankles, and lower legs. Laboratory evaluation revealed a thyroid stimulating immunoglobulin level of 617% (reference range, <140%) and mild anemia. His thyroid stimulating hormone and free T4 levels, a comprehensive metabolic panel, and lipid panel were all within reference range.

Treatment with oral, intravenous, and intralesional steroids; cyclosporine; and azathioprine were tried prior to presentation to our clinic with no improvement. The patient was started on pentoxifylline (400 mg 3 times daily), intralesional triamcinolone acetonide (5 mg/mL every 3–4 weeks), clobetasol propionate ointment 0.05% under occlusion twice daily, short-stretch bandages, and compression stockings (20–30 mm Hg). The baseline circumference of the extremities also were measured (right ankle, 12 in; left ankle, 11.5 in; right and left mid-plantar feet, 12 in).

At 3-week follow-up, the lesions had flattened with softening of the skin. The patient reported his legs were smaller and he had bought a new pair of shoes at size 8.5 (Figure, C). He noted less pain and difficulty with walking. The circumference of the extremities was measured again (right ankle, 10.2 in; left ankle, 10 in; right and left mid-plantar feet, 10.5 in). The patient continued treatment and was followed for 3 months. At each visit, clinical improvement was noted as well as report of decreased pain while walking (Figure, D).

Pretibial myxedema is a known manifestation of Graves disease that almost always occurs in the presence of Graves ophthalmopathy. Pretibial myxedema occurs in 0.5% to 4.3% of patients with Graves disease and variably manifests as diffuse nonpitting edema or localized, waxy, indurated plaques or nodules.^1,2

The proposed pathogenesis of PM is that autoantibodies directed against the thyroid receptors cross-react with the fibroblasts of the skin,^2,3 which stimulates the fibroblasts to produce high amounts of glycosaminoglycans, especially hyaluronic acid, in the dermis and subcutis of the pretibial area. It is not known why there is a predilection for the anterior shins, but mechanical factors and dependent position (ie, leg position is lower than the level of the heart) may be involved.⁴

The mainstay of treatment for PM is topical and intralesional corticosteroids, which may have a benefit in mild to moderate disease; however, in cases of severe disease that is refractory to intralesional and topical corticosteroids under occlusion, more aggressive treatment is required. Systemic immunosuppressants such as cyclosporine, azathioprine, and corticosteroids have proven useful in some but not all cases.^5,6

Our patient did not respond to treatment with systemic and intralesional corticosteroids, cyclosporine, or azathioprine before he presented to our clinic; however, the lesions were dramatically improved after 3 weeks of treatment with pentoxifylline, intralesional and topical corticosteroids under occlusion, short-stretch bandages, and compression stockings.

Pentoxifylline inhibits the proliferation and glycosaminoglycan synthesis of cultured fibroblasts derived from patients with Graves ophthalmology and PM.⁷ It has been shown to reduce thickness of skin lesions when used in combination with topical or intralesional steroids.^3,8 Corticosteroids are thought to block fibroblast-mediated glycosaminoglycan production.^3,9 The deposition of mucin, which is comprised of glycosaminoglycans, expands the dermal tissue and causes fluid to accumulate; it also causes compression of dermal lymphatics, worsening the dermal edema. Because fluid accumulates, the use of short-stretch bandages and compression stockings may provide additional benefit, as was seen in our patient, whose shoe size decreased from a 13 to an 8.5 within 3 weeks of treatment.

In conclusion, the combination of pentoxifylline, intralesional and topical corticosteroids under occlusion, short-stretch bandages, and compression garments can cause substantial improvement in severe PM refractory to systemic immunosuppressants.

To the Editor:

A 55-year-old man with a history of Graves disease treated with radioactive iodine and Graves ophthalmopathy was referred to our dermatology clinic by his endocrinologist with a 2-year history of severe pretibial myxedema (PM) that had failed treatment with systemic immunosuppressants after diagnosis by an outside dermatologist in the United Kingdom approximately 2 years prior. In addition to burning pain and difficulty walking associated with progressive “enlarging” of the lower legs and feet (Figure, A and B), the patient reported that he consistently had to find larger shoes (size 13 at the current presentation). His medications included gabapentin for foot pain and levothyroxine for hypothyroidism.

Physical examination revealed diffuse, waxy, indurated, flesh-colored and erythematous plaques and nodules with a peau d’orange appearance on the dorsal feet, ankles, and lower legs. Laboratory evaluation revealed a thyroid stimulating immunoglobulin level of 617% (reference range, <140%) and mild anemia. His thyroid stimulating hormone and free T4 levels, a comprehensive metabolic panel, and lipid panel were all within reference range.

Treatment with oral, intravenous, and intralesional steroids; cyclosporine; and azathioprine were tried prior to presentation to our clinic with no improvement. The patient was started on pentoxifylline (400 mg 3 times daily), intralesional triamcinolone acetonide (5 mg/mL every 3–4 weeks), clobetasol propionate ointment 0.05% under occlusion twice daily, short-stretch bandages, and compression stockings (20–30 mm Hg). The baseline circumference of the extremities also were measured (right ankle, 12 in; left ankle, 11.5 in; right and left mid-plantar feet, 12 in).

At 3-week follow-up, the lesions had flattened with softening of the skin. The patient reported his legs were smaller and he had bought a new pair of shoes at size 8.5 (Figure, C). He noted less pain and difficulty with walking. The circumference of the extremities was measured again (right ankle, 10.2 in; left ankle, 10 in; right and left mid-plantar feet, 10.5 in). The patient continued treatment and was followed for 3 months. At each visit, clinical improvement was noted as well as report of decreased pain while walking (Figure, D).

Pretibial myxedema is a known manifestation of Graves disease that almost always occurs in the presence of Graves ophthalmopathy. Pretibial myxedema occurs in 0.5% to 4.3% of patients with Graves disease and variably manifests as diffuse nonpitting edema or localized, waxy, indurated plaques or nodules.^1,2

The proposed pathogenesis of PM is that autoantibodies directed against the thyroid receptors cross-react with the fibroblasts of the skin,^2,3 which stimulates the fibroblasts to produce high amounts of glycosaminoglycans, especially hyaluronic acid, in the dermis and subcutis of the pretibial area. It is not known why there is a predilection for the anterior shins, but mechanical factors and dependent position (ie, leg position is lower than the level of the heart) may be involved.⁴

The mainstay of treatment for PM is topical and intralesional corticosteroids, which may have a benefit in mild to moderate disease; however, in cases of severe disease that is refractory to intralesional and topical corticosteroids under occlusion, more aggressive treatment is required. Systemic immunosuppressants such as cyclosporine, azathioprine, and corticosteroids have proven useful in some but not all cases.^5,6

Our patient did not respond to treatment with systemic and intralesional corticosteroids, cyclosporine, or azathioprine before he presented to our clinic; however, the lesions were dramatically improved after 3 weeks of treatment with pentoxifylline, intralesional and topical corticosteroids under occlusion, short-stretch bandages, and compression stockings.

Pentoxifylline inhibits the proliferation and glycosaminoglycan synthesis of cultured fibroblasts derived from patients with Graves ophthalmology and PM.⁷ It has been shown to reduce thickness of skin lesions when used in combination with topical or intralesional steroids.^3,8 Corticosteroids are thought to block fibroblast-mediated glycosaminoglycan production.^3,9 The deposition of mucin, which is comprised of glycosaminoglycans, expands the dermal tissue and causes fluid to accumulate; it also causes compression of dermal lymphatics, worsening the dermal edema. Because fluid accumulates, the use of short-stretch bandages and compression stockings may provide additional benefit, as was seen in our patient, whose shoe size decreased from a 13 to an 8.5 within 3 weeks of treatment.

In conclusion, the combination of pentoxifylline, intralesional and topical corticosteroids under occlusion, short-stretch bandages, and compression garments can cause substantial improvement in severe PM refractory to systemic immunosuppressants.

To the Editor:

A 43-year-old woman presented with a mole on the central back that had been present since childhood and had changed and grown over the last few years. The patient reported that her 2-year-old rescue dog frequently sniffed the mole and would subsequently get agitated and try to scratch and bite the lesion. This behavior prompted the patient to visit a dermatologist.

She reported no personal history of melanoma or nonmelanoma skin cancer, tanning booth exposure, blistering sunburns, or use of immunosuppressant medications. Her family history was remarkable for basal cell carcinoma in her father but no family history of melanoma. Physical examination revealed a 1.2×1.5-cm brown patch along with a 1×1-cm ulcerated nodule on the lower aspect of the lesion (Figure 1). Dermoscopy showed a blue-white veil and an irregular vascular pattern (Figure 2). No cervical, axillary, or inguinal lymphadenopathy was appreciated on physical examination. Reflectance confocal microscopy showed pagetoid spread of atypical round melanocytes as well as melanocytes in the stratum corneum (Figure 3).

The patient was referred to a surgical oncologist for wide local excision and sentinel lymph node biopsy. Pathology showed a 4-mm-thick melanoma with numerous positive lymph nodes (Figure 4). The patient subsequently underwent a right axillary lymphadenectomy and was diagnosed with stage IIIB malignant melanoma. After surgery, the patient reported that her dog would now sniff her back and calmly rest his head in her lap.

Both anecdotal and systematic evidence have emerged on the role of canine olfaction in the detection of lung, breast, colorectal, ovarian, prostate, and skin cancers, including malignant melanoma.^1-6 A 1989 case report described a woman who was prompted to seek dermatologic evaluation of a pigmented lesion because her dog consistently targeted the lesion. Excision and subsequent histopathologic examination of the lesion revealed that it was malignant melanoma.⁵ Another case report described a patient whose dog, which was not trained to detect cancers in humans, persistently licked a lesion behind the patient’s ear that eventually was found to be malignant melanoma.⁶ These reports have inspired considerable research interest regarding canine olfaction as a potential method to noninvasively screen for and even diagnose malignant melanomas in humans.

Both physiologic and pathologic metabolic processes result in the production of volatile organic compounds (VOCs), or small odorant molecules that evaporate at normal temperatures and pressures.¹ Individual cells release VOCs in extremely low concentrations into the blood, urine, feces, and breath, as well as onto the skin’s surface, but there are methods for detecting these VOCs, including gas chromatography–mass spectrometry and canine olfaction.^7,8 Pathologic processes, such as infection and malignancy, result in irregular protein synthesis and metabolism, producing new VOCs or differing concentrations of VOCs as compared to normal processes.¹

Dimethyl disulfide and dimethyl trisulfide compounds have been identified in malignant melanoma, and these compounds are not produced by normal melanocytes.⁷ Furthermore, malignant melanoma produces differing quantities of these compounds as compared to normal melanocytes, including isovaleric acid, 2-methylbutyric acid, isoamyl alcohol (3-methyl-1-butanol), and 2-methyl-1-butanol, resulting in a distinct odorant profile that previously has been detected via canine olfaction.⁷ Canine olfaction can identify odorant molecules at up to 1 part per trillion (a magnitude more sensitive than the currently available gas chromatography–mass spectrometry technologies) and can detect the production of new VOCs or altered VOC ratios due to pathologic processes.¹ Systematic studies with dogs that are trained to detect cancers in humans have shown that canine olfaction correctly identified malignant melanomas against healthy skin, benign nevi, and even basal cell carcinomas at higher rates than what would have been expected by chance alone.^2,3

Canine olfaction can identify new or altered ratios of odorant VOCs associated with pathologic metabolic processes, and canines can be trained to target odor profiles associated with specific diseases.¹ Canine olfaction for melanoma screening and diagnosis may seem appealing, as it provides an easily transportable, real-time, low-cost method compared to other techniques such as gas chromatography–mass spectrometry.¹ Although preliminary results have shown that canine olfaction detects melanoma at higher rates than would be expected by chance alone, these findings have not approached clinical utility for the widespread use of canine olfaction as a screening method for melanoma.^2,3,9 Further studies are needed to understand the role of canine olfaction in melanoma screening and diagnosis as well as to explore methods to optimize sensitivity and specificity. Until then, patients and dermatologists should not ignore the behavior of dogs toward skin lesions. Dogs may be beneficial in the detection of melanoma and help save lives, as was seen in our case.

To the Editor:

A 43-year-old woman presented with a mole on the central back that had been present since childhood and had changed and grown over the last few years. The patient reported that her 2-year-old rescue dog frequently sniffed the mole and would subsequently get agitated and try to scratch and bite the lesion. This behavior prompted the patient to visit a dermatologist.

She reported no personal history of melanoma or nonmelanoma skin cancer, tanning booth exposure, blistering sunburns, or use of immunosuppressant medications. Her family history was remarkable for basal cell carcinoma in her father but no family history of melanoma. Physical examination revealed a 1.2×1.5-cm brown patch along with a 1×1-cm ulcerated nodule on the lower aspect of the lesion (Figure 1). Dermoscopy showed a blue-white veil and an irregular vascular pattern (Figure 2). No cervical, axillary, or inguinal lymphadenopathy was appreciated on physical examination. Reflectance confocal microscopy showed pagetoid spread of atypical round melanocytes as well as melanocytes in the stratum corneum (Figure 3).

The patient was referred to a surgical oncologist for wide local excision and sentinel lymph node biopsy. Pathology showed a 4-mm-thick melanoma with numerous positive lymph nodes (Figure 4). The patient subsequently underwent a right axillary lymphadenectomy and was diagnosed with stage IIIB malignant melanoma. After surgery, the patient reported that her dog would now sniff her back and calmly rest his head in her lap.

Both anecdotal and systematic evidence have emerged on the role of canine olfaction in the detection of lung, breast, colorectal, ovarian, prostate, and skin cancers, including malignant melanoma.^1-6 A 1989 case report described a woman who was prompted to seek dermatologic evaluation of a pigmented lesion because her dog consistently targeted the lesion. Excision and subsequent histopathologic examination of the lesion revealed that it was malignant melanoma.⁵ Another case report described a patient whose dog, which was not trained to detect cancers in humans, persistently licked a lesion behind the patient’s ear that eventually was found to be malignant melanoma.⁶ These reports have inspired considerable research interest regarding canine olfaction as a potential method to noninvasively screen for and even diagnose malignant melanomas in humans.

Both physiologic and pathologic metabolic processes result in the production of volatile organic compounds (VOCs), or small odorant molecules that evaporate at normal temperatures and pressures.¹ Individual cells release VOCs in extremely low concentrations into the blood, urine, feces, and breath, as well as onto the skin’s surface, but there are methods for detecting these VOCs, including gas chromatography–mass spectrometry and canine olfaction.^7,8 Pathologic processes, such as infection and malignancy, result in irregular protein synthesis and metabolism, producing new VOCs or differing concentrations of VOCs as compared to normal processes.¹

Dimethyl disulfide and dimethyl trisulfide compounds have been identified in malignant melanoma, and these compounds are not produced by normal melanocytes.⁷ Furthermore, malignant melanoma produces differing quantities of these compounds as compared to normal melanocytes, including isovaleric acid, 2-methylbutyric acid, isoamyl alcohol (3-methyl-1-butanol), and 2-methyl-1-butanol, resulting in a distinct odorant profile that previously has been detected via canine olfaction.⁷ Canine olfaction can identify odorant molecules at up to 1 part per trillion (a magnitude more sensitive than the currently available gas chromatography–mass spectrometry technologies) and can detect the production of new VOCs or altered VOC ratios due to pathologic processes.¹ Systematic studies with dogs that are trained to detect cancers in humans have shown that canine olfaction correctly identified malignant melanomas against healthy skin, benign nevi, and even basal cell carcinomas at higher rates than what would have been expected by chance alone.^2,3

Canine olfaction can identify new or altered ratios of odorant VOCs associated with pathologic metabolic processes, and canines can be trained to target odor profiles associated with specific diseases.¹ Canine olfaction for melanoma screening and diagnosis may seem appealing, as it provides an easily transportable, real-time, low-cost method compared to other techniques such as gas chromatography–mass spectrometry.¹ Although preliminary results have shown that canine olfaction detects melanoma at higher rates than would be expected by chance alone, these findings have not approached clinical utility for the widespread use of canine olfaction as a screening method for melanoma.^2,3,9 Further studies are needed to understand the role of canine olfaction in melanoma screening and diagnosis as well as to explore methods to optimize sensitivity and specificity. Until then, patients and dermatologists should not ignore the behavior of dogs toward skin lesions. Dogs may be beneficial in the detection of melanoma and help save lives, as was seen in our case.

To the Editor:

A 43-year-old woman presented with a mole on the central back that had been present since childhood and had changed and grown over the last few years. The patient reported that her 2-year-old rescue dog frequently sniffed the mole and would subsequently get agitated and try to scratch and bite the lesion. This behavior prompted the patient to visit a dermatologist.

She reported no personal history of melanoma or nonmelanoma skin cancer, tanning booth exposure, blistering sunburns, or use of immunosuppressant medications. Her family history was remarkable for basal cell carcinoma in her father but no family history of melanoma. Physical examination revealed a 1.2×1.5-cm brown patch along with a 1×1-cm ulcerated nodule on the lower aspect of the lesion (Figure 1). Dermoscopy showed a blue-white veil and an irregular vascular pattern (Figure 2). No cervical, axillary, or inguinal lymphadenopathy was appreciated on physical examination. Reflectance confocal microscopy showed pagetoid spread of atypical round melanocytes as well as melanocytes in the stratum corneum (Figure 3).

The patient was referred to a surgical oncologist for wide local excision and sentinel lymph node biopsy. Pathology showed a 4-mm-thick melanoma with numerous positive lymph nodes (Figure 4). The patient subsequently underwent a right axillary lymphadenectomy and was diagnosed with stage IIIB malignant melanoma. After surgery, the patient reported that her dog would now sniff her back and calmly rest his head in her lap.

Both anecdotal and systematic evidence have emerged on the role of canine olfaction in the detection of lung, breast, colorectal, ovarian, prostate, and skin cancers, including malignant melanoma.^1-6 A 1989 case report described a woman who was prompted to seek dermatologic evaluation of a pigmented lesion because her dog consistently targeted the lesion. Excision and subsequent histopathologic examination of the lesion revealed that it was malignant melanoma.⁵ Another case report described a patient whose dog, which was not trained to detect cancers in humans, persistently licked a lesion behind the patient’s ear that eventually was found to be malignant melanoma.⁶ These reports have inspired considerable research interest regarding canine olfaction as a potential method to noninvasively screen for and even diagnose malignant melanomas in humans.

Both physiologic and pathologic metabolic processes result in the production of volatile organic compounds (VOCs), or small odorant molecules that evaporate at normal temperatures and pressures.¹ Individual cells release VOCs in extremely low concentrations into the blood, urine, feces, and breath, as well as onto the skin’s surface, but there are methods for detecting these VOCs, including gas chromatography–mass spectrometry and canine olfaction.^7,8 Pathologic processes, such as infection and malignancy, result in irregular protein synthesis and metabolism, producing new VOCs or differing concentrations of VOCs as compared to normal processes.¹

Dimethyl disulfide and dimethyl trisulfide compounds have been identified in malignant melanoma, and these compounds are not produced by normal melanocytes.⁷ Furthermore, malignant melanoma produces differing quantities of these compounds as compared to normal melanocytes, including isovaleric acid, 2-methylbutyric acid, isoamyl alcohol (3-methyl-1-butanol), and 2-methyl-1-butanol, resulting in a distinct odorant profile that previously has been detected via canine olfaction.⁷ Canine olfaction can identify odorant molecules at up to 1 part per trillion (a magnitude more sensitive than the currently available gas chromatography–mass spectrometry technologies) and can detect the production of new VOCs or altered VOC ratios due to pathologic processes.¹ Systematic studies with dogs that are trained to detect cancers in humans have shown that canine olfaction correctly identified malignant melanomas against healthy skin, benign nevi, and even basal cell carcinomas at higher rates than what would have been expected by chance alone.^2,3

Canine olfaction can identify new or altered ratios of odorant VOCs associated with pathologic metabolic processes, and canines can be trained to target odor profiles associated with specific diseases.¹ Canine olfaction for melanoma screening and diagnosis may seem appealing, as it provides an easily transportable, real-time, low-cost method compared to other techniques such as gas chromatography–mass spectrometry.¹ Although preliminary results have shown that canine olfaction detects melanoma at higher rates than would be expected by chance alone, these findings have not approached clinical utility for the widespread use of canine olfaction as a screening method for melanoma.^2,3,9 Further studies are needed to understand the role of canine olfaction in melanoma screening and diagnosis as well as to explore methods to optimize sensitivity and specificity. Until then, patients and dermatologists should not ignore the behavior of dogs toward skin lesions. Dogs may be beneficial in the detection of melanoma and help save lives, as was seen in our case.

To the Editor:

A 53-year-old woman presented to our dermatology clinic with a painful growth on the right ear of 2 months’ duration. A complete review of systems was negative except for an isolated episode of shortness of breath prior to presentation that resolved without intervention. During this episode, her primary care physician made a diagnosis of chronic obstructive pulmonary disease based on a chest radiograph. The patient reported minimal tobacco use, specifically that she had smoked a few cigarettes daily for several years but had quit 6 months prior to the current presentation.

Physical examination at our clinic revealed a tender, hyperkeratotic, cone-shaped papule with mild erythema on the right antitragus that was consistent with a cutaneous horn (Figure 1). Although she denied any other skin lesions, further evaluation revealed a cluster of firm flesh-colored papules surrounding the left medial canthus as well as a pink scaly plaque on the posterior neck.

Studies analyzing the underlying diagnoses and clinical features of cutaneous horns are limited. In a large retrospective study of 643 cutaneous horns, 61% were benign, 23% were premalignant, and 16% were malignant. In this study, 4 features were associated with premalignant or malignant pathology: (1) older age (mid- 60s to 70s); (2) male sex; (3) location on the nose, pinnae, dorsal hands, scalp, forearms, or face; and (4) a wide base (4.4 mm or larger) and a lower height-to-base ratio than benign lesions.¹ Two additional studies of more than 200 horns each showed higher rates of premalignant horns (42% and 38%, respectively) with malignancy found in 7% and 20% of horns, respectively.^2,3 One prospective study sought to identify clinical and dermatoscopic features of SCCs underlying cutaneous horns, concluding that SCC diagnosis was more likely if a horn had (1) a height less than the diameter of its base, (2) a lack of terrace morphology (a dermatoscopic feature defined as horizontal parallel layers of keratin), (3) erythema at the base, and (4) the presence of pain.⁴

Our patient had a cutaneous horn on the pinna that was painful, wider than it was tall, and erythematous at the base, suggesting a malignant process; however, a complete cutaneous physical examination revealed other skin lesions that were concerning for sarcoidosis and raised suspicion that the horn also was a manifestation of the same inflammatory process.

Although unusual, cutaneous sarcoidosis presenting as a cutaneous horn is not unexpected. In a histopathologic study of 62 cases of cutaneous sarcoidosis, 79% (49/62) showed epidermal changes and 13% (8/62) demonstrated hyperkeratosis. Other epidermal changes included parakeratosis (16% [10/62]), acanthosis (10% [6/62]), and epidermal atrophy (57% [35/62]).⁵ The spectrum of epidermal pathology in cutaneous sarcoidosis is evident in its well-documented verrucous, psoriasiform, and ichthyosiform presentations. For completeness, cutaneous horn is added to the list of clinical morphologies for this “great imitator” of cutaneous diseases.

To the Editor:

A 53-year-old woman presented to our dermatology clinic with a painful growth on the right ear of 2 months’ duration. A complete review of systems was negative except for an isolated episode of shortness of breath prior to presentation that resolved without intervention. During this episode, her primary care physician made a diagnosis of chronic obstructive pulmonary disease based on a chest radiograph. The patient reported minimal tobacco use, specifically that she had smoked a few cigarettes daily for several years but had quit 6 months prior to the current presentation.

Physical examination at our clinic revealed a tender, hyperkeratotic, cone-shaped papule with mild erythema on the right antitragus that was consistent with a cutaneous horn (Figure 1). Although she denied any other skin lesions, further evaluation revealed a cluster of firm flesh-colored papules surrounding the left medial canthus as well as a pink scaly plaque on the posterior neck.

Studies analyzing the underlying diagnoses and clinical features of cutaneous horns are limited. In a large retrospective study of 643 cutaneous horns, 61% were benign, 23% were premalignant, and 16% were malignant. In this study, 4 features were associated with premalignant or malignant pathology: (1) older age (mid- 60s to 70s); (2) male sex; (3) location on the nose, pinnae, dorsal hands, scalp, forearms, or face; and (4) a wide base (4.4 mm or larger) and a lower height-to-base ratio than benign lesions.¹ Two additional studies of more than 200 horns each showed higher rates of premalignant horns (42% and 38%, respectively) with malignancy found in 7% and 20% of horns, respectively.^2,3 One prospective study sought to identify clinical and dermatoscopic features of SCCs underlying cutaneous horns, concluding that SCC diagnosis was more likely if a horn had (1) a height less than the diameter of its base, (2) a lack of terrace morphology (a dermatoscopic feature defined as horizontal parallel layers of keratin), (3) erythema at the base, and (4) the presence of pain.⁴

Our patient had a cutaneous horn on the pinna that was painful, wider than it was tall, and erythematous at the base, suggesting a malignant process; however, a complete cutaneous physical examination revealed other skin lesions that were concerning for sarcoidosis and raised suspicion that the horn also was a manifestation of the same inflammatory process.

Although unusual, cutaneous sarcoidosis presenting as a cutaneous horn is not unexpected. In a histopathologic study of 62 cases of cutaneous sarcoidosis, 79% (49/62) showed epidermal changes and 13% (8/62) demonstrated hyperkeratosis. Other epidermal changes included parakeratosis (16% [10/62]), acanthosis (10% [6/62]), and epidermal atrophy (57% [35/62]).⁵ The spectrum of epidermal pathology in cutaneous sarcoidosis is evident in its well-documented verrucous, psoriasiform, and ichthyosiform presentations. For completeness, cutaneous horn is added to the list of clinical morphologies for this “great imitator” of cutaneous diseases.

To the Editor:

A 53-year-old woman presented to our dermatology clinic with a painful growth on the right ear of 2 months’ duration. A complete review of systems was negative except for an isolated episode of shortness of breath prior to presentation that resolved without intervention. During this episode, her primary care physician made a diagnosis of chronic obstructive pulmonary disease based on a chest radiograph. The patient reported minimal tobacco use, specifically that she had smoked a few cigarettes daily for several years but had quit 6 months prior to the current presentation.

Physical examination at our clinic revealed a tender, hyperkeratotic, cone-shaped papule with mild erythema on the right antitragus that was consistent with a cutaneous horn (Figure 1). Although she denied any other skin lesions, further evaluation revealed a cluster of firm flesh-colored papules surrounding the left medial canthus as well as a pink scaly plaque on the posterior neck.

Studies analyzing the underlying diagnoses and clinical features of cutaneous horns are limited. In a large retrospective study of 643 cutaneous horns, 61% were benign, 23% were premalignant, and 16% were malignant. In this study, 4 features were associated with premalignant or malignant pathology: (1) older age (mid- 60s to 70s); (2) male sex; (3) location on the nose, pinnae, dorsal hands, scalp, forearms, or face; and (4) a wide base (4.4 mm or larger) and a lower height-to-base ratio than benign lesions.¹ Two additional studies of more than 200 horns each showed higher rates of premalignant horns (42% and 38%, respectively) with malignancy found in 7% and 20% of horns, respectively.^2,3 One prospective study sought to identify clinical and dermatoscopic features of SCCs underlying cutaneous horns, concluding that SCC diagnosis was more likely if a horn had (1) a height less than the diameter of its base, (2) a lack of terrace morphology (a dermatoscopic feature defined as horizontal parallel layers of keratin), (3) erythema at the base, and (4) the presence of pain.⁴

Our patient had a cutaneous horn on the pinna that was painful, wider than it was tall, and erythematous at the base, suggesting a malignant process; however, a complete cutaneous physical examination revealed other skin lesions that were concerning for sarcoidosis and raised suspicion that the horn also was a manifestation of the same inflammatory process.

Although unusual, cutaneous sarcoidosis presenting as a cutaneous horn is not unexpected. In a histopathologic study of 62 cases of cutaneous sarcoidosis, 79% (49/62) showed epidermal changes and 13% (8/62) demonstrated hyperkeratosis. Other epidermal changes included parakeratosis (16% [10/62]), acanthosis (10% [6/62]), and epidermal atrophy (57% [35/62]).⁵ The spectrum of epidermal pathology in cutaneous sarcoidosis is evident in its well-documented verrucous, psoriasiform, and ichthyosiform presentations. For completeness, cutaneous horn is added to the list of clinical morphologies for this “great imitator” of cutaneous diseases.

To the Editor:

Verrucous carcinoma (VC) is a rare type of squamous cell carcinoma characterized by a well-differentiated low-grade tumor with a high degree of keratinization. First described by Ackerman¹ in 1948, VC presents on the skin or oral and genital mucosae with minimal atypical cytologic findings.^1-3 It most commonly is seen in late middle-aged men (85% of cases) and presents as a slow-growing mass, often of more than 10 years’ duration.^2,3 Verrucous carcinoma frequently is observed at 3 particular anatomic sites: the oral cavity, known as oral florid papillomatosis; the anogenital area, known as Buschke-Löwenstein tumor; and on the plantar surface, known as epithelioma cuniculatum.^2-13

A 19-year-old man presented with an ulcerous lesion on the right big toe of 2 years’ duration. He reported that the lesion had gradually increased in size and was painful when walking. Physical examination revealed an ulcerated lesion on the right big toe with purulent inflammation and necrosis, unclear edges, and border nodules containing a fatty, yellowish, foul-smelling material (Figure 1). Histologic examination of purulent material from deep within the primary lesion revealed gram-negative rods and gram-positive diplococci. Erlich-Ziehl-Neelsen staining and culture in Lowenstein-Jensen medium were negative for mycobacteria. Histologic examination and fungal culture were not diagnostic for fungal infection.

At the initial presentation, radiography of the right big toe revealed porotic signs and cortical irregularity of the distal phalanx. A deep incisional biopsy of the lesion was performed for pathologic and microbiologic analysis. Erlich-Ziehl-Neelsen staining was negative, fungal elements could not be observed, and there was no growth in Lowenstein-Jensen medium or Sabouraud dextrose agar. Polymerase chain reaction for human papillomavirus, M tuberculosis, and atypical mycobacterium was negative. Periodic acid–Schiff staining was negative for fungal elements. Histopathologic examination revealed an exophytic as well as endophytic squamous cell proliferation infiltrating deeper layers of the dermis with a desmoplastic stroma (Figure 2). Slight cytologic atypia was noted. A diagnosis of VC was made based on the clinical and histopathologic findings. The patient’s right big toe was amputated by plastic surgery 6 months after the initial presentation.

Histopathologic examination, especially of superficial biopsies, generally reveals squamous cell proliferation demonstrating minimal pleomorphism and cytologic atypia with sparse mitotic figures.^4-6 Diagnosis of VC can be challenging if the endophytic proliferation, which characteristically pushes into the dermis and even deeper tissues at the base of the lesion, is not seen. This feature is uncommon in squamous cell carcinomas.^3,4,6 Histopathologic detection of koilocytes can lead to difficulty in distinguishing VC from warts.⁵ The growth of lesions is exophytic in plantar verrucae, whereas in VC it may be either exophytic or endophytic.⁴ At early stages, it is too difficult to distinguish VC from pseudoepitheliomatous hyperplasia caused by chronic inflammation, as well as from tuberculosis and subcutaneous mycoses.^3,6 In these situations, possible responsible microorganisms must be sought out. Amelanotic malignant melanoma and eccrine poroma also should be considered in the differential diagnosis.^3,5 If the biopsy specimen is obtained superficially and is fragmented, the diagnosis is more difficult, making deep biopsies essential in suspicious cases.⁴ Excision is the best treatment, and Mohs micrographic surgery may be required in some cases.^2,3,11 It is important to consider that radiotherapy may lead to anaplastic transformation and metastasis.² Metastasis to lymph nodes is very rare, and the prognosis is excellent when complete excision is performed.² Recurrence may be observed.⁴

Our case of plantar VC is notable because of the patient’s young age, which is uncommon, as the typical age for developing VC is late middle age (ie, fifth and sixth decades of life). A long-standing lesion that is therapy resistant and without a detectable microorganism should be investigated for malignancy by repetitive deep biopsy regardless of the patient’s age, as demonstrated in our case.

To the Editor:

Verrucous carcinoma (VC) is a rare type of squamous cell carcinoma characterized by a well-differentiated low-grade tumor with a high degree of keratinization. First described by Ackerman¹ in 1948, VC presents on the skin or oral and genital mucosae with minimal atypical cytologic findings.^1-3 It most commonly is seen in late middle-aged men (85% of cases) and presents as a slow-growing mass, often of more than 10 years’ duration.^2,3 Verrucous carcinoma frequently is observed at 3 particular anatomic sites: the oral cavity, known as oral florid papillomatosis; the anogenital area, known as Buschke-Löwenstein tumor; and on the plantar surface, known as epithelioma cuniculatum.^2-13

A 19-year-old man presented with an ulcerous lesion on the right big toe of 2 years’ duration. He reported that the lesion had gradually increased in size and was painful when walking. Physical examination revealed an ulcerated lesion on the right big toe with purulent inflammation and necrosis, unclear edges, and border nodules containing a fatty, yellowish, foul-smelling material (Figure 1). Histologic examination of purulent material from deep within the primary lesion revealed gram-negative rods and gram-positive diplococci. Erlich-Ziehl-Neelsen staining and culture in Lowenstein-Jensen medium were negative for mycobacteria. Histologic examination and fungal culture were not diagnostic for fungal infection.

At the initial presentation, radiography of the right big toe revealed porotic signs and cortical irregularity of the distal phalanx. A deep incisional biopsy of the lesion was performed for pathologic and microbiologic analysis. Erlich-Ziehl-Neelsen staining was negative, fungal elements could not be observed, and there was no growth in Lowenstein-Jensen medium or Sabouraud dextrose agar. Polymerase chain reaction for human papillomavirus, M tuberculosis, and atypical mycobacterium was negative. Periodic acid–Schiff staining was negative for fungal elements. Histopathologic examination revealed an exophytic as well as endophytic squamous cell proliferation infiltrating deeper layers of the dermis with a desmoplastic stroma (Figure 2). Slight cytologic atypia was noted. A diagnosis of VC was made based on the clinical and histopathologic findings. The patient’s right big toe was amputated by plastic surgery 6 months after the initial presentation.

Histopathologic examination, especially of superficial biopsies, generally reveals squamous cell proliferation demonstrating minimal pleomorphism and cytologic atypia with sparse mitotic figures.^4-6 Diagnosis of VC can be challenging if the endophytic proliferation, which characteristically pushes into the dermis and even deeper tissues at the base of the lesion, is not seen. This feature is uncommon in squamous cell carcinomas.^3,4,6 Histopathologic detection of koilocytes can lead to difficulty in distinguishing VC from warts.⁵ The growth of lesions is exophytic in plantar verrucae, whereas in VC it may be either exophytic or endophytic.⁴ At early stages, it is too difficult to distinguish VC from pseudoepitheliomatous hyperplasia caused by chronic inflammation, as well as from tuberculosis and subcutaneous mycoses.^3,6 In these situations, possible responsible microorganisms must be sought out. Amelanotic malignant melanoma and eccrine poroma also should be considered in the differential diagnosis.^3,5 If the biopsy specimen is obtained superficially and is fragmented, the diagnosis is more difficult, making deep biopsies essential in suspicious cases.⁴ Excision is the best treatment, and Mohs micrographic surgery may be required in some cases.^2,3,11 It is important to consider that radiotherapy may lead to anaplastic transformation and metastasis.² Metastasis to lymph nodes is very rare, and the prognosis is excellent when complete excision is performed.² Recurrence may be observed.⁴

Our case of plantar VC is notable because of the patient’s young age, which is uncommon, as the typical age for developing VC is late middle age (ie, fifth and sixth decades of life). A long-standing lesion that is therapy resistant and without a detectable microorganism should be investigated for malignancy by repetitive deep biopsy regardless of the patient’s age, as demonstrated in our case.

To the Editor:

Verrucous carcinoma (VC) is a rare type of squamous cell carcinoma characterized by a well-differentiated low-grade tumor with a high degree of keratinization. First described by Ackerman¹ in 1948, VC presents on the skin or oral and genital mucosae with minimal atypical cytologic findings.^1-3 It most commonly is seen in late middle-aged men (85% of cases) and presents as a slow-growing mass, often of more than 10 years’ duration.^2,3 Verrucous carcinoma frequently is observed at 3 particular anatomic sites: the oral cavity, known as oral florid papillomatosis; the anogenital area, known as Buschke-Löwenstein tumor; and on the plantar surface, known as epithelioma cuniculatum.^2-13

A 19-year-old man presented with an ulcerous lesion on the right big toe of 2 years’ duration. He reported that the lesion had gradually increased in size and was painful when walking. Physical examination revealed an ulcerated lesion on the right big toe with purulent inflammation and necrosis, unclear edges, and border nodules containing a fatty, yellowish, foul-smelling material (Figure 1). Histologic examination of purulent material from deep within the primary lesion revealed gram-negative rods and gram-positive diplococci. Erlich-Ziehl-Neelsen staining and culture in Lowenstein-Jensen medium were negative for mycobacteria. Histologic examination and fungal culture were not diagnostic for fungal infection.

At the initial presentation, radiography of the right big toe revealed porotic signs and cortical irregularity of the distal phalanx. A deep incisional biopsy of the lesion was performed for pathologic and microbiologic analysis. Erlich-Ziehl-Neelsen staining was negative, fungal elements could not be observed, and there was no growth in Lowenstein-Jensen medium or Sabouraud dextrose agar. Polymerase chain reaction for human papillomavirus, M tuberculosis, and atypical mycobacterium was negative. Periodic acid–Schiff staining was negative for fungal elements. Histopathologic examination revealed an exophytic as well as endophytic squamous cell proliferation infiltrating deeper layers of the dermis with a desmoplastic stroma (Figure 2). Slight cytologic atypia was noted. A diagnosis of VC was made based on the clinical and histopathologic findings. The patient’s right big toe was amputated by plastic surgery 6 months after the initial presentation.

Histopathologic examination, especially of superficial biopsies, generally reveals squamous cell proliferation demonstrating minimal pleomorphism and cytologic atypia with sparse mitotic figures.^4-6 Diagnosis of VC can be challenging if the endophytic proliferation, which characteristically pushes into the dermis and even deeper tissues at the base of the lesion, is not seen. This feature is uncommon in squamous cell carcinomas.^3,4,6 Histopathologic detection of koilocytes can lead to difficulty in distinguishing VC from warts.⁵ The growth of lesions is exophytic in plantar verrucae, whereas in VC it may be either exophytic or endophytic.⁴ At early stages, it is too difficult to distinguish VC from pseudoepitheliomatous hyperplasia caused by chronic inflammation, as well as from tuberculosis and subcutaneous mycoses.^3,6 In these situations, possible responsible microorganisms must be sought out. Amelanotic malignant melanoma and eccrine poroma also should be considered in the differential diagnosis.^3,5 If the biopsy specimen is obtained superficially and is fragmented, the diagnosis is more difficult, making deep biopsies essential in suspicious cases.⁴ Excision is the best treatment, and Mohs micrographic surgery may be required in some cases.^2,3,11 It is important to consider that radiotherapy may lead to anaplastic transformation and metastasis.² Metastasis to lymph nodes is very rare, and the prognosis is excellent when complete excision is performed.² Recurrence may be observed.⁴

Our case of plantar VC is notable because of the patient’s young age, which is uncommon, as the typical age for developing VC is late middle age (ie, fifth and sixth decades of life). A long-standing lesion that is therapy resistant and without a detectable microorganism should be investigated for malignancy by repetitive deep biopsy regardless of the patient’s age, as demonstrated in our case.

To the Editor:

Hyperkeratosis lenticularis perstans (HLP), or Flegel disease, is a rare keratinization disorder characterized by asymptomatic, red-brown, 1- to 5-mm papules with irregular horny scales commonly seen on the dorsal feet and lower legs.¹ Hyperkeratosis lenticularis perstans is notorious for being difficult to treat. Various treatment options, including 5-fluorouracil, topical and oral retinoids, vitamin D₃ derivatives, psoralen plus UVA therapy, and dermabrasion, have been explored but none have proven to be consistently effective.

A woman in her 50s presented with an asymptomatic eruption on the legs and thighs that had been present for the last 20 years. She had been misdiagnosed by multiple outside providers with atopic dermatitis and was treated with topical steroids without considerable improvement. Upon initial presentation to our clinic , physical examination revealed a woman with Fitzpatrick skin type II with multiple hyperpigmented, red-brown, 2- to 6-mm papules on the extensor surfaces of the lower legs and upper thighs (Figure, A). A 3-mm punch biopsy of a lesion on the right upper thigh revealed hyperkeratosis and parakeratosis with basal layer degeneration and a perivascular lymphocytic infiltrate. The clinical and histopathologic findings were consistent with HLP.

The patient was started on treatment with 5-fluorouracil cream on the right leg and tazarotene cream 0.1% on the left leg to determine which agent would work best. After 9 weeks of treatment, slight improvement was observed on both legs, but the lesions were still erythematous (Figure, B). Treatment was continued, and after 14 weeks complete resolution of the lesions was noted on both legs; however, postinflammatory hyperpigmentation (PIH) was observed on the left leg, which had been treated with tazarotene (Figure, C). The patient was lost to follow-up prior to treatment of the PIH.

In PIH, there is either abnormal production or distribution of melanin pigment in the epidermis and/or dermis. Several mechanisms for PIH have been suggested. One potential mechanism is disruption of the basal cell layer due to dermal lymphocytic inflammation, causing melanin to be released and trapped by macrophages present in the dermal papillae. Another possible mechanism is epidermal hypermelanosis, in which the release and oxidation of arachidonic acid to prostaglandins and leukotrienes alters immune cells and melanocytes, causing an increase in melanin and increased transfer of melanin to keratinocytes in the surrounding epidermis.⁴

Treatment of PIH can be a difficult and prolonged process, especially when a dermal rather than epidermal melanosis is observed. Topical retinoids, topical hydroquinone, azelaic acid, corticosteroids, tretinoin cream, glycolic acid, and trichloroacetic acid have been shown to be effective in treating epidermal PIH. Tazarotene is a synthetic retinoid that has been proven to be an effective treatment of PIH³; however, in our patient the PIH progressed with treatment. One plausible explanation is that irritation caused by the medication led to further PIH.^2,5

It is uncommon for tazarotene to cause PIH. Hyperpigmentation is listed as an adverse effect observed during the postmarketing experience according to one manufacturer⁶ and the US Food and Drug Administration; however, details about prior incidents of hyperpigmentation have not been reported in the literature. Our case is unique because both treatments showed considerable improvement in HLP, but more PIH was observed on the tazarotene-treated leg.

To the Editor:

Hyperkeratosis lenticularis perstans (HLP), or Flegel disease, is a rare keratinization disorder characterized by asymptomatic, red-brown, 1- to 5-mm papules with irregular horny scales commonly seen on the dorsal feet and lower legs.¹ Hyperkeratosis lenticularis perstans is notorious for being difficult to treat. Various treatment options, including 5-fluorouracil, topical and oral retinoids, vitamin D₃ derivatives, psoralen plus UVA therapy, and dermabrasion, have been explored but none have proven to be consistently effective.

A woman in her 50s presented with an asymptomatic eruption on the legs and thighs that had been present for the last 20 years. She had been misdiagnosed by multiple outside providers with atopic dermatitis and was treated with topical steroids without considerable improvement. Upon initial presentation to our clinic , physical examination revealed a woman with Fitzpatrick skin type II with multiple hyperpigmented, red-brown, 2- to 6-mm papules on the extensor surfaces of the lower legs and upper thighs (Figure, A). A 3-mm punch biopsy of a lesion on the right upper thigh revealed hyperkeratosis and parakeratosis with basal layer degeneration and a perivascular lymphocytic infiltrate. The clinical and histopathologic findings were consistent with HLP.

The patient was started on treatment with 5-fluorouracil cream on the right leg and tazarotene cream 0.1% on the left leg to determine which agent would work best. After 9 weeks of treatment, slight improvement was observed on both legs, but the lesions were still erythematous (Figure, B). Treatment was continued, and after 14 weeks complete resolution of the lesions was noted on both legs; however, postinflammatory hyperpigmentation (PIH) was observed on the left leg, which had been treated with tazarotene (Figure, C). The patient was lost to follow-up prior to treatment of the PIH.

In PIH, there is either abnormal production or distribution of melanin pigment in the epidermis and/or dermis. Several mechanisms for PIH have been suggested. One potential mechanism is disruption of the basal cell layer due to dermal lymphocytic inflammation, causing melanin to be released and trapped by macrophages present in the dermal papillae. Another possible mechanism is epidermal hypermelanosis, in which the release and oxidation of arachidonic acid to prostaglandins and leukotrienes alters immune cells and melanocytes, causing an increase in melanin and increased transfer of melanin to keratinocytes in the surrounding epidermis.⁴

Treatment of PIH can be a difficult and prolonged process, especially when a dermal rather than epidermal melanosis is observed. Topical retinoids, topical hydroquinone, azelaic acid, corticosteroids, tretinoin cream, glycolic acid, and trichloroacetic acid have been shown to be effective in treating epidermal PIH. Tazarotene is a synthetic retinoid that has been proven to be an effective treatment of PIH³; however, in our patient the PIH progressed with treatment. One plausible explanation is that irritation caused by the medication led to further PIH.^2,5

It is uncommon for tazarotene to cause PIH. Hyperpigmentation is listed as an adverse effect observed during the postmarketing experience according to one manufacturer⁶ and the US Food and Drug Administration; however, details about prior incidents of hyperpigmentation have not been reported in the literature. Our case is unique because both treatments showed considerable improvement in HLP, but more PIH was observed on the tazarotene-treated leg.

To the Editor:

Hyperkeratosis lenticularis perstans (HLP), or Flegel disease, is a rare keratinization disorder characterized by asymptomatic, red-brown, 1- to 5-mm papules with irregular horny scales commonly seen on the dorsal feet and lower legs.¹ Hyperkeratosis lenticularis perstans is notorious for being difficult to treat. Various treatment options, including 5-fluorouracil, topical and oral retinoids, vitamin D₃ derivatives, psoralen plus UVA therapy, and dermabrasion, have been explored but none have proven to be consistently effective.

A woman in her 50s presented with an asymptomatic eruption on the legs and thighs that had been present for the last 20 years. She had been misdiagnosed by multiple outside providers with atopic dermatitis and was treated with topical steroids without considerable improvement. Upon initial presentation to our clinic , physical examination revealed a woman with Fitzpatrick skin type II with multiple hyperpigmented, red-brown, 2- to 6-mm papules on the extensor surfaces of the lower legs and upper thighs (Figure, A). A 3-mm punch biopsy of a lesion on the right upper thigh revealed hyperkeratosis and parakeratosis with basal layer degeneration and a perivascular lymphocytic infiltrate. The clinical and histopathologic findings were consistent with HLP.

The patient was started on treatment with 5-fluorouracil cream on the right leg and tazarotene cream 0.1% on the left leg to determine which agent would work best. After 9 weeks of treatment, slight improvement was observed on both legs, but the lesions were still erythematous (Figure, B). Treatment was continued, and after 14 weeks complete resolution of the lesions was noted on both legs; however, postinflammatory hyperpigmentation (PIH) was observed on the left leg, which had been treated with tazarotene (Figure, C). The patient was lost to follow-up prior to treatment of the PIH.

In PIH, there is either abnormal production or distribution of melanin pigment in the epidermis and/or dermis. Several mechanisms for PIH have been suggested. One potential mechanism is disruption of the basal cell layer due to dermal lymphocytic inflammation, causing melanin to be released and trapped by macrophages present in the dermal papillae. Another possible mechanism is epidermal hypermelanosis, in which the release and oxidation of arachidonic acid to prostaglandins and leukotrienes alters immune cells and melanocytes, causing an increase in melanin and increased transfer of melanin to keratinocytes in the surrounding epidermis.⁴

Treatment of PIH can be a difficult and prolonged process, especially when a dermal rather than epidermal melanosis is observed. Topical retinoids, topical hydroquinone, azelaic acid, corticosteroids, tretinoin cream, glycolic acid, and trichloroacetic acid have been shown to be effective in treating epidermal PIH. Tazarotene is a synthetic retinoid that has been proven to be an effective treatment of PIH³; however, in our patient the PIH progressed with treatment. One plausible explanation is that irritation caused by the medication led to further PIH.^2,5

It is uncommon for tazarotene to cause PIH. Hyperpigmentation is listed as an adverse effect observed during the postmarketing experience according to one manufacturer⁶ and the US Food and Drug Administration; however, details about prior incidents of hyperpigmentation have not been reported in the literature. Our case is unique because both treatments showed considerable improvement in HLP, but more PIH was observed on the tazarotene-treated leg.

To the Editor:

A 75-year-old woman with a history of hypertension, gout, and adult-onset diabetes mellitus was started on dapagliflozin (5 mg) for glycemic control (hemoglobin A_1c, 7.9 [reference range, 4–7]). Within 1 week of starting the medication, she developed a fine papular eruption in a photodistributed area on the neck and chest with associated malaise. The rash progressed over the next 2 weeks, evolving into edematous papules and plaques, some with vesicles involving the neck, chest, postauricular areas, and nose. Approximately 3 weeks after starting dapagliflozin, the patient also developed bilateral painful, hemorrhagic, bullous plaques (10×3 cm overall) without satellite lesions on the dorsal aspects of the hands. The borders of the bullae had rapidly expanding geographic margins and were extremely painful. The patient’s primary care physician advised to discontinue dapagliflozin, as this medication was thought to be triggering the eruption. She was administered triamcinolone (40 mg intramuscularly) and advised to take ibuprofen as needed. She had malaise and reported that she felt hot but had no known fever. No laboratory tests were ordered. 

The lesions on the neck and chest began to fade within 1 week of stopping the medication and administering corticosteroids; however, the hand lesions continued to progress and began to involve the base of the digits (Figure 1). The patient was then seen by a dermatologist who biopsied the hand lesions. Histopathology was characteristic of Sweet syndrome, also known as acute febrile neutrophilic dermatosis and Gomm-Button disease. Notably, there was a dense nodular infiltrate of neutrophils, papillary dermal edema, and leukocytoclastic debris without leukocytoclastic vasculitis (Figure 2).

Because of the presence of lesions on the dorsal aspects of the hands in our patient, the differential diagnosis included the localized variant of Sweet syndrome known as neutrophilic dermatosis of the dorsal hands, but a diagnosis of classic Sweet syndrome was favored due to the lack of intense papillary dermal edema and vasculitis.^1,2 Although the hand lesions appeared after the neck and chest lesions, the temporal relationship of their appearance with medication usage and clearing once the medication was stopped favored these lesions as part of the same drug-induced response.

Dapagliflozin is a member of a new class of medications (gliflozins) used for the treatment of type 2 diabetes mellitus.^3,4 The medication lowers blood glucose by inhibiting the sodium-glucose cotransport protein 2, thus lowering the blood glucose levels by increasing urinary excretion of glucose. Because many patients with type 2 diabetes mellitus are overweight, these medications are poised to gain popularity for weight loss and decreased blood pressure side effects. Three other medications in this class also have been approved by US Food and Drug Administration: empagliflozin, canagliflozin, and ertugliflozin.

Sweet syndrome consists of 4 cardinal features that were first described in 1964: fever, leukocytosis, tender red plaques, and a dermal neutrophilic infiltrate.⁵ Since then, Su and Liu⁶ proposed guidelines consisting of major and minor criteria. In 1996, Walker and Cohen⁷ suggested a set of diagnostic criteria specifically for drug-induced Sweet syndrome, including painful erythematous plaques, histopathologic neutrophilic infiltrate, and fever. Additional criteria included a temporal relationship between drug ingestion and clinical presentation as well as resolution of lesions after drug withdrawal or treatment with systemic corticosteroids.⁷ The lesions of drug-induced Sweet syndrome often are described as painful red papules that can form plaques, may appear vesicular, and are more common in women. These lesions classically appear on the upper extremities, as well as the head, neck, trunk, and back.⁸ Clinically, symptoms most commonly include fever and musculoskeletal involvement, both of which were experienced by the patient who described herself as feeling feverish when the lesions first appeared and reported malaise. Our patient experienced all of these features, and although a fever was not measured in the acute stage of presentation, she reported feeling hot. Other symptoms that may occur include arthralgia, headache, and myalgia.⁹ Microscopically, there is a nodular infiltrate of neutrophils, papillary dermal edema, and leukocytoclastic debris. The pathogenesis of Sweet syndrome remains unclear but can be associated with malignancy, pregnancy, autoimmune disorders, and drug reactions.¹⁰ Many different classes of medications have been reported to cause drug-induced Sweet syndrome and are listed in the Table.^1,8,11 The recommended treatment of Sweet syndrome is systemic corticosteroids.¹²

To the Editor:

A 75-year-old woman with a history of hypertension, gout, and adult-onset diabetes mellitus was started on dapagliflozin (5 mg) for glycemic control (hemoglobin A_1c, 7.9 [reference range, 4–7]). Within 1 week of starting the medication, she developed a fine papular eruption in a photodistributed area on the neck and chest with associated malaise. The rash progressed over the next 2 weeks, evolving into edematous papules and plaques, some with vesicles involving the neck, chest, postauricular areas, and nose. Approximately 3 weeks after starting dapagliflozin, the patient also developed bilateral painful, hemorrhagic, bullous plaques (10×3 cm overall) without satellite lesions on the dorsal aspects of the hands. The borders of the bullae had rapidly expanding geographic margins and were extremely painful. The patient’s primary care physician advised to discontinue dapagliflozin, as this medication was thought to be triggering the eruption. She was administered triamcinolone (40 mg intramuscularly) and advised to take ibuprofen as needed. She had malaise and reported that she felt hot but had no known fever. No laboratory tests were ordered. 

The lesions on the neck and chest began to fade within 1 week of stopping the medication and administering corticosteroids; however, the hand lesions continued to progress and began to involve the base of the digits (Figure 1). The patient was then seen by a dermatologist who biopsied the hand lesions. Histopathology was characteristic of Sweet syndrome, also known as acute febrile neutrophilic dermatosis and Gomm-Button disease. Notably, there was a dense nodular infiltrate of neutrophils, papillary dermal edema, and leukocytoclastic debris without leukocytoclastic vasculitis (Figure 2).

Because of the presence of lesions on the dorsal aspects of the hands in our patient, the differential diagnosis included the localized variant of Sweet syndrome known as neutrophilic dermatosis of the dorsal hands, but a diagnosis of classic Sweet syndrome was favored due to the lack of intense papillary dermal edema and vasculitis.^1,2 Although the hand lesions appeared after the neck and chest lesions, the temporal relationship of their appearance with medication usage and clearing once the medication was stopped favored these lesions as part of the same drug-induced response.

Dapagliflozin is a member of a new class of medications (gliflozins) used for the treatment of type 2 diabetes mellitus.^3,4 The medication lowers blood glucose by inhibiting the sodium-glucose cotransport protein 2, thus lowering the blood glucose levels by increasing urinary excretion of glucose. Because many patients with type 2 diabetes mellitus are overweight, these medications are poised to gain popularity for weight loss and decreased blood pressure side effects. Three other medications in this class also have been approved by US Food and Drug Administration: empagliflozin, canagliflozin, and ertugliflozin.

Sweet syndrome consists of 4 cardinal features that were first described in 1964: fever, leukocytosis, tender red plaques, and a dermal neutrophilic infiltrate.⁵ Since then, Su and Liu⁶ proposed guidelines consisting of major and minor criteria. In 1996, Walker and Cohen⁷ suggested a set of diagnostic criteria specifically for drug-induced Sweet syndrome, including painful erythematous plaques, histopathologic neutrophilic infiltrate, and fever. Additional criteria included a temporal relationship between drug ingestion and clinical presentation as well as resolution of lesions after drug withdrawal or treatment with systemic corticosteroids.⁷ The lesions of drug-induced Sweet syndrome often are described as painful red papules that can form plaques, may appear vesicular, and are more common in women. These lesions classically appear on the upper extremities, as well as the head, neck, trunk, and back.⁸ Clinically, symptoms most commonly include fever and musculoskeletal involvement, both of which were experienced by the patient who described herself as feeling feverish when the lesions first appeared and reported malaise. Our patient experienced all of these features, and although a fever was not measured in the acute stage of presentation, she reported feeling hot. Other symptoms that may occur include arthralgia, headache, and myalgia.⁹ Microscopically, there is a nodular infiltrate of neutrophils, papillary dermal edema, and leukocytoclastic debris. The pathogenesis of Sweet syndrome remains unclear but can be associated with malignancy, pregnancy, autoimmune disorders, and drug reactions.¹⁰ Many different classes of medications have been reported to cause drug-induced Sweet syndrome and are listed in the Table.^1,8,11 The recommended treatment of Sweet syndrome is systemic corticosteroids.¹²

To the Editor:

A 75-year-old woman with a history of hypertension, gout, and adult-onset diabetes mellitus was started on dapagliflozin (5 mg) for glycemic control (hemoglobin A_1c, 7.9 [reference range, 4–7]). Within 1 week of starting the medication, she developed a fine papular eruption in a photodistributed area on the neck and chest with associated malaise. The rash progressed over the next 2 weeks, evolving into edematous papules and plaques, some with vesicles involving the neck, chest, postauricular areas, and nose. Approximately 3 weeks after starting dapagliflozin, the patient also developed bilateral painful, hemorrhagic, bullous plaques (10×3 cm overall) without satellite lesions on the dorsal aspects of the hands. The borders of the bullae had rapidly expanding geographic margins and were extremely painful. The patient’s primary care physician advised to discontinue dapagliflozin, as this medication was thought to be triggering the eruption. She was administered triamcinolone (40 mg intramuscularly) and advised to take ibuprofen as needed. She had malaise and reported that she felt hot but had no known fever. No laboratory tests were ordered. 

The lesions on the neck and chest began to fade within 1 week of stopping the medication and administering corticosteroids; however, the hand lesions continued to progress and began to involve the base of the digits (Figure 1). The patient was then seen by a dermatologist who biopsied the hand lesions. Histopathology was characteristic of Sweet syndrome, also known as acute febrile neutrophilic dermatosis and Gomm-Button disease. Notably, there was a dense nodular infiltrate of neutrophils, papillary dermal edema, and leukocytoclastic debris without leukocytoclastic vasculitis (Figure 2).

Because of the presence of lesions on the dorsal aspects of the hands in our patient, the differential diagnosis included the localized variant of Sweet syndrome known as neutrophilic dermatosis of the dorsal hands, but a diagnosis of classic Sweet syndrome was favored due to the lack of intense papillary dermal edema and vasculitis.^1,2 Although the hand lesions appeared after the neck and chest lesions, the temporal relationship of their appearance with medication usage and clearing once the medication was stopped favored these lesions as part of the same drug-induced response.

Dapagliflozin is a member of a new class of medications (gliflozins) used for the treatment of type 2 diabetes mellitus.^3,4 The medication lowers blood glucose by inhibiting the sodium-glucose cotransport protein 2, thus lowering the blood glucose levels by increasing urinary excretion of glucose. Because many patients with type 2 diabetes mellitus are overweight, these medications are poised to gain popularity for weight loss and decreased blood pressure side effects. Three other medications in this class also have been approved by US Food and Drug Administration: empagliflozin, canagliflozin, and ertugliflozin.

Sweet syndrome consists of 4 cardinal features that were first described in 1964: fever, leukocytosis, tender red plaques, and a dermal neutrophilic infiltrate.⁵ Since then, Su and Liu⁶ proposed guidelines consisting of major and minor criteria. In 1996, Walker and Cohen⁷ suggested a set of diagnostic criteria specifically for drug-induced Sweet syndrome, including painful erythematous plaques, histopathologic neutrophilic infiltrate, and fever. Additional criteria included a temporal relationship between drug ingestion and clinical presentation as well as resolution of lesions after drug withdrawal or treatment with systemic corticosteroids.⁷ The lesions of drug-induced Sweet syndrome often are described as painful red papules that can form plaques, may appear vesicular, and are more common in women. These lesions classically appear on the upper extremities, as well as the head, neck, trunk, and back.⁸ Clinically, symptoms most commonly include fever and musculoskeletal involvement, both of which were experienced by the patient who described herself as feeling feverish when the lesions first appeared and reported malaise. Our patient experienced all of these features, and although a fever was not measured in the acute stage of presentation, she reported feeling hot. Other symptoms that may occur include arthralgia, headache, and myalgia.⁹ Microscopically, there is a nodular infiltrate of neutrophils, papillary dermal edema, and leukocytoclastic debris. The pathogenesis of Sweet syndrome remains unclear but can be associated with malignancy, pregnancy, autoimmune disorders, and drug reactions.¹⁰ Many different classes of medications have been reported to cause drug-induced Sweet syndrome and are listed in the Table.^1,8,11 The recommended treatment of Sweet syndrome is systemic corticosteroids.¹²

To the Editor:

Evidence-based recommendations for optimal medical management of patients with immunobullous diseases prior to elective surgery are sparse.^1,2 There is an uncertain balance between the use of immunomodulators and immunosuppressants, and implementation of these agents is heavily weighted against an increased infection risk from both active disease with denuded skin and suboptimal wound healing due to iatrogenic immunosuppression.^1-5 Historically, clinical management of epidermolysis bullosa acquisita (EBA) seldomly has resulted in substantial disease resolution.^1,3,4 Herein, we describe a case of recalcitrant EBA that was treated with a combination of intravenous immunoglobulin (IVIG) and dapsone, which resulted in a favorable clinical response and successful hip arthroplasty without cutaneous complications.

A 66-year-old man presented to an outside clinic with nonhealing ulcers on the oral mucosa, hands, groin, and feet. He was treated with systemic steroids after a histologic examination suggested bullous pemphigoid, but the lesions did not exhibit any appreciable improvement after several months of treatment. Despite the lack of improvement, the patient was continued on systemic steroids with a waxing and waning disease course.

Within a year, the patient presented to an orthopedist at our institution with severe left hip pain that had been limiting his mobility and had become unresponsive to conservative therapy. Radiologic investigations suggested advanced osteoarthritis and avascular necrosis of the left hip. Surgical intervention was delayed, as his orthopedist expressed concern that the extent of the body surface area affected by cutaneous denudation placed him at an unacceptable risk for infection. The orthopedic surgeon then referred the patient to our clinic for evaluation of the lesions. Physical examination revealed numerous crusted erosions in various stages of healing on the oral mucosa, palms, groin, and soles. Repeat biopsy of a denuded ulcer on the patient’s arm was obtained by our providers (nearly 1 year after the first biopsy by the outside physician). Histologic examination showed a pauci-immune subepidermal blister without acantholysis, which in combination with the clinical presentation of tense bullae on trauma-prone surfaces led to a favored diagnosis of EBA.

The patient began trials of several immunomodulatory and immunosuppressive agents, both in isolation and in combination, including systemic steroids, mycophenolate mofetil, four 1000-mg infusions of rituximab, and dapsone. Although results were suboptimal, dapsone 150 mg once daily for 3 months yielded the greatest clinical improvement with subsequent granulation and/or re-epithelialization of the chronic ulcers. After discussion during our department’s Grand Rounds, it was determined that the patient should undergo a trial of IVIG infusions, which were initiated with a loading dose of 2000 mg/kg over 5 consecutive days, followed by once-monthly maintenance infusion doses of 1200 mg/kg for 4 consecutive months. While receiving IVIG, he was maintained on a once-daily dose of dapsone 150 mg. This dual approach was designed to suppress both the humoral and cellular-mediated disease mechanisms so that his treatment would obviate the need for systemic corticosteroids.

Following this treatment regimen, he was noted to have marked improvement with only few scattered healing erosions. Upon completion of his last IVIG infusion, his cutaneous and mucosal manifestations of EBA were greatly minimized, demonstrating the best level of control that had been achieved during the disease course (Figure 1). This therapy completely cleared the cutaneous and mucosal ulcerations, thus permitting the patient to undergo a total left hip arthroplasty without complications (Figure 2).

Our report is novel in that it supports a combination of IVIG and dapsone as a viable presurgical therapy for patients with EBA, and this treatment also may be applicable for other primary immunobullous disorders.^2,5 Our case was particularly challenging in that the severity of the patient’s bullous disease precluded him from an elective orthopedic joint replacement due to the risk for wound dehiscence and surgical site infection.² We determined that IVIG and dapsone would be the most optimal combination therapy to facilitate superior disease control and concurrently allow for appropriate wound healing without impairing the host immune response. This report is unique from a clinical perspective in that a balance was successfully achieved between immune suppression, with avoidance of associated side effects, and disease activity.

To the Editor:

Evidence-based recommendations for optimal medical management of patients with immunobullous diseases prior to elective surgery are sparse.^1,2 There is an uncertain balance between the use of immunomodulators and immunosuppressants, and implementation of these agents is heavily weighted against an increased infection risk from both active disease with denuded skin and suboptimal wound healing due to iatrogenic immunosuppression.^1-5 Historically, clinical management of epidermolysis bullosa acquisita (EBA) seldomly has resulted in substantial disease resolution.^1,3,4 Herein, we describe a case of recalcitrant EBA that was treated with a combination of intravenous immunoglobulin (IVIG) and dapsone, which resulted in a favorable clinical response and successful hip arthroplasty without cutaneous complications.

A 66-year-old man presented to an outside clinic with nonhealing ulcers on the oral mucosa, hands, groin, and feet. He was treated with systemic steroids after a histologic examination suggested bullous pemphigoid, but the lesions did not exhibit any appreciable improvement after several months of treatment. Despite the lack of improvement, the patient was continued on systemic steroids with a waxing and waning disease course.

Within a year, the patient presented to an orthopedist at our institution with severe left hip pain that had been limiting his mobility and had become unresponsive to conservative therapy. Radiologic investigations suggested advanced osteoarthritis and avascular necrosis of the left hip. Surgical intervention was delayed, as his orthopedist expressed concern that the extent of the body surface area affected by cutaneous denudation placed him at an unacceptable risk for infection. The orthopedic surgeon then referred the patient to our clinic for evaluation of the lesions. Physical examination revealed numerous crusted erosions in various stages of healing on the oral mucosa, palms, groin, and soles. Repeat biopsy of a denuded ulcer on the patient’s arm was obtained by our providers (nearly 1 year after the first biopsy by the outside physician). Histologic examination showed a pauci-immune subepidermal blister without acantholysis, which in combination with the clinical presentation of tense bullae on trauma-prone surfaces led to a favored diagnosis of EBA.

The patient began trials of several immunomodulatory and immunosuppressive agents, both in isolation and in combination, including systemic steroids, mycophenolate mofetil, four 1000-mg infusions of rituximab, and dapsone. Although results were suboptimal, dapsone 150 mg once daily for 3 months yielded the greatest clinical improvement with subsequent granulation and/or re-epithelialization of the chronic ulcers. After discussion during our department’s Grand Rounds, it was determined that the patient should undergo a trial of IVIG infusions, which were initiated with a loading dose of 2000 mg/kg over 5 consecutive days, followed by once-monthly maintenance infusion doses of 1200 mg/kg for 4 consecutive months. While receiving IVIG, he was maintained on a once-daily dose of dapsone 150 mg. This dual approach was designed to suppress both the humoral and cellular-mediated disease mechanisms so that his treatment would obviate the need for systemic corticosteroids.

Following this treatment regimen, he was noted to have marked improvement with only few scattered healing erosions. Upon completion of his last IVIG infusion, his cutaneous and mucosal manifestations of EBA were greatly minimized, demonstrating the best level of control that had been achieved during the disease course (Figure 1). This therapy completely cleared the cutaneous and mucosal ulcerations, thus permitting the patient to undergo a total left hip arthroplasty without complications (Figure 2).

Our report is novel in that it supports a combination of IVIG and dapsone as a viable presurgical therapy for patients with EBA, and this treatment also may be applicable for other primary immunobullous disorders.^2,5 Our case was particularly challenging in that the severity of the patient’s bullous disease precluded him from an elective orthopedic joint replacement due to the risk for wound dehiscence and surgical site infection.² We determined that IVIG and dapsone would be the most optimal combination therapy to facilitate superior disease control and concurrently allow for appropriate wound healing without impairing the host immune response. This report is unique from a clinical perspective in that a balance was successfully achieved between immune suppression, with avoidance of associated side effects, and disease activity.

To the Editor:

Evidence-based recommendations for optimal medical management of patients with immunobullous diseases prior to elective surgery are sparse.^1,2 There is an uncertain balance between the use of immunomodulators and immunosuppressants, and implementation of these agents is heavily weighted against an increased infection risk from both active disease with denuded skin and suboptimal wound healing due to iatrogenic immunosuppression.^1-5 Historically, clinical management of epidermolysis bullosa acquisita (EBA) seldomly has resulted in substantial disease resolution.^1,3,4 Herein, we describe a case of recalcitrant EBA that was treated with a combination of intravenous immunoglobulin (IVIG) and dapsone, which resulted in a favorable clinical response and successful hip arthroplasty without cutaneous complications.

A 66-year-old man presented to an outside clinic with nonhealing ulcers on the oral mucosa, hands, groin, and feet. He was treated with systemic steroids after a histologic examination suggested bullous pemphigoid, but the lesions did not exhibit any appreciable improvement after several months of treatment. Despite the lack of improvement, the patient was continued on systemic steroids with a waxing and waning disease course.

Within a year, the patient presented to an orthopedist at our institution with severe left hip pain that had been limiting his mobility and had become unresponsive to conservative therapy. Radiologic investigations suggested advanced osteoarthritis and avascular necrosis of the left hip. Surgical intervention was delayed, as his orthopedist expressed concern that the extent of the body surface area affected by cutaneous denudation placed him at an unacceptable risk for infection. The orthopedic surgeon then referred the patient to our clinic for evaluation of the lesions. Physical examination revealed numerous crusted erosions in various stages of healing on the oral mucosa, palms, groin, and soles. Repeat biopsy of a denuded ulcer on the patient’s arm was obtained by our providers (nearly 1 year after the first biopsy by the outside physician). Histologic examination showed a pauci-immune subepidermal blister without acantholysis, which in combination with the clinical presentation of tense bullae on trauma-prone surfaces led to a favored diagnosis of EBA.

The patient began trials of several immunomodulatory and immunosuppressive agents, both in isolation and in combination, including systemic steroids, mycophenolate mofetil, four 1000-mg infusions of rituximab, and dapsone. Although results were suboptimal, dapsone 150 mg once daily for 3 months yielded the greatest clinical improvement with subsequent granulation and/or re-epithelialization of the chronic ulcers. After discussion during our department’s Grand Rounds, it was determined that the patient should undergo a trial of IVIG infusions, which were initiated with a loading dose of 2000 mg/kg over 5 consecutive days, followed by once-monthly maintenance infusion doses of 1200 mg/kg for 4 consecutive months. While receiving IVIG, he was maintained on a once-daily dose of dapsone 150 mg. This dual approach was designed to suppress both the humoral and cellular-mediated disease mechanisms so that his treatment would obviate the need for systemic corticosteroids.

Following this treatment regimen, he was noted to have marked improvement with only few scattered healing erosions. Upon completion of his last IVIG infusion, his cutaneous and mucosal manifestations of EBA were greatly minimized, demonstrating the best level of control that had been achieved during the disease course (Figure 1). This therapy completely cleared the cutaneous and mucosal ulcerations, thus permitting the patient to undergo a total left hip arthroplasty without complications (Figure 2).

Our report is novel in that it supports a combination of IVIG and dapsone as a viable presurgical therapy for patients with EBA, and this treatment also may be applicable for other primary immunobullous disorders.^2,5 Our case was particularly challenging in that the severity of the patient’s bullous disease precluded him from an elective orthopedic joint replacement due to the risk for wound dehiscence and surgical site infection.² We determined that IVIG and dapsone would be the most optimal combination therapy to facilitate superior disease control and concurrently allow for appropriate wound healing without impairing the host immune response. This report is unique from a clinical perspective in that a balance was successfully achieved between immune suppression, with avoidance of associated side effects, and disease activity.

To the Editor:

A 3.5-year-old boy presented with asymptomatic subcutaneous nodules on the left side of the forehead and frontal scalp of approximately 6 months’ duration. There was no history of trauma or preceding rash. His medical history was remarkable only for allergic rhinitis. A review of systems was otherwise negative. Computed tomography ordered by the patient’s pediatrician prior to referral to dermatology showed soft tissue masses on the forehead and frontal scalp with no associated bone or brain parenchymal signal abnormalities.

At presentation to dermatology, physical examination revealed a 6×7-cm, flesh-colored cluster of firm, nontender, fixed, subcutaneous nodules on the left superior forehead and anterior part of the left frontal scalp (Figure 1A), as well as 2×1.5-cm, firm, fixed, flesh-colored nodule inferior to the larger cluster of lesions (Figure 1B). The remainder of the skin examination was unremarkable.

Granuloma annulare is a benign dermatosis that presents in various forms, including localized, generalized, perforating, and subcutaneous subtypes. Subcutaneous GA (SGA) occurs most commonly in young children. The typical presentation of SGA is single or multiple flesh-colored to pink subcutaneous nodules on the arms, legs, or scalp.¹ On the scalp, SGA has a predilection for the parietal and occipital regions. In some cases, there may be a history of preceding trauma to the area. Typically, lesions on the arms and legs are mobile whereas lesions on the scalp may be fixed due to their close proximity to the periosteum. Patients often are asymptomatic, and in the majority of cases, lesions resolve spontaneously over several months to years. Approximately 50% of cases resolve within 2 years of onset.²

Histologically, SGA appears as a nodule of fibrinoid or necrotic degeneration surrounded by palisaded histiocytes and lymphocytes in the deep dermis or subcutaneous tissue. Subcutaneous granuloma annulare is an accurate term for our case due to the subcutaneous location of the granulomatous change; however, some practitioners may prefer to use the term deep GA when the histologic findings are in the deep dermis vs the subcutis. Often, prominent deposition of mucin may be found. Histologically, SGA can closely resemble a rheumatoid nodule or necrobiosis lipoidica.¹

Subcutaneous GA presenting on the scalp and forehead, such as in our case, can present a diagnostic challenge due to the extensive differential diagnoses that must be considered, including trauma, infection, bone or skin disease, and inflammatory or autoimmune disease.^2,3 Additionally, the firm fixed characteristics of some lesions may raise additional concerns for possible malignant diagnoses such as epithelial sarcoma, peripheral nerve sheath tumor, rhabdomyosarcoma, or Langerhans cell histiocytosis, as highlighted by Agrawal et al.⁴ For these reasons, imaging and biopsy often are necessary for histologic diagnosis.

There is no consensus on the etiology of SGA, and no specific disease associations have been proven. Some case reports and case series have proposed a link between SGA and type 1 diabetes mellitus.^1,4 In one retrospective case series, Grogg and Nascimento¹ found that 2 of 34 (5.9%) pediatric patients with SGA had known or subsequently diagnosed diabetes mellitus; however, a definitive association between the 2 entities has not been elucidated. Underlying type 1 diabetes mellitus should be considered in patients with isolated SGA, but laboratory screening for diabetes is not necessary in patients with a negative review of systems.

Treatment of SGA typically is not required, as it is a self-limited condition. Often, once a histologic diagnosis is established, no further evaluation or treatment is warranted. Multiple treatment modalities have been reported, including intralesional and topical corticosteroids, laser therapy, cryotherapy, and systemic agents such as isotretinoin or corticosteroids; however, no treatment has been shown to be consistently efficacious.⁵ Excision of the lesions may be performed, but the risk for recurrence often precludes it as a viable option. In some case series, there have been recurrence rates as high as 40% to 75% in the months to years following surgical excision/biopsy.^1,6

Patients presenting with presumed SGA should undergo a thorough history, review of systems, and full-body skin examination. In some cases, imaging and biopsy may be necessary to make a definitive diagnosis and exclude a more serious condition.

To the Editor:

A 3.5-year-old boy presented with asymptomatic subcutaneous nodules on the left side of the forehead and frontal scalp of approximately 6 months’ duration. There was no history of trauma or preceding rash. His medical history was remarkable only for allergic rhinitis. A review of systems was otherwise negative. Computed tomography ordered by the patient’s pediatrician prior to referral to dermatology showed soft tissue masses on the forehead and frontal scalp with no associated bone or brain parenchymal signal abnormalities.

At presentation to dermatology, physical examination revealed a 6×7-cm, flesh-colored cluster of firm, nontender, fixed, subcutaneous nodules on the left superior forehead and anterior part of the left frontal scalp (Figure 1A), as well as 2×1.5-cm, firm, fixed, flesh-colored nodule inferior to the larger cluster of lesions (Figure 1B). The remainder of the skin examination was unremarkable.

Granuloma annulare is a benign dermatosis that presents in various forms, including localized, generalized, perforating, and subcutaneous subtypes. Subcutaneous GA (SGA) occurs most commonly in young children. The typical presentation of SGA is single or multiple flesh-colored to pink subcutaneous nodules on the arms, legs, or scalp.¹ On the scalp, SGA has a predilection for the parietal and occipital regions. In some cases, there may be a history of preceding trauma to the area. Typically, lesions on the arms and legs are mobile whereas lesions on the scalp may be fixed due to their close proximity to the periosteum. Patients often are asymptomatic, and in the majority of cases, lesions resolve spontaneously over several months to years. Approximately 50% of cases resolve within 2 years of onset.²

Histologically, SGA appears as a nodule of fibrinoid or necrotic degeneration surrounded by palisaded histiocytes and lymphocytes in the deep dermis or subcutaneous tissue. Subcutaneous granuloma annulare is an accurate term for our case due to the subcutaneous location of the granulomatous change; however, some practitioners may prefer to use the term deep GA when the histologic findings are in the deep dermis vs the subcutis. Often, prominent deposition of mucin may be found. Histologically, SGA can closely resemble a rheumatoid nodule or necrobiosis lipoidica.¹

Subcutaneous GA presenting on the scalp and forehead, such as in our case, can present a diagnostic challenge due to the extensive differential diagnoses that must be considered, including trauma, infection, bone or skin disease, and inflammatory or autoimmune disease.^2,3 Additionally, the firm fixed characteristics of some lesions may raise additional concerns for possible malignant diagnoses such as epithelial sarcoma, peripheral nerve sheath tumor, rhabdomyosarcoma, or Langerhans cell histiocytosis, as highlighted by Agrawal et al.⁴ For these reasons, imaging and biopsy often are necessary for histologic diagnosis.

There is no consensus on the etiology of SGA, and no specific disease associations have been proven. Some case reports and case series have proposed a link between SGA and type 1 diabetes mellitus.^1,4 In one retrospective case series, Grogg and Nascimento¹ found that 2 of 34 (5.9%) pediatric patients with SGA had known or subsequently diagnosed diabetes mellitus; however, a definitive association between the 2 entities has not been elucidated. Underlying type 1 diabetes mellitus should be considered in patients with isolated SGA, but laboratory screening for diabetes is not necessary in patients with a negative review of systems.

Treatment of SGA typically is not required, as it is a self-limited condition. Often, once a histologic diagnosis is established, no further evaluation or treatment is warranted. Multiple treatment modalities have been reported, including intralesional and topical corticosteroids, laser therapy, cryotherapy, and systemic agents such as isotretinoin or corticosteroids; however, no treatment has been shown to be consistently efficacious.⁵ Excision of the lesions may be performed, but the risk for recurrence often precludes it as a viable option. In some case series, there have been recurrence rates as high as 40% to 75% in the months to years following surgical excision/biopsy.^1,6

Patients presenting with presumed SGA should undergo a thorough history, review of systems, and full-body skin examination. In some cases, imaging and biopsy may be necessary to make a definitive diagnosis and exclude a more serious condition.

To the Editor:

A 3.5-year-old boy presented with asymptomatic subcutaneous nodules on the left side of the forehead and frontal scalp of approximately 6 months’ duration. There was no history of trauma or preceding rash. His medical history was remarkable only for allergic rhinitis. A review of systems was otherwise negative. Computed tomography ordered by the patient’s pediatrician prior to referral to dermatology showed soft tissue masses on the forehead and frontal scalp with no associated bone or brain parenchymal signal abnormalities.

At presentation to dermatology, physical examination revealed a 6×7-cm, flesh-colored cluster of firm, nontender, fixed, subcutaneous nodules on the left superior forehead and anterior part of the left frontal scalp (Figure 1A), as well as 2×1.5-cm, firm, fixed, flesh-colored nodule inferior to the larger cluster of lesions (Figure 1B). The remainder of the skin examination was unremarkable.

Granuloma annulare is a benign dermatosis that presents in various forms, including localized, generalized, perforating, and subcutaneous subtypes. Subcutaneous GA (SGA) occurs most commonly in young children. The typical presentation of SGA is single or multiple flesh-colored to pink subcutaneous nodules on the arms, legs, or scalp.¹ On the scalp, SGA has a predilection for the parietal and occipital regions. In some cases, there may be a history of preceding trauma to the area. Typically, lesions on the arms and legs are mobile whereas lesions on the scalp may be fixed due to their close proximity to the periosteum. Patients often are asymptomatic, and in the majority of cases, lesions resolve spontaneously over several months to years. Approximately 50% of cases resolve within 2 years of onset.²

Histologically, SGA appears as a nodule of fibrinoid or necrotic degeneration surrounded by palisaded histiocytes and lymphocytes in the deep dermis or subcutaneous tissue. Subcutaneous granuloma annulare is an accurate term for our case due to the subcutaneous location of the granulomatous change; however, some practitioners may prefer to use the term deep GA when the histologic findings are in the deep dermis vs the subcutis. Often, prominent deposition of mucin may be found. Histologically, SGA can closely resemble a rheumatoid nodule or necrobiosis lipoidica.¹

Subcutaneous GA presenting on the scalp and forehead, such as in our case, can present a diagnostic challenge due to the extensive differential diagnoses that must be considered, including trauma, infection, bone or skin disease, and inflammatory or autoimmune disease.^2,3 Additionally, the firm fixed characteristics of some lesions may raise additional concerns for possible malignant diagnoses such as epithelial sarcoma, peripheral nerve sheath tumor, rhabdomyosarcoma, or Langerhans cell histiocytosis, as highlighted by Agrawal et al.⁴ For these reasons, imaging and biopsy often are necessary for histologic diagnosis.

There is no consensus on the etiology of SGA, and no specific disease associations have been proven. Some case reports and case series have proposed a link between SGA and type 1 diabetes mellitus.^1,4 In one retrospective case series, Grogg and Nascimento¹ found that 2 of 34 (5.9%) pediatric patients with SGA had known or subsequently diagnosed diabetes mellitus; however, a definitive association between the 2 entities has not been elucidated. Underlying type 1 diabetes mellitus should be considered in patients with isolated SGA, but laboratory screening for diabetes is not necessary in patients with a negative review of systems.

Treatment of SGA typically is not required, as it is a self-limited condition. Often, once a histologic diagnosis is established, no further evaluation or treatment is warranted. Multiple treatment modalities have been reported, including intralesional and topical corticosteroids, laser therapy, cryotherapy, and systemic agents such as isotretinoin or corticosteroids; however, no treatment has been shown to be consistently efficacious.⁵ Excision of the lesions may be performed, but the risk for recurrence often precludes it as a viable option. In some case series, there have been recurrence rates as high as 40% to 75% in the months to years following surgical excision/biopsy.^1,6

Patients presenting with presumed SGA should undergo a thorough history, review of systems, and full-body skin examination. In some cases, imaging and biopsy may be necessary to make a definitive diagnosis and exclude a more serious condition.

To the Editor:

A 60-year-old man with a history of basal cell carcinoma, rosacea, and seborrheic dermatitis presented for a routine skin examination. The patient mentioned incidentally that both of his ears were “rock hard” and had been so for the last 10 to 20 years. He was not experiencing hearing abnormalities and denied any history of external ear trauma, frostbite injury of the ears, or history of endocrinopathy. Physical examination revealed normal-appearing skin on the bilateral ears (Figure 1), and palpation confirmed a bonelike consistency of the auricles with sparing of the earlobes. The differential diagnosis included osteoma cutis, ectopic calcification, tophaceous gout, localized scleroderma, and relapsing polychondritis. Incisional biopsy of the left posterior auricle to the level of cartilage revealed a histologically normal epidermis and dermis, with small fragments of cartilage calcification and lacunar bone formation (Figure 2). A radiograph of the skull showed faint calcification of the auricular cartilage, but no other osseous abnormalities were observed (Figure 3). Further laboratory workup including a comprehensive metabolic panel; complete blood cell count; and thyroid stimulating hormone, parathyroid hormone, and cortisol levels were normal. Based on these findings, a diagnosis of bilateral idiopathic auricular ossificans was made. Therapy was not pursued because the patient was asymptomatic, but referral to otolaryngology would have been considered if hearing impairment had occurred.

Auricular ossificans, which is characterized by the replacement of external ear cartilage by bone, is a rare condition with as few as 22 histologically proven cases documented in the literature.^1,2 One case was reported in 2012 with consistent clinical and radiographic findings, but the patient declined biopsy.³ Similar to our patient, many pathologically documented cases have been determined to be idiopathic after workup, with identifiable triggering factors including cold injury, trauma, perichondritis, Addison disease, diabetes, and postpartum hypopituitarism.¹ The male-to-female ratio is 18 to 5, the average age at diagnosis is 57 years, and as many as 70% of cases have demonstrated bilateral involvement.^1,2

The majority of cases of auricular ossificans are asymptomatic at presentation with an insidious onset of the disease process over several years. Physical examination of the ear generally reveals a petrified auricle with sparing of the lobule and an otherwise normal clinical appearance. Radiographs demonstrate calcification, sometimes exactly mimicking the pattern seen in normal bone. Biopsy and histologic analysis show not only calcified cartilage but also actual lamellar bone formation.⁴ Depending on the precipitating factors, laboratory workup may uncover underlying metabolic abnormalities but often is unremarkable. Expert opinion generally recommends against extensive workup, which should be guided by the clinical presentation and the physician’s judgement.⁵ An insufficient number of patients with auricular ossificans have been definitively identified to provide clearer evidence-based recommendations.

Most patients present without pain or hearing abnormalities and do not require treatment. In one case, involvement of both the auricle and external ear canal resulted in intractable cerumen impaction that caused conductive hearing loss, eventually requiring resection of the ossified external ear cartilage and tragus.⁶ The most common reason for treatment has been discomfort impairing sleep, with surgical intervention including conchal reduction or wedge resection.⁵ A combined paucity of cases and poor understanding of the pathophysiologic mechanisms behind auricular ossificans limits current therapeutic options. Fortunately, this process appears to be benign in the majority of patients and generally represents a phenomenon that is much more interesting to the clinician than it is vexing to the patient.

To the Editor:

A 60-year-old man with a history of basal cell carcinoma, rosacea, and seborrheic dermatitis presented for a routine skin examination. The patient mentioned incidentally that both of his ears were “rock hard” and had been so for the last 10 to 20 years. He was not experiencing hearing abnormalities and denied any history of external ear trauma, frostbite injury of the ears, or history of endocrinopathy. Physical examination revealed normal-appearing skin on the bilateral ears (Figure 1), and palpation confirmed a bonelike consistency of the auricles with sparing of the earlobes. The differential diagnosis included osteoma cutis, ectopic calcification, tophaceous gout, localized scleroderma, and relapsing polychondritis. Incisional biopsy of the left posterior auricle to the level of cartilage revealed a histologically normal epidermis and dermis, with small fragments of cartilage calcification and lacunar bone formation (Figure 2). A radiograph of the skull showed faint calcification of the auricular cartilage, but no other osseous abnormalities were observed (Figure 3). Further laboratory workup including a comprehensive metabolic panel; complete blood cell count; and thyroid stimulating hormone, parathyroid hormone, and cortisol levels were normal. Based on these findings, a diagnosis of bilateral idiopathic auricular ossificans was made. Therapy was not pursued because the patient was asymptomatic, but referral to otolaryngology would have been considered if hearing impairment had occurred.

Auricular ossificans, which is characterized by the replacement of external ear cartilage by bone, is a rare condition with as few as 22 histologically proven cases documented in the literature.^1,2 One case was reported in 2012 with consistent clinical and radiographic findings, but the patient declined biopsy.³ Similar to our patient, many pathologically documented cases have been determined to be idiopathic after workup, with identifiable triggering factors including cold injury, trauma, perichondritis, Addison disease, diabetes, and postpartum hypopituitarism.¹ The male-to-female ratio is 18 to 5, the average age at diagnosis is 57 years, and as many as 70% of cases have demonstrated bilateral involvement.^1,2

The majority of cases of auricular ossificans are asymptomatic at presentation with an insidious onset of the disease process over several years. Physical examination of the ear generally reveals a petrified auricle with sparing of the lobule and an otherwise normal clinical appearance. Radiographs demonstrate calcification, sometimes exactly mimicking the pattern seen in normal bone. Biopsy and histologic analysis show not only calcified cartilage but also actual lamellar bone formation.⁴ Depending on the precipitating factors, laboratory workup may uncover underlying metabolic abnormalities but often is unremarkable. Expert opinion generally recommends against extensive workup, which should be guided by the clinical presentation and the physician’s judgement.⁵ An insufficient number of patients with auricular ossificans have been definitively identified to provide clearer evidence-based recommendations.

Most patients present without pain or hearing abnormalities and do not require treatment. In one case, involvement of both the auricle and external ear canal resulted in intractable cerumen impaction that caused conductive hearing loss, eventually requiring resection of the ossified external ear cartilage and tragus.⁶ The most common reason for treatment has been discomfort impairing sleep, with surgical intervention including conchal reduction or wedge resection.⁵ A combined paucity of cases and poor understanding of the pathophysiologic mechanisms behind auricular ossificans limits current therapeutic options. Fortunately, this process appears to be benign in the majority of patients and generally represents a phenomenon that is much more interesting to the clinician than it is vexing to the patient.

To the Editor:

A 60-year-old man with a history of basal cell carcinoma, rosacea, and seborrheic dermatitis presented for a routine skin examination. The patient mentioned incidentally that both of his ears were “rock hard” and had been so for the last 10 to 20 years. He was not experiencing hearing abnormalities and denied any history of external ear trauma, frostbite injury of the ears, or history of endocrinopathy. Physical examination revealed normal-appearing skin on the bilateral ears (Figure 1), and palpation confirmed a bonelike consistency of the auricles with sparing of the earlobes. The differential diagnosis included osteoma cutis, ectopic calcification, tophaceous gout, localized scleroderma, and relapsing polychondritis. Incisional biopsy of the left posterior auricle to the level of cartilage revealed a histologically normal epidermis and dermis, with small fragments of cartilage calcification and lacunar bone formation (Figure 2). A radiograph of the skull showed faint calcification of the auricular cartilage, but no other osseous abnormalities were observed (Figure 3). Further laboratory workup including a comprehensive metabolic panel; complete blood cell count; and thyroid stimulating hormone, parathyroid hormone, and cortisol levels were normal. Based on these findings, a diagnosis of bilateral idiopathic auricular ossificans was made. Therapy was not pursued because the patient was asymptomatic, but referral to otolaryngology would have been considered if hearing impairment had occurred.

Auricular ossificans, which is characterized by the replacement of external ear cartilage by bone, is a rare condition with as few as 22 histologically proven cases documented in the literature.^1,2 One case was reported in 2012 with consistent clinical and radiographic findings, but the patient declined biopsy.³ Similar to our patient, many pathologically documented cases have been determined to be idiopathic after workup, with identifiable triggering factors including cold injury, trauma, perichondritis, Addison disease, diabetes, and postpartum hypopituitarism.¹ The male-to-female ratio is 18 to 5, the average age at diagnosis is 57 years, and as many as 70% of cases have demonstrated bilateral involvement.^1,2

The majority of cases of auricular ossificans are asymptomatic at presentation with an insidious onset of the disease process over several years. Physical examination of the ear generally reveals a petrified auricle with sparing of the lobule and an otherwise normal clinical appearance. Radiographs demonstrate calcification, sometimes exactly mimicking the pattern seen in normal bone. Biopsy and histologic analysis show not only calcified cartilage but also actual lamellar bone formation.⁴ Depending on the precipitating factors, laboratory workup may uncover underlying metabolic abnormalities but often is unremarkable. Expert opinion generally recommends against extensive workup, which should be guided by the clinical presentation and the physician’s judgement.⁵ An insufficient number of patients with auricular ossificans have been definitively identified to provide clearer evidence-based recommendations.

Most patients present without pain or hearing abnormalities and do not require treatment. In one case, involvement of both the auricle and external ear canal resulted in intractable cerumen impaction that caused conductive hearing loss, eventually requiring resection of the ossified external ear cartilage and tragus.⁶ The most common reason for treatment has been discomfort impairing sleep, with surgical intervention including conchal reduction or wedge resection.⁵ A combined paucity of cases and poor understanding of the pathophysiologic mechanisms behind auricular ossificans limits current therapeutic options. Fortunately, this process appears to be benign in the majority of patients and generally represents a phenomenon that is much more interesting to the clinician than it is vexing to the patient.

To the Editor:

Long, dark, and thick eyelashes have been a focal point of society’s perception of beauty for thousands of years,¹ and the use of makeup products such as mascaras, eyeliners, and eye shadows has further increased the perception of attractiveness of the eyes.² Many eyelash enhancement methods have been developed or in some instances have been serendipitously discovered. Bimatoprost ophthalmic solution 0.03% originally was developed as an eye drop that was approved by the US Food and Drug Association (FDA) in 2001 for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. An unexpected side effect of this product was eyelash hypertrichosis.^3,4 As a result, the FDA approved bimatoprost ophthalmic solution 0.03% as an eyelash solution with an eyelid applicator for treatment of eyelash hypotrichosis in 2008.⁵

Because all follicular development occurs during embryogenesis, the number of eyelash follicles does not increase over time.⁶ Bitmatoprost eyelash solution works by prolonging the anagen (growth) phase of the eyelashes and stimulating the transition from the telogen (dormant) phase to the anagen phase. It also has been shown to increase the hair bulb diameter of follicles undergoing the anagen phase, resulting in thicker eyelashes.⁷ Although many patients have enjoyed this unexpected indication, prostaglandin (PG) analogues such as bimatoprost and latanoprost have a well-documented history of ocular side effects when applied directly to the eye. The most common adverse reactions include eye pruritus, conjunctival hyperemia, and eyelid pigmentation.³ The product safety information indicates that eyelid pigmentation typically is reversible.^3,5 Iris pigmentation is perhaps the least desirable side effect of PG analogues and was first noted in latanoprost studies on primates.⁸ The underlying mechanism appears to be due to an increase in melanogenesis that results in an increase in melanin granules without concomitant proliferation of melanocytes, cellular atypia, or evidence of inflammatory reaction. Unfortunately, this pigmentation typically is permanent.^3,5,9

Studies have shown that iris hyperpigmentation can occur when bimatoprost eye drops are applied to the eyes for the treatment of glaucoma and ocular hypertension, but reports associated with bimatoprost eyelash solution are rare.^3,4,10 We report a case of iris hyperpigmentation following cosmetic use of bimatoprost eyelash solution.

An otherwise healthy 63-year-old woman presented to our clinic for an annual skin examination. She noted that she had worsening dark pigmentation of the bilateral irises. The patient did not have any personal or family history of melanoma or ocular nevi, and there were no associated symptoms of eye tearing, pruritus, burning, or discharge. No prior surgical procedures had been performed on or around the eyes, and the patient never used contact lenses. She had been intermittently using bimatoprost eyelash solution prescribed by an outside physician for approximately 3 years to enhance her eyelashes. Although she never applied the product directly into her eyes, she noted that she often was unmethodical in application of the product and that runoff from the product may have occasionally leaked into the eyes. Physical examination revealed bilateral blue irises with ink spot–like, grayish black patches encircling the bilateral pupils (Figure).

There have been several studies of iris hyperpigmentation with use of PG analogues in the treatment of glaucoma. In a phase 3 clinical trial of the safety and efficacy of latanoprost for treatment of ocular hypertension, it was noted that 24 (12%) of 198 patients experienced iris hyperpigmentation and that patients with heterogeneous pigmentation (ie, hazel irises and mixed coloring) were at an increased risk.¹¹ Other studies also have shown an increased risk of iris hyperpigmentation due to heterogeneous phenotype¹² as well as older age.¹³

Reports of bimatoprost eye drops used for treatment of glaucoma have shown a high incidence of iris hyperpigmentation with long-term use. A prospective study conducted in 2012 investigated the adverse events of bimatoprost eye drops in 52 Japanese patients with glaucoma or ocular hypertension. Clinical photographs of the irises, eyelids, and eyelashes were taken at baseline and after 6 months of treatment. It was noted that 50% (26/52) of participants experienced iris hyperpigmentation upon completion of treatment.¹⁰

In our patient, bimatoprost eyelash solution was applied to the top eyelid margins using an applicator; our patient did not use the eye drop formulation, which is directed for use in ocular hypertension or glaucoma. A PubMed search of articles indexed for MEDLINE using the terms bimatoprost and iris hyperpigmentation yielded no published peer-reviewed studies or case reports of iris hyperpigmentation caused by bimatoprost eyelash solution for treatment of eyelid hypotrichosis, which makes this case report novel. With that said, the package insert states iris hyperpigmentation as a side effect in the prescribing information for both a bimatoprost eye drop formulation used to treat ocular hypertension³ as well as a formulation for topical application on the eyelids/eyelashes.⁵ A 2014 retrospective review of long-term safety with bimatoprost eyelash solution for eyelash hypotrichosis reported 4 instances (0.7%) of documented adverse events after 12 months of use in 585 patients, including dry eye, eyelid erythema, ocular pruritus, and low ocular pressure. Iris hyperpigmentation was not reported.¹⁴

The method of bimatoprost application likely is a determining factor in the number of reported adverse events. Studies with similar treatment periods have demonstrated more adverse events associated with bimatoprost eye drops vs eyelash solution.^15,16 When bimatoprost is used in the eye drop formulation for treatment of glaucoma, iris hyperpigmentation has been estimated to occur in 1.5%⁴ to 50%⁹ of cases. To our knowledge, there are no documented cases when bimatoprost eyelash solution is applied with a dermal applicator for treatment of eyelash hypotrichosis.^15,17 These results may be explained using an ocular splash test. In one study using lissamine green dye, decreased delivery of bimatoprost eyelash solution with the dermal applicator was noted vs eye drop application. Additionally, it has been demonstrated that approximately 5% (based on weight) of a one-drop dose of bimatoprost eyelash solution applied to the dermal applicator is actually delivered to the patient.¹⁸ The rest of the solution remains on the applicator.

It is important that patients use bimatoprost eyelash solution as instructed in the prescribing information (eg, clean the face, remove makeup and contact lenses prior to applying the product). The eyelid should not be rinsed after application, which limits the possibility of the bimatoprost solution from contacting or pooling in the eye. One drop of bimatoprost eyelash solution should be applied to the applicator supplied by the manufacturer and distributed evenly along the skin of the upper eyelid margin at the base of the eyelashes. It is important to blot any excess solution runoff outside the upper eyelid margin.⁵ Of note, our patient admitted to not always doing this step, which may have contributed to her susceptibility to this rare side effect.

Prostaglandin analogues have been observed to cause iris hyperpigmentation when applied directly to the eye for use in the treatment of glaucoma.¹⁹ Theoretically, the same side-effect profile should apply in their use as a dermal application on the eyelids. For this reason, one manufacturer includes iris hyperpigmentation as an adverse side effect in the prescribing information.⁵ It is important for physicians who prescribe bimatoprost eyelash solution to inform patients of this rare yet possible side effect and to instruct patients on proper application to minimize hyperpigmentation.

Our literature review did not demonstrate previous cases of iris hyperpigmentation associated with bimatoprost eyelash solution. One study suggested that 2 patients experienced hypopigmentation; however, this was not clinically significant and was not consistent with the proposed iris pigmentation thought to be caused by bimatoprost eyelash solution.²⁰

Potential future applications and off-label uses of bimatoprost include treatment of eyelash hypotrichosis on the lower eyelid margin and eyebrow hypertrichosis, as well as androgenic alopecia, alopecia areata, chemotherapy-induced alopecia, vitiligo, and hypopigmented scarring.²¹ Currently, investigational studies are looking at bimatoprost ophthalmic solution 0.03% for chemotherapy-induced eyelash hypotrichosis with positive results.²² In the future, bimatoprost may be used for other off-label and possibly FDA-approved uses.

To the Editor:

Long, dark, and thick eyelashes have been a focal point of society’s perception of beauty for thousands of years,¹ and the use of makeup products such as mascaras, eyeliners, and eye shadows has further increased the perception of attractiveness of the eyes.² Many eyelash enhancement methods have been developed or in some instances have been serendipitously discovered. Bimatoprost ophthalmic solution 0.03% originally was developed as an eye drop that was approved by the US Food and Drug Association (FDA) in 2001 for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. An unexpected side effect of this product was eyelash hypertrichosis.^3,4 As a result, the FDA approved bimatoprost ophthalmic solution 0.03% as an eyelash solution with an eyelid applicator for treatment of eyelash hypotrichosis in 2008.⁵

Because all follicular development occurs during embryogenesis, the number of eyelash follicles does not increase over time.⁶ Bitmatoprost eyelash solution works by prolonging the anagen (growth) phase of the eyelashes and stimulating the transition from the telogen (dormant) phase to the anagen phase. It also has been shown to increase the hair bulb diameter of follicles undergoing the anagen phase, resulting in thicker eyelashes.⁷ Although many patients have enjoyed this unexpected indication, prostaglandin (PG) analogues such as bimatoprost and latanoprost have a well-documented history of ocular side effects when applied directly to the eye. The most common adverse reactions include eye pruritus, conjunctival hyperemia, and eyelid pigmentation.³ The product safety information indicates that eyelid pigmentation typically is reversible.^3,5 Iris pigmentation is perhaps the least desirable side effect of PG analogues and was first noted in latanoprost studies on primates.⁸ The underlying mechanism appears to be due to an increase in melanogenesis that results in an increase in melanin granules without concomitant proliferation of melanocytes, cellular atypia, or evidence of inflammatory reaction. Unfortunately, this pigmentation typically is permanent.^3,5,9

Studies have shown that iris hyperpigmentation can occur when bimatoprost eye drops are applied to the eyes for the treatment of glaucoma and ocular hypertension, but reports associated with bimatoprost eyelash solution are rare.^3,4,10 We report a case of iris hyperpigmentation following cosmetic use of bimatoprost eyelash solution.

An otherwise healthy 63-year-old woman presented to our clinic for an annual skin examination. She noted that she had worsening dark pigmentation of the bilateral irises. The patient did not have any personal or family history of melanoma or ocular nevi, and there were no associated symptoms of eye tearing, pruritus, burning, or discharge. No prior surgical procedures had been performed on or around the eyes, and the patient never used contact lenses. She had been intermittently using bimatoprost eyelash solution prescribed by an outside physician for approximately 3 years to enhance her eyelashes. Although she never applied the product directly into her eyes, she noted that she often was unmethodical in application of the product and that runoff from the product may have occasionally leaked into the eyes. Physical examination revealed bilateral blue irises with ink spot–like, grayish black patches encircling the bilateral pupils (Figure).

There have been several studies of iris hyperpigmentation with use of PG analogues in the treatment of glaucoma. In a phase 3 clinical trial of the safety and efficacy of latanoprost for treatment of ocular hypertension, it was noted that 24 (12%) of 198 patients experienced iris hyperpigmentation and that patients with heterogeneous pigmentation (ie, hazel irises and mixed coloring) were at an increased risk.¹¹ Other studies also have shown an increased risk of iris hyperpigmentation due to heterogeneous phenotype¹² as well as older age.¹³

Reports of bimatoprost eye drops used for treatment of glaucoma have shown a high incidence of iris hyperpigmentation with long-term use. A prospective study conducted in 2012 investigated the adverse events of bimatoprost eye drops in 52 Japanese patients with glaucoma or ocular hypertension. Clinical photographs of the irises, eyelids, and eyelashes were taken at baseline and after 6 months of treatment. It was noted that 50% (26/52) of participants experienced iris hyperpigmentation upon completion of treatment.¹⁰

In our patient, bimatoprost eyelash solution was applied to the top eyelid margins using an applicator; our patient did not use the eye drop formulation, which is directed for use in ocular hypertension or glaucoma. A PubMed search of articles indexed for MEDLINE using the terms bimatoprost and iris hyperpigmentation yielded no published peer-reviewed studies or case reports of iris hyperpigmentation caused by bimatoprost eyelash solution for treatment of eyelid hypotrichosis, which makes this case report novel. With that said, the package insert states iris hyperpigmentation as a side effect in the prescribing information for both a bimatoprost eye drop formulation used to treat ocular hypertension³ as well as a formulation for topical application on the eyelids/eyelashes.⁵ A 2014 retrospective review of long-term safety with bimatoprost eyelash solution for eyelash hypotrichosis reported 4 instances (0.7%) of documented adverse events after 12 months of use in 585 patients, including dry eye, eyelid erythema, ocular pruritus, and low ocular pressure. Iris hyperpigmentation was not reported.¹⁴

The method of bimatoprost application likely is a determining factor in the number of reported adverse events. Studies with similar treatment periods have demonstrated more adverse events associated with bimatoprost eye drops vs eyelash solution.^15,16 When bimatoprost is used in the eye drop formulation for treatment of glaucoma, iris hyperpigmentation has been estimated to occur in 1.5%⁴ to 50%⁹ of cases. To our knowledge, there are no documented cases when bimatoprost eyelash solution is applied with a dermal applicator for treatment of eyelash hypotrichosis.^15,17 These results may be explained using an ocular splash test. In one study using lissamine green dye, decreased delivery of bimatoprost eyelash solution with the dermal applicator was noted vs eye drop application. Additionally, it has been demonstrated that approximately 5% (based on weight) of a one-drop dose of bimatoprost eyelash solution applied to the dermal applicator is actually delivered to the patient.¹⁸ The rest of the solution remains on the applicator.

It is important that patients use bimatoprost eyelash solution as instructed in the prescribing information (eg, clean the face, remove makeup and contact lenses prior to applying the product). The eyelid should not be rinsed after application, which limits the possibility of the bimatoprost solution from contacting or pooling in the eye. One drop of bimatoprost eyelash solution should be applied to the applicator supplied by the manufacturer and distributed evenly along the skin of the upper eyelid margin at the base of the eyelashes. It is important to blot any excess solution runoff outside the upper eyelid margin.⁵ Of note, our patient admitted to not always doing this step, which may have contributed to her susceptibility to this rare side effect.

Prostaglandin analogues have been observed to cause iris hyperpigmentation when applied directly to the eye for use in the treatment of glaucoma.¹⁹ Theoretically, the same side-effect profile should apply in their use as a dermal application on the eyelids. For this reason, one manufacturer includes iris hyperpigmentation as an adverse side effect in the prescribing information.⁵ It is important for physicians who prescribe bimatoprost eyelash solution to inform patients of this rare yet possible side effect and to instruct patients on proper application to minimize hyperpigmentation.

Our literature review did not demonstrate previous cases of iris hyperpigmentation associated with bimatoprost eyelash solution. One study suggested that 2 patients experienced hypopigmentation; however, this was not clinically significant and was not consistent with the proposed iris pigmentation thought to be caused by bimatoprost eyelash solution.²⁰

Potential future applications and off-label uses of bimatoprost include treatment of eyelash hypotrichosis on the lower eyelid margin and eyebrow hypertrichosis, as well as androgenic alopecia, alopecia areata, chemotherapy-induced alopecia, vitiligo, and hypopigmented scarring.²¹ Currently, investigational studies are looking at bimatoprost ophthalmic solution 0.03% for chemotherapy-induced eyelash hypotrichosis with positive results.²² In the future, bimatoprost may be used for other off-label and possibly FDA-approved uses.

To the Editor:

Long, dark, and thick eyelashes have been a focal point of society’s perception of beauty for thousands of years,¹ and the use of makeup products such as mascaras, eyeliners, and eye shadows has further increased the perception of attractiveness of the eyes.² Many eyelash enhancement methods have been developed or in some instances have been serendipitously discovered. Bimatoprost ophthalmic solution 0.03% originally was developed as an eye drop that was approved by the US Food and Drug Association (FDA) in 2001 for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. An unexpected side effect of this product was eyelash hypertrichosis.^3,4 As a result, the FDA approved bimatoprost ophthalmic solution 0.03% as an eyelash solution with an eyelid applicator for treatment of eyelash hypotrichosis in 2008.⁵

Because all follicular development occurs during embryogenesis, the number of eyelash follicles does not increase over time.⁶ Bitmatoprost eyelash solution works by prolonging the anagen (growth) phase of the eyelashes and stimulating the transition from the telogen (dormant) phase to the anagen phase. It also has been shown to increase the hair bulb diameter of follicles undergoing the anagen phase, resulting in thicker eyelashes.⁷ Although many patients have enjoyed this unexpected indication, prostaglandin (PG) analogues such as bimatoprost and latanoprost have a well-documented history of ocular side effects when applied directly to the eye. The most common adverse reactions include eye pruritus, conjunctival hyperemia, and eyelid pigmentation.³ The product safety information indicates that eyelid pigmentation typically is reversible.^3,5 Iris pigmentation is perhaps the least desirable side effect of PG analogues and was first noted in latanoprost studies on primates.⁸ The underlying mechanism appears to be due to an increase in melanogenesis that results in an increase in melanin granules without concomitant proliferation of melanocytes, cellular atypia, or evidence of inflammatory reaction. Unfortunately, this pigmentation typically is permanent.^3,5,9

Studies have shown that iris hyperpigmentation can occur when bimatoprost eye drops are applied to the eyes for the treatment of glaucoma and ocular hypertension, but reports associated with bimatoprost eyelash solution are rare.^3,4,10 We report a case of iris hyperpigmentation following cosmetic use of bimatoprost eyelash solution.

An otherwise healthy 63-year-old woman presented to our clinic for an annual skin examination. She noted that she had worsening dark pigmentation of the bilateral irises. The patient did not have any personal or family history of melanoma or ocular nevi, and there were no associated symptoms of eye tearing, pruritus, burning, or discharge. No prior surgical procedures had been performed on or around the eyes, and the patient never used contact lenses. She had been intermittently using bimatoprost eyelash solution prescribed by an outside physician for approximately 3 years to enhance her eyelashes. Although she never applied the product directly into her eyes, she noted that she often was unmethodical in application of the product and that runoff from the product may have occasionally leaked into the eyes. Physical examination revealed bilateral blue irises with ink spot–like, grayish black patches encircling the bilateral pupils (Figure).

There have been several studies of iris hyperpigmentation with use of PG analogues in the treatment of glaucoma. In a phase 3 clinical trial of the safety and efficacy of latanoprost for treatment of ocular hypertension, it was noted that 24 (12%) of 198 patients experienced iris hyperpigmentation and that patients with heterogeneous pigmentation (ie, hazel irises and mixed coloring) were at an increased risk.¹¹ Other studies also have shown an increased risk of iris hyperpigmentation due to heterogeneous phenotype¹² as well as older age.¹³

Reports of bimatoprost eye drops used for treatment of glaucoma have shown a high incidence of iris hyperpigmentation with long-term use. A prospective study conducted in 2012 investigated the adverse events of bimatoprost eye drops in 52 Japanese patients with glaucoma or ocular hypertension. Clinical photographs of the irises, eyelids, and eyelashes were taken at baseline and after 6 months of treatment. It was noted that 50% (26/52) of participants experienced iris hyperpigmentation upon completion of treatment.¹⁰

In our patient, bimatoprost eyelash solution was applied to the top eyelid margins using an applicator; our patient did not use the eye drop formulation, which is directed for use in ocular hypertension or glaucoma. A PubMed search of articles indexed for MEDLINE using the terms bimatoprost and iris hyperpigmentation yielded no published peer-reviewed studies or case reports of iris hyperpigmentation caused by bimatoprost eyelash solution for treatment of eyelid hypotrichosis, which makes this case report novel. With that said, the package insert states iris hyperpigmentation as a side effect in the prescribing information for both a bimatoprost eye drop formulation used to treat ocular hypertension³ as well as a formulation for topical application on the eyelids/eyelashes.⁵ A 2014 retrospective review of long-term safety with bimatoprost eyelash solution for eyelash hypotrichosis reported 4 instances (0.7%) of documented adverse events after 12 months of use in 585 patients, including dry eye, eyelid erythema, ocular pruritus, and low ocular pressure. Iris hyperpigmentation was not reported.¹⁴

The method of bimatoprost application likely is a determining factor in the number of reported adverse events. Studies with similar treatment periods have demonstrated more adverse events associated with bimatoprost eye drops vs eyelash solution.^15,16 When bimatoprost is used in the eye drop formulation for treatment of glaucoma, iris hyperpigmentation has been estimated to occur in 1.5%⁴ to 50%⁹ of cases. To our knowledge, there are no documented cases when bimatoprost eyelash solution is applied with a dermal applicator for treatment of eyelash hypotrichosis.^15,17 These results may be explained using an ocular splash test. In one study using lissamine green dye, decreased delivery of bimatoprost eyelash solution with the dermal applicator was noted vs eye drop application. Additionally, it has been demonstrated that approximately 5% (based on weight) of a one-drop dose of bimatoprost eyelash solution applied to the dermal applicator is actually delivered to the patient.¹⁸ The rest of the solution remains on the applicator.

It is important that patients use bimatoprost eyelash solution as instructed in the prescribing information (eg, clean the face, remove makeup and contact lenses prior to applying the product). The eyelid should not be rinsed after application, which limits the possibility of the bimatoprost solution from contacting or pooling in the eye. One drop of bimatoprost eyelash solution should be applied to the applicator supplied by the manufacturer and distributed evenly along the skin of the upper eyelid margin at the base of the eyelashes. It is important to blot any excess solution runoff outside the upper eyelid margin.⁵ Of note, our patient admitted to not always doing this step, which may have contributed to her susceptibility to this rare side effect.

Prostaglandin analogues have been observed to cause iris hyperpigmentation when applied directly to the eye for use in the treatment of glaucoma.¹⁹ Theoretically, the same side-effect profile should apply in their use as a dermal application on the eyelids. For this reason, one manufacturer includes iris hyperpigmentation as an adverse side effect in the prescribing information.⁵ It is important for physicians who prescribe bimatoprost eyelash solution to inform patients of this rare yet possible side effect and to instruct patients on proper application to minimize hyperpigmentation.

Our literature review did not demonstrate previous cases of iris hyperpigmentation associated with bimatoprost eyelash solution. One study suggested that 2 patients experienced hypopigmentation; however, this was not clinically significant and was not consistent with the proposed iris pigmentation thought to be caused by bimatoprost eyelash solution.²⁰

Potential future applications and off-label uses of bimatoprost include treatment of eyelash hypotrichosis on the lower eyelid margin and eyebrow hypertrichosis, as well as androgenic alopecia, alopecia areata, chemotherapy-induced alopecia, vitiligo, and hypopigmented scarring.²¹ Currently, investigational studies are looking at bimatoprost ophthalmic solution 0.03% for chemotherapy-induced eyelash hypotrichosis with positive results.²² In the future, bimatoprost may be used for other off-label and possibly FDA-approved uses.