Case Letter

To the Editor:

Hailey-Hailey disease (HHD), or familial benign chronic pemphigus, is a genetic disorder caused by an autosomal-dominant mutation in ATPase secretory pathway Ca²⁺ transporting 1 gene, ATP2C1, which disrupts intracellular calcium signaling and blocks synthesis of junctional proteins required for cell-cell adhesion.^1,2 As a result, patients develop acantholysis of the suprabasilar epidermis resulting in chronic flaccid blisters and erosions, particularly in intertriginous areas.³ Patients often report associated itching, pain, and burning, and they frequently present with secondary polymicrobial infections.⁴ Although HHD is genetic, patients may present without a family history due to variable expressivity and sporadic germline mutations.⁵ Therapeutic options are numerous, and patients may attempt many treatments before a benefit is observed.⁴ Local disease improvement was noted in a case series of 3 patients treated with electron beam radiotherapy with no disease recurrence in treated sites at 38, 33, and 9 months’ follow-up.⁶ Herein, we present a case of HHD refractory to numerous prior therapies that was successfully treated with electron beam radiotherapy, highlighting the potential role for palliative radiotherapy in select refractory cases of HHD.

A 35-year-old woman with a 7-year of history of HHD presented with severe recalcitrant disease including extensive erosive patches and plaques in the intertriginous areas of the bilateral axillae, groin, and inframammary folds (Figure 1). The skin eruptions first appeared at 28 years of age after her last pregnancy and continued as painful blistering that worsened with each menstrual cycle. Initially the affected desquamated skin would heal between menstrual cycles, but large areas of desquamation remained unhealed in the groin and inframammary regions throughout her full menstrual cycles by the time of referral. Family history included 4 family members with HHD: 2 aunts, an uncle, and a cousin on the paternal side of her family. Over a 7-year period, treatment with clobetasol cream, clindamycin gel, tacrolimus ointment, doxycycline, dapsone, cyclosporine, methotrexate, etanercept, isotretinoin, and prednisone (15 mg every other day) all failed. Most recently, axillary abobotulinumtoxinA injections were attempted but failed. She had been prednisone dependent for more than 1 year. Due to the ongoing refractory disease, she was referred to radiation oncology to discuss radiotherapy treatment options.

One month after treatment she had total resolution of the erosive patches and plaques with mild residual hyperpigmentation in the axillae, establishing that radiation therapy was reasonably effective. To lower the total radiation dose and decrease the risk of radiation-induced malignancy, we treated the bilateral groin and the inframammary region with a treatment schedule of 8 Gy in 2 fractions at a higher dose of 4 Gy per fraction instead of 2 Gy. At 12 days posttreatment, she had a dramatic response in the groin and a mixed response in the inframammary region, with a focus that had not yet regressed. Given the dramatic response in the treated sites, the patient requested treatment to the right side of the neck. Thus, we treated this area with a similar 8 Gy in 2 fractions, and an additional 6 Gy in 2 fractions boost was added to the slow responding focus in the inframammary fold for a total of 14 Gy in 4 fractions. The patient tolerated all treatments well with mild grade 1 skin irritation that was unlike the blistering of the typical HHD flares. Two months following completion of the first course of radiotherapy to the axillae and 2 weeks from the most recent course, she tapered off her prednisone regimen (15 mg every other day) but had a relapse of disease with her subsequent menstrual cycles that presented as a blistering skin reaction in the inframammary region, which healed in response to restarting steroids. This flare was less severe than those prior to radiotherapy. At 10 months posttreatment, the patient was free of disease in the neck and axillae (Figure 2). She continued to have relapses in the inframammary region with menstrual cycles and noted new disease in the popliteal regions; however, the relapses were less severe, and her skin had improved more with radiation than any of the prior therapies.

To the Editor:

Hailey-Hailey disease (HHD), or familial benign chronic pemphigus, is a genetic disorder caused by an autosomal-dominant mutation in ATPase secretory pathway Ca²⁺ transporting 1 gene, ATP2C1, which disrupts intracellular calcium signaling and blocks synthesis of junctional proteins required for cell-cell adhesion.^1,2 As a result, patients develop acantholysis of the suprabasilar epidermis resulting in chronic flaccid blisters and erosions, particularly in intertriginous areas.³ Patients often report associated itching, pain, and burning, and they frequently present with secondary polymicrobial infections.⁴ Although HHD is genetic, patients may present without a family history due to variable expressivity and sporadic germline mutations.⁵ Therapeutic options are numerous, and patients may attempt many treatments before a benefit is observed.⁴ Local disease improvement was noted in a case series of 3 patients treated with electron beam radiotherapy with no disease recurrence in treated sites at 38, 33, and 9 months’ follow-up.⁶ Herein, we present a case of HHD refractory to numerous prior therapies that was successfully treated with electron beam radiotherapy, highlighting the potential role for palliative radiotherapy in select refractory cases of HHD.

A 35-year-old woman with a 7-year of history of HHD presented with severe recalcitrant disease including extensive erosive patches and plaques in the intertriginous areas of the bilateral axillae, groin, and inframammary folds (Figure 1). The skin eruptions first appeared at 28 years of age after her last pregnancy and continued as painful blistering that worsened with each menstrual cycle. Initially the affected desquamated skin would heal between menstrual cycles, but large areas of desquamation remained unhealed in the groin and inframammary regions throughout her full menstrual cycles by the time of referral. Family history included 4 family members with HHD: 2 aunts, an uncle, and a cousin on the paternal side of her family. Over a 7-year period, treatment with clobetasol cream, clindamycin gel, tacrolimus ointment, doxycycline, dapsone, cyclosporine, methotrexate, etanercept, isotretinoin, and prednisone (15 mg every other day) all failed. Most recently, axillary abobotulinumtoxinA injections were attempted but failed. She had been prednisone dependent for more than 1 year. Due to the ongoing refractory disease, she was referred to radiation oncology to discuss radiotherapy treatment options.

One month after treatment she had total resolution of the erosive patches and plaques with mild residual hyperpigmentation in the axillae, establishing that radiation therapy was reasonably effective. To lower the total radiation dose and decrease the risk of radiation-induced malignancy, we treated the bilateral groin and the inframammary region with a treatment schedule of 8 Gy in 2 fractions at a higher dose of 4 Gy per fraction instead of 2 Gy. At 12 days posttreatment, she had a dramatic response in the groin and a mixed response in the inframammary region, with a focus that had not yet regressed. Given the dramatic response in the treated sites, the patient requested treatment to the right side of the neck. Thus, we treated this area with a similar 8 Gy in 2 fractions, and an additional 6 Gy in 2 fractions boost was added to the slow responding focus in the inframammary fold for a total of 14 Gy in 4 fractions. The patient tolerated all treatments well with mild grade 1 skin irritation that was unlike the blistering of the typical HHD flares. Two months following completion of the first course of radiotherapy to the axillae and 2 weeks from the most recent course, she tapered off her prednisone regimen (15 mg every other day) but had a relapse of disease with her subsequent menstrual cycles that presented as a blistering skin reaction in the inframammary region, which healed in response to restarting steroids. This flare was less severe than those prior to radiotherapy. At 10 months posttreatment, the patient was free of disease in the neck and axillae (Figure 2). She continued to have relapses in the inframammary region with menstrual cycles and noted new disease in the popliteal regions; however, the relapses were less severe, and her skin had improved more with radiation than any of the prior therapies.

To the Editor:

Hailey-Hailey disease (HHD), or familial benign chronic pemphigus, is a genetic disorder caused by an autosomal-dominant mutation in ATPase secretory pathway Ca²⁺ transporting 1 gene, ATP2C1, which disrupts intracellular calcium signaling and blocks synthesis of junctional proteins required for cell-cell adhesion.^1,2 As a result, patients develop acantholysis of the suprabasilar epidermis resulting in chronic flaccid blisters and erosions, particularly in intertriginous areas.³ Patients often report associated itching, pain, and burning, and they frequently present with secondary polymicrobial infections.⁴ Although HHD is genetic, patients may present without a family history due to variable expressivity and sporadic germline mutations.⁵ Therapeutic options are numerous, and patients may attempt many treatments before a benefit is observed.⁴ Local disease improvement was noted in a case series of 3 patients treated with electron beam radiotherapy with no disease recurrence in treated sites at 38, 33, and 9 months’ follow-up.⁶ Herein, we present a case of HHD refractory to numerous prior therapies that was successfully treated with electron beam radiotherapy, highlighting the potential role for palliative radiotherapy in select refractory cases of HHD.

A 35-year-old woman with a 7-year of history of HHD presented with severe recalcitrant disease including extensive erosive patches and plaques in the intertriginous areas of the bilateral axillae, groin, and inframammary folds (Figure 1). The skin eruptions first appeared at 28 years of age after her last pregnancy and continued as painful blistering that worsened with each menstrual cycle. Initially the affected desquamated skin would heal between menstrual cycles, but large areas of desquamation remained unhealed in the groin and inframammary regions throughout her full menstrual cycles by the time of referral. Family history included 4 family members with HHD: 2 aunts, an uncle, and a cousin on the paternal side of her family. Over a 7-year period, treatment with clobetasol cream, clindamycin gel, tacrolimus ointment, doxycycline, dapsone, cyclosporine, methotrexate, etanercept, isotretinoin, and prednisone (15 mg every other day) all failed. Most recently, axillary abobotulinumtoxinA injections were attempted but failed. She had been prednisone dependent for more than 1 year. Due to the ongoing refractory disease, she was referred to radiation oncology to discuss radiotherapy treatment options.

One month after treatment she had total resolution of the erosive patches and plaques with mild residual hyperpigmentation in the axillae, establishing that radiation therapy was reasonably effective. To lower the total radiation dose and decrease the risk of radiation-induced malignancy, we treated the bilateral groin and the inframammary region with a treatment schedule of 8 Gy in 2 fractions at a higher dose of 4 Gy per fraction instead of 2 Gy. At 12 days posttreatment, she had a dramatic response in the groin and a mixed response in the inframammary region, with a focus that had not yet regressed. Given the dramatic response in the treated sites, the patient requested treatment to the right side of the neck. Thus, we treated this area with a similar 8 Gy in 2 fractions, and an additional 6 Gy in 2 fractions boost was added to the slow responding focus in the inframammary fold for a total of 14 Gy in 4 fractions. The patient tolerated all treatments well with mild grade 1 skin irritation that was unlike the blistering of the typical HHD flares. Two months following completion of the first course of radiotherapy to the axillae and 2 weeks from the most recent course, she tapered off her prednisone regimen (15 mg every other day) but had a relapse of disease with her subsequent menstrual cycles that presented as a blistering skin reaction in the inframammary region, which healed in response to restarting steroids. This flare was less severe than those prior to radiotherapy. At 10 months posttreatment, the patient was free of disease in the neck and axillae (Figure 2). She continued to have relapses in the inframammary region with menstrual cycles and noted new disease in the popliteal regions; however, the relapses were less severe, and her skin had improved more with radiation than any of the prior therapies.

To the Editor:

Pembrolizumab, a humanized monoclonal anti–programmed cell death protein 1 (PD-1) antibody, acts by blocking negative immune regulators such as PD-1.¹ Since its approval by the US Food and Drug Administration in 2014, the use of PD-1 inhibitors such as pembrolizumab has dramatically increased, and they are now the standard of care for cancers such as melanoma, lung cancer, and renal cell carcinoma.^2,3 With increased use comes a better understanding of the cutaneous adverse effects that may occur. To date, almost 50% of patients treated with PD-1 inhibitors will develop an adverse cutaneous reaction.⁴ Thus far, cases of patients developing vitiligo, bullous pemphigoid, psoriasis, granulomatous skin reactions, severe cutaneous reactions (ie, toxic epidermal necrolysis), lupus erythematosus, and lichenoid reactions have been described.^3,5,6 There are fewer than 30 documented cases of lichenoid reactions due to anti–PD-1 treatment described in the literature, increasing the importance of case reports to demonstrate a full range of cutaneous findings.³ We present a case of a reaction to pembrolizumab with an eruption of lichenoid papules predominantly involving the hands and feet as well as nail changes.

A 60-year-old man with ocular melanoma metastatic to the right lung, transverse colon, and right axillary lymph nodes presented with a chief concern of growing skin lesions present for 6 weeks on the hands and feet. The lesions were tender to the touch and occasionally drained a clear fluid. He also reported nail fragility. Of note, the patient was being treated for metastatic melanoma with pembrolizumab infusions every 3 weeks, which started 6 weeks prior to the onset of the eruption. 

Physical examination demonstrated lichenoid papules on the dorsal and ventral aspects of the hands and feet (Figure 1), as well as longitudinal ridging on numerous fingernails and mild koilonychia. A punch biopsy revealed lichenoid interface dermatitis with irregular epidermal hyperplasia (Figure 2). A diagnosis of hypertrophic lichen planus–like drug eruption in response to pembrolizumab was made and clobetasol cream was prescribed.

At 1-month follow-up, the patient reported notable improvement with clobetasol, and he was transitioned to tacrolimus ointment 0.1%. He continued to improve until a month later when he reported new lesions arising a week after a pembrolizumab infusion. He continued to use clobetasol cream for flares and tacrolimus ointment for maintenance.

Almost 3 months after the initial visit, the patient presented with inflammation around his right third fingernail of 1 week’s duration, with more notable fragility than his other nails. No trauma was described, and the nail abnormality was attributed to pembrolizumab. Clobetasol cream and biotin 3 mg daily resulted in improvement, and no other nails were affected in a similar way.

Programmed cell death protein 1 blockers are associated with a variety of adverse events including hypothyroidism, gastrointestinal abnormalities, fatigue, and skin disorders.⁷ In one study (N=83), cutaneous adverse drug events were found to occur in 42% (35/83) of patients following pembrolizumab therapy, with the most common cutaneous lesions being maculopapular eruptions (29% [24/83]), pruritus (12% [10/83]), and hypopigmentation (8% [7/83]).⁵

A total of 29 cases of lichenoid dermatitis following anti–PD-1 therapy have been described in the literature.³ Cases range from an eruption of photodistributed hyperkeratotic papules and plaques to hypertrophic vesiculobullous lesions.^3,6 Suggested pathophysiology involves blocking the interaction of programmed death ligand 1 on keratinocytes with PD-1 on T cells.³ Management typically includes topical or systemic steroids. Cyclosporine and acitretin also have been successful in a small number of patients. Most patients continue anti–PD-1 treatment with systemic therapy.³

Our patient represents a similar lichenoid eruption; however, the distribution on the dorsal and ventral aspects of the hands and feet as well as nail dystrophy make the presentation unique. Anticancer drugs that increase the T-cell immune response by altering the complex signaling among T cells, antigen-presenting cells, and tumor cells have been associated with cutaneous eruptions. Although the exact mechanism is still not fully understood, clinical suspicion of a pembrolizumab reaction should remain high on the differential in the setting of hyperkeratotic papules in association with anti–PD-1 therapy.

To the Editor:

Pembrolizumab, a humanized monoclonal anti–programmed cell death protein 1 (PD-1) antibody, acts by blocking negative immune regulators such as PD-1.¹ Since its approval by the US Food and Drug Administration in 2014, the use of PD-1 inhibitors such as pembrolizumab has dramatically increased, and they are now the standard of care for cancers such as melanoma, lung cancer, and renal cell carcinoma.^2,3 With increased use comes a better understanding of the cutaneous adverse effects that may occur. To date, almost 50% of patients treated with PD-1 inhibitors will develop an adverse cutaneous reaction.⁴ Thus far, cases of patients developing vitiligo, bullous pemphigoid, psoriasis, granulomatous skin reactions, severe cutaneous reactions (ie, toxic epidermal necrolysis), lupus erythematosus, and lichenoid reactions have been described.^3,5,6 There are fewer than 30 documented cases of lichenoid reactions due to anti–PD-1 treatment described in the literature, increasing the importance of case reports to demonstrate a full range of cutaneous findings.³ We present a case of a reaction to pembrolizumab with an eruption of lichenoid papules predominantly involving the hands and feet as well as nail changes.

A 60-year-old man with ocular melanoma metastatic to the right lung, transverse colon, and right axillary lymph nodes presented with a chief concern of growing skin lesions present for 6 weeks on the hands and feet. The lesions were tender to the touch and occasionally drained a clear fluid. He also reported nail fragility. Of note, the patient was being treated for metastatic melanoma with pembrolizumab infusions every 3 weeks, which started 6 weeks prior to the onset of the eruption. 

Physical examination demonstrated lichenoid papules on the dorsal and ventral aspects of the hands and feet (Figure 1), as well as longitudinal ridging on numerous fingernails and mild koilonychia. A punch biopsy revealed lichenoid interface dermatitis with irregular epidermal hyperplasia (Figure 2). A diagnosis of hypertrophic lichen planus–like drug eruption in response to pembrolizumab was made and clobetasol cream was prescribed.

At 1-month follow-up, the patient reported notable improvement with clobetasol, and he was transitioned to tacrolimus ointment 0.1%. He continued to improve until a month later when he reported new lesions arising a week after a pembrolizumab infusion. He continued to use clobetasol cream for flares and tacrolimus ointment for maintenance.

Almost 3 months after the initial visit, the patient presented with inflammation around his right third fingernail of 1 week’s duration, with more notable fragility than his other nails. No trauma was described, and the nail abnormality was attributed to pembrolizumab. Clobetasol cream and biotin 3 mg daily resulted in improvement, and no other nails were affected in a similar way.

Programmed cell death protein 1 blockers are associated with a variety of adverse events including hypothyroidism, gastrointestinal abnormalities, fatigue, and skin disorders.⁷ In one study (N=83), cutaneous adverse drug events were found to occur in 42% (35/83) of patients following pembrolizumab therapy, with the most common cutaneous lesions being maculopapular eruptions (29% [24/83]), pruritus (12% [10/83]), and hypopigmentation (8% [7/83]).⁵

A total of 29 cases of lichenoid dermatitis following anti–PD-1 therapy have been described in the literature.³ Cases range from an eruption of photodistributed hyperkeratotic papules and plaques to hypertrophic vesiculobullous lesions.^3,6 Suggested pathophysiology involves blocking the interaction of programmed death ligand 1 on keratinocytes with PD-1 on T cells.³ Management typically includes topical or systemic steroids. Cyclosporine and acitretin also have been successful in a small number of patients. Most patients continue anti–PD-1 treatment with systemic therapy.³

Our patient represents a similar lichenoid eruption; however, the distribution on the dorsal and ventral aspects of the hands and feet as well as nail dystrophy make the presentation unique. Anticancer drugs that increase the T-cell immune response by altering the complex signaling among T cells, antigen-presenting cells, and tumor cells have been associated with cutaneous eruptions. Although the exact mechanism is still not fully understood, clinical suspicion of a pembrolizumab reaction should remain high on the differential in the setting of hyperkeratotic papules in association with anti–PD-1 therapy.

To the Editor:

Pembrolizumab, a humanized monoclonal anti–programmed cell death protein 1 (PD-1) antibody, acts by blocking negative immune regulators such as PD-1.¹ Since its approval by the US Food and Drug Administration in 2014, the use of PD-1 inhibitors such as pembrolizumab has dramatically increased, and they are now the standard of care for cancers such as melanoma, lung cancer, and renal cell carcinoma.^2,3 With increased use comes a better understanding of the cutaneous adverse effects that may occur. To date, almost 50% of patients treated with PD-1 inhibitors will develop an adverse cutaneous reaction.⁴ Thus far, cases of patients developing vitiligo, bullous pemphigoid, psoriasis, granulomatous skin reactions, severe cutaneous reactions (ie, toxic epidermal necrolysis), lupus erythematosus, and lichenoid reactions have been described.^3,5,6 There are fewer than 30 documented cases of lichenoid reactions due to anti–PD-1 treatment described in the literature, increasing the importance of case reports to demonstrate a full range of cutaneous findings.³ We present a case of a reaction to pembrolizumab with an eruption of lichenoid papules predominantly involving the hands and feet as well as nail changes.

A 60-year-old man with ocular melanoma metastatic to the right lung, transverse colon, and right axillary lymph nodes presented with a chief concern of growing skin lesions present for 6 weeks on the hands and feet. The lesions were tender to the touch and occasionally drained a clear fluid. He also reported nail fragility. Of note, the patient was being treated for metastatic melanoma with pembrolizumab infusions every 3 weeks, which started 6 weeks prior to the onset of the eruption. 

Physical examination demonstrated lichenoid papules on the dorsal and ventral aspects of the hands and feet (Figure 1), as well as longitudinal ridging on numerous fingernails and mild koilonychia. A punch biopsy revealed lichenoid interface dermatitis with irregular epidermal hyperplasia (Figure 2). A diagnosis of hypertrophic lichen planus–like drug eruption in response to pembrolizumab was made and clobetasol cream was prescribed.

At 1-month follow-up, the patient reported notable improvement with clobetasol, and he was transitioned to tacrolimus ointment 0.1%. He continued to improve until a month later when he reported new lesions arising a week after a pembrolizumab infusion. He continued to use clobetasol cream for flares and tacrolimus ointment for maintenance.

Almost 3 months after the initial visit, the patient presented with inflammation around his right third fingernail of 1 week’s duration, with more notable fragility than his other nails. No trauma was described, and the nail abnormality was attributed to pembrolizumab. Clobetasol cream and biotin 3 mg daily resulted in improvement, and no other nails were affected in a similar way.

Programmed cell death protein 1 blockers are associated with a variety of adverse events including hypothyroidism, gastrointestinal abnormalities, fatigue, and skin disorders.⁷ In one study (N=83), cutaneous adverse drug events were found to occur in 42% (35/83) of patients following pembrolizumab therapy, with the most common cutaneous lesions being maculopapular eruptions (29% [24/83]), pruritus (12% [10/83]), and hypopigmentation (8% [7/83]).⁵

A total of 29 cases of lichenoid dermatitis following anti–PD-1 therapy have been described in the literature.³ Cases range from an eruption of photodistributed hyperkeratotic papules and plaques to hypertrophic vesiculobullous lesions.^3,6 Suggested pathophysiology involves blocking the interaction of programmed death ligand 1 on keratinocytes with PD-1 on T cells.³ Management typically includes topical or systemic steroids. Cyclosporine and acitretin also have been successful in a small number of patients. Most patients continue anti–PD-1 treatment with systemic therapy.³

Our patient represents a similar lichenoid eruption; however, the distribution on the dorsal and ventral aspects of the hands and feet as well as nail dystrophy make the presentation unique. Anticancer drugs that increase the T-cell immune response by altering the complex signaling among T cells, antigen-presenting cells, and tumor cells have been associated with cutaneous eruptions. Although the exact mechanism is still not fully understood, clinical suspicion of a pembrolizumab reaction should remain high on the differential in the setting of hyperkeratotic papules in association with anti–PD-1 therapy.

To the Editor:

Testosterone-replacement therapy (TRT) is indicated for hypogonadism. The benefits of TRT are well documented, with multiple options available for delivery. Testosterone pellet implantation (TPI) is an effective treatment option for hypogonadism with minimal adverse reactions. Availability of TRT is increasing, as facilities are offering off-label applications. Although TPI generally is well tolerated, cutaneous reactions have been documented. We present a patient with drug-induced dermatitis following TPI.

A 51-year-old man with hypogonadism presented with an extremely pruritic rash that began on the left buttock 3 days after receiving his fourth TPI. The patient had received subcutaneous insertions of 8 testosterone pellets (75 mg per pellet every 6 months) to the left buttock. He denied any history of a similar rash. His medical history was remarkable for hyperlipidemia, which was controlled with niacin and omega-3 fatty acids (fish oil). Other medications included glucosamine. Before presenting to our clinic, he was given a 40-mg intramuscular injection of triamcinolone acetonide and trimethoprim-sulfamethoxazole twice daily for 7 days, a methylprednisolone dose pack, and triamcinolone ointment 0.1% twice daily by his primary care physician, all without improvement of the rash.

Physical examination revealed multiple well-circumscribed, coalescing clusters of darkly erythematous papules and dermal plaques of varying size on the buttocks with extension to the lower back, abdomen, and thighs (Figure 1). The differential diagnosis included lichenoid eruption, pseudolymphoma, sarcoidosis, and granuloma annulare.

Testosterone-replacement therapy is becoming more widely available. Lack of regulation of proper marketing by such facilities as medical spas that offer TPI for off-label applications has led to a rampant increase in TRT prescribing, possibly foreshadowing an increase in adverse cutaneous reactions to TRT.⁶

Our case of histologically consistent testosterone pellet–induced dermatitis highlights a rare cutaneous adverse reaction that can occur subsequent to TPI and illustrates the efficacy of high-dose oral steroids as a treatment option. With increased use of TRT, physicians should be cognizant of the potential adverse cutaneous effects related to this treatment and counsel patients appropriately prior to initiating treatment.

Acknowledgment
We thank the patient for granting permission to publish this case.

To the Editor:

Testosterone-replacement therapy (TRT) is indicated for hypogonadism. The benefits of TRT are well documented, with multiple options available for delivery. Testosterone pellet implantation (TPI) is an effective treatment option for hypogonadism with minimal adverse reactions. Availability of TRT is increasing, as facilities are offering off-label applications. Although TPI generally is well tolerated, cutaneous reactions have been documented. We present a patient with drug-induced dermatitis following TPI.

A 51-year-old man with hypogonadism presented with an extremely pruritic rash that began on the left buttock 3 days after receiving his fourth TPI. The patient had received subcutaneous insertions of 8 testosterone pellets (75 mg per pellet every 6 months) to the left buttock. He denied any history of a similar rash. His medical history was remarkable for hyperlipidemia, which was controlled with niacin and omega-3 fatty acids (fish oil). Other medications included glucosamine. Before presenting to our clinic, he was given a 40-mg intramuscular injection of triamcinolone acetonide and trimethoprim-sulfamethoxazole twice daily for 7 days, a methylprednisolone dose pack, and triamcinolone ointment 0.1% twice daily by his primary care physician, all without improvement of the rash.

Physical examination revealed multiple well-circumscribed, coalescing clusters of darkly erythematous papules and dermal plaques of varying size on the buttocks with extension to the lower back, abdomen, and thighs (Figure 1). The differential diagnosis included lichenoid eruption, pseudolymphoma, sarcoidosis, and granuloma annulare.

Testosterone-replacement therapy is becoming more widely available. Lack of regulation of proper marketing by such facilities as medical spas that offer TPI for off-label applications has led to a rampant increase in TRT prescribing, possibly foreshadowing an increase in adverse cutaneous reactions to TRT.⁶

Our case of histologically consistent testosterone pellet–induced dermatitis highlights a rare cutaneous adverse reaction that can occur subsequent to TPI and illustrates the efficacy of high-dose oral steroids as a treatment option. With increased use of TRT, physicians should be cognizant of the potential adverse cutaneous effects related to this treatment and counsel patients appropriately prior to initiating treatment.

Acknowledgment
We thank the patient for granting permission to publish this case.

To the Editor:

Testosterone-replacement therapy (TRT) is indicated for hypogonadism. The benefits of TRT are well documented, with multiple options available for delivery. Testosterone pellet implantation (TPI) is an effective treatment option for hypogonadism with minimal adverse reactions. Availability of TRT is increasing, as facilities are offering off-label applications. Although TPI generally is well tolerated, cutaneous reactions have been documented. We present a patient with drug-induced dermatitis following TPI.

A 51-year-old man with hypogonadism presented with an extremely pruritic rash that began on the left buttock 3 days after receiving his fourth TPI. The patient had received subcutaneous insertions of 8 testosterone pellets (75 mg per pellet every 6 months) to the left buttock. He denied any history of a similar rash. His medical history was remarkable for hyperlipidemia, which was controlled with niacin and omega-3 fatty acids (fish oil). Other medications included glucosamine. Before presenting to our clinic, he was given a 40-mg intramuscular injection of triamcinolone acetonide and trimethoprim-sulfamethoxazole twice daily for 7 days, a methylprednisolone dose pack, and triamcinolone ointment 0.1% twice daily by his primary care physician, all without improvement of the rash.

Physical examination revealed multiple well-circumscribed, coalescing clusters of darkly erythematous papules and dermal plaques of varying size on the buttocks with extension to the lower back, abdomen, and thighs (Figure 1). The differential diagnosis included lichenoid eruption, pseudolymphoma, sarcoidosis, and granuloma annulare.

Testosterone-replacement therapy is becoming more widely available. Lack of regulation of proper marketing by such facilities as medical spas that offer TPI for off-label applications has led to a rampant increase in TRT prescribing, possibly foreshadowing an increase in adverse cutaneous reactions to TRT.⁶

Our case of histologically consistent testosterone pellet–induced dermatitis highlights a rare cutaneous adverse reaction that can occur subsequent to TPI and illustrates the efficacy of high-dose oral steroids as a treatment option. With increased use of TRT, physicians should be cognizant of the potential adverse cutaneous effects related to this treatment and counsel patients appropriately prior to initiating treatment.

Acknowledgment
We thank the patient for granting permission to publish this case.

To the Editor:

Female pattern hair loss is common, and the literature suggests that up to 56% of women experience hair thinning in their lifetime, with increased prevalence in older women.¹ Pathophysiology is incompletely understood and involves the nonscarring progressive miniaturization of hair follicles, causing decreased production of terminal hairs relative to more delicate vellus hairs. Because vellus hairs have a shorter anagen growth phase than terminal hairs, hair loss is expedited. Androgen excess, when present, hastens the process by inducing early transition of hair follicles from the anagen phase to the senescent telogen phase. Serum testosterone levels are within reference range in most female patients with hair loss, suggesting the presence of additional contributing factors.²

Given the high prevalence of female pattern hair loss and the harm of overlooking androgen excess and an androgen-secreting neoplasm, dermatologists must recognize indications for further evaluation. Additional signs of hyperandrogenism, such as menstrual irregularities, acne, hirsutism, anabolic appearance, voice deepening, and clitoromegaly, are reasons for concern.³ Elevated serum androgen levels also should raise suspicion of malignancy. Historically, a total testosterone level above 200 ng/dL or a dehydroepiandrosterone sulfate (DHEA-S) level greater than 700 µg/dL prompted evaluation for a tumor.⁴ More recent studies show that tumor-induced increases in serum androgen levels are highly variable, challenging the utility of these cutoffs.⁵

A 70-year-old woman presented with hair loss over the last 12 years with accentuated thinning on the frontal and vertex scalp. The patient’s primary care physician previously made a diagnosis of androgenetic alopecia and recommended topical minoxidil. Although the patient had a history of excess facial and body hair since young adulthood, she noted a progressive increase in the density of chest and back hair, prominent coarsening of the texture of the facial and body hair, and new facial acne in the last 3 years. Prior to these changes, the density and texture of the scalp and body hair had been stable for many years.

Although other postmenopausal females in the patient’s family displayed patterned hair loss, they did not possess coarse and dense hair on the face and trunk. Her family history was notable for ovarian cancer in her mother (in her 70s) and breast cancer in her maternal grandmother (in her 80s).

A review of systems was notable only for decreased energy. Physical examination revealed a well-appearing older woman with coarse terminal hair growth on the cheeks, submental chin, neck, chest, back, and forearms. Scalp examination indicated diffusely decreased hair density, most marked over the vertex, crown, and frontal scalp, without scale, erythema, or loss of follicular ostia (Figure 1).

Pelvic ultrasonography was suspicious for an ovarian pathology. Follow-up pelvic magnetic resonance imaging (MRI) demonstrated a 2.5-cm mass abutting the left ovary (Figure 2). The patient was given a diagnosis of stage IIIA high-grade ovarian serous carcinoma with lymph node involvement. Other notable findings from the workup included a BRCA2 mutation and concurrent renal cell carcinoma. After bilateral salpingo-oophorectomy, partial nephrectomy, and chemotherapy with carboplatin and paclitaxel, the testosterone level returned to within reference range and remained stable for the next 2 years of follow-up.

Imaging is indicated for a patient presenting with both clinical and biochemical hyperandrogenism. Patients with an isolated testosterone level elevation can be evaluated with transvaginal ultrasonography; however, detection and characterization of malignancies is highly dependent on the skill of the examiner.^8,9 The higher sensitivity and specificity of pelvic MRI reduces the likelihood of missing a malignancy and unnecessary surgery. Tumors too small to be visualized by MRI rarely are malignant.¹⁰

Sex cord-stromal cell tumors, despite representing fewer than 10% of ovarian tumors, are responsible for the majority of androgen-secreting malignancies. Our patient presented with clinical hyperandrogenism with an elevated testosterone level in the setting of a serous ovarian carcinoma, which is an epithelial neoplasm. Epithelial tumors are the most common type of ovarian tumor and typically are nonfunctional, though they have been reported to cause hyperandrogenism through indirect mechanisms. It is thought that both benign and malignant epithelial tumors can induce stromal hyperplasia or luteinization, leading to an increase in androgen levels.⁶

Due to the high prevalence of androgenetic alopecia and hirsutism in aging women, identification of androgen-secreting neoplasms by clinical presentation is challenging. A wide range of serum testosterone levels is possible at presentation, which complicates diagnosis. This case highlights the importance of correlating clinical and biochemical hyperandrogenism in raising suspicion of malignancy in older women presenting with hair loss.

To the Editor:

Female pattern hair loss is common, and the literature suggests that up to 56% of women experience hair thinning in their lifetime, with increased prevalence in older women.¹ Pathophysiology is incompletely understood and involves the nonscarring progressive miniaturization of hair follicles, causing decreased production of terminal hairs relative to more delicate vellus hairs. Because vellus hairs have a shorter anagen growth phase than terminal hairs, hair loss is expedited. Androgen excess, when present, hastens the process by inducing early transition of hair follicles from the anagen phase to the senescent telogen phase. Serum testosterone levels are within reference range in most female patients with hair loss, suggesting the presence of additional contributing factors.²

Given the high prevalence of female pattern hair loss and the harm of overlooking androgen excess and an androgen-secreting neoplasm, dermatologists must recognize indications for further evaluation. Additional signs of hyperandrogenism, such as menstrual irregularities, acne, hirsutism, anabolic appearance, voice deepening, and clitoromegaly, are reasons for concern.³ Elevated serum androgen levels also should raise suspicion of malignancy. Historically, a total testosterone level above 200 ng/dL or a dehydroepiandrosterone sulfate (DHEA-S) level greater than 700 µg/dL prompted evaluation for a tumor.⁴ More recent studies show that tumor-induced increases in serum androgen levels are highly variable, challenging the utility of these cutoffs.⁵

A 70-year-old woman presented with hair loss over the last 12 years with accentuated thinning on the frontal and vertex scalp. The patient’s primary care physician previously made a diagnosis of androgenetic alopecia and recommended topical minoxidil. Although the patient had a history of excess facial and body hair since young adulthood, she noted a progressive increase in the density of chest and back hair, prominent coarsening of the texture of the facial and body hair, and new facial acne in the last 3 years. Prior to these changes, the density and texture of the scalp and body hair had been stable for many years.

Although other postmenopausal females in the patient’s family displayed patterned hair loss, they did not possess coarse and dense hair on the face and trunk. Her family history was notable for ovarian cancer in her mother (in her 70s) and breast cancer in her maternal grandmother (in her 80s).

A review of systems was notable only for decreased energy. Physical examination revealed a well-appearing older woman with coarse terminal hair growth on the cheeks, submental chin, neck, chest, back, and forearms. Scalp examination indicated diffusely decreased hair density, most marked over the vertex, crown, and frontal scalp, without scale, erythema, or loss of follicular ostia (Figure 1).

Pelvic ultrasonography was suspicious for an ovarian pathology. Follow-up pelvic magnetic resonance imaging (MRI) demonstrated a 2.5-cm mass abutting the left ovary (Figure 2). The patient was given a diagnosis of stage IIIA high-grade ovarian serous carcinoma with lymph node involvement. Other notable findings from the workup included a BRCA2 mutation and concurrent renal cell carcinoma. After bilateral salpingo-oophorectomy, partial nephrectomy, and chemotherapy with carboplatin and paclitaxel, the testosterone level returned to within reference range and remained stable for the next 2 years of follow-up.

Imaging is indicated for a patient presenting with both clinical and biochemical hyperandrogenism. Patients with an isolated testosterone level elevation can be evaluated with transvaginal ultrasonography; however, detection and characterization of malignancies is highly dependent on the skill of the examiner.^8,9 The higher sensitivity and specificity of pelvic MRI reduces the likelihood of missing a malignancy and unnecessary surgery. Tumors too small to be visualized by MRI rarely are malignant.¹⁰

Sex cord-stromal cell tumors, despite representing fewer than 10% of ovarian tumors, are responsible for the majority of androgen-secreting malignancies. Our patient presented with clinical hyperandrogenism with an elevated testosterone level in the setting of a serous ovarian carcinoma, which is an epithelial neoplasm. Epithelial tumors are the most common type of ovarian tumor and typically are nonfunctional, though they have been reported to cause hyperandrogenism through indirect mechanisms. It is thought that both benign and malignant epithelial tumors can induce stromal hyperplasia or luteinization, leading to an increase in androgen levels.⁶

Due to the high prevalence of androgenetic alopecia and hirsutism in aging women, identification of androgen-secreting neoplasms by clinical presentation is challenging. A wide range of serum testosterone levels is possible at presentation, which complicates diagnosis. This case highlights the importance of correlating clinical and biochemical hyperandrogenism in raising suspicion of malignancy in older women presenting with hair loss.

To the Editor:

Female pattern hair loss is common, and the literature suggests that up to 56% of women experience hair thinning in their lifetime, with increased prevalence in older women.¹ Pathophysiology is incompletely understood and involves the nonscarring progressive miniaturization of hair follicles, causing decreased production of terminal hairs relative to more delicate vellus hairs. Because vellus hairs have a shorter anagen growth phase than terminal hairs, hair loss is expedited. Androgen excess, when present, hastens the process by inducing early transition of hair follicles from the anagen phase to the senescent telogen phase. Serum testosterone levels are within reference range in most female patients with hair loss, suggesting the presence of additional contributing factors.²

Given the high prevalence of female pattern hair loss and the harm of overlooking androgen excess and an androgen-secreting neoplasm, dermatologists must recognize indications for further evaluation. Additional signs of hyperandrogenism, such as menstrual irregularities, acne, hirsutism, anabolic appearance, voice deepening, and clitoromegaly, are reasons for concern.³ Elevated serum androgen levels also should raise suspicion of malignancy. Historically, a total testosterone level above 200 ng/dL or a dehydroepiandrosterone sulfate (DHEA-S) level greater than 700 µg/dL prompted evaluation for a tumor.⁴ More recent studies show that tumor-induced increases in serum androgen levels are highly variable, challenging the utility of these cutoffs.⁵

A 70-year-old woman presented with hair loss over the last 12 years with accentuated thinning on the frontal and vertex scalp. The patient’s primary care physician previously made a diagnosis of androgenetic alopecia and recommended topical minoxidil. Although the patient had a history of excess facial and body hair since young adulthood, she noted a progressive increase in the density of chest and back hair, prominent coarsening of the texture of the facial and body hair, and new facial acne in the last 3 years. Prior to these changes, the density and texture of the scalp and body hair had been stable for many years.

Although other postmenopausal females in the patient’s family displayed patterned hair loss, they did not possess coarse and dense hair on the face and trunk. Her family history was notable for ovarian cancer in her mother (in her 70s) and breast cancer in her maternal grandmother (in her 80s).

A review of systems was notable only for decreased energy. Physical examination revealed a well-appearing older woman with coarse terminal hair growth on the cheeks, submental chin, neck, chest, back, and forearms. Scalp examination indicated diffusely decreased hair density, most marked over the vertex, crown, and frontal scalp, without scale, erythema, or loss of follicular ostia (Figure 1).

Pelvic ultrasonography was suspicious for an ovarian pathology. Follow-up pelvic magnetic resonance imaging (MRI) demonstrated a 2.5-cm mass abutting the left ovary (Figure 2). The patient was given a diagnosis of stage IIIA high-grade ovarian serous carcinoma with lymph node involvement. Other notable findings from the workup included a BRCA2 mutation and concurrent renal cell carcinoma. After bilateral salpingo-oophorectomy, partial nephrectomy, and chemotherapy with carboplatin and paclitaxel, the testosterone level returned to within reference range and remained stable for the next 2 years of follow-up.

Imaging is indicated for a patient presenting with both clinical and biochemical hyperandrogenism. Patients with an isolated testosterone level elevation can be evaluated with transvaginal ultrasonography; however, detection and characterization of malignancies is highly dependent on the skill of the examiner.^8,9 The higher sensitivity and specificity of pelvic MRI reduces the likelihood of missing a malignancy and unnecessary surgery. Tumors too small to be visualized by MRI rarely are malignant.¹⁰

Sex cord-stromal cell tumors, despite representing fewer than 10% of ovarian tumors, are responsible for the majority of androgen-secreting malignancies. Our patient presented with clinical hyperandrogenism with an elevated testosterone level in the setting of a serous ovarian carcinoma, which is an epithelial neoplasm. Epithelial tumors are the most common type of ovarian tumor and typically are nonfunctional, though they have been reported to cause hyperandrogenism through indirect mechanisms. It is thought that both benign and malignant epithelial tumors can induce stromal hyperplasia or luteinization, leading to an increase in androgen levels.⁶

Due to the high prevalence of androgenetic alopecia and hirsutism in aging women, identification of androgen-secreting neoplasms by clinical presentation is challenging. A wide range of serum testosterone levels is possible at presentation, which complicates diagnosis. This case highlights the importance of correlating clinical and biochemical hyperandrogenism in raising suspicion of malignancy in older women presenting with hair loss.

To the Editor:

Symmetric drug-related intertriginous and flexural exanthema (SDRIFE) is a curious disorder that has undergone many clinical transformations since first being described by Andersen et al¹ in 1984 using the term baboon syndrome. Initially described as a mercury hypersensitivity reaction resulting in an eruption resembling the red-bottomed baboon, this exanthema has expanded in definition with inciting agents, clinical features, and diagnostic criteria. Its prognosis, however, has remained stable and favorable throughout the decades. The condition is almost universally benign and self-limited.^1-3 As new cases are reported in the literature and the paradigm of SDRIFE continues to shift, its prognosis also may warrant reconsideration and respect as a potentially destructive reaction.

A 39-year-old woman who was otherwise healthy presented to the emergency department after developing a rapidly evolving and blistering rash on the left flank. Hours later, the rash had progressed to a sharply demarcated, confluent, erythematous plaque with central ulceration and large flaccid bullae peripherally, encompassing 18% of total body surface area and extending from the gluteal cleft to the tip of the scapula along the left flank (Figure 1) with no vaginal or mucosal involvement. The patient recently had completed a 10-day course of amoxicillin–clavulanic acid 2 days prior for a cat bite on the right dorsal wrist. Additional history confirmed the absence of prodromal fever, fatigue, or chills. Inciting trauma, including chemical and thermal burns, was denied. Potential underlying psychosocial cofounders were explored and were unrevealing.

In the undifferentiated patient, categorization of the clinical syndrome proves helpful in prognostication and therapeutic approach. The complexities and commonalities intrinsic to these syndromes, however, may simultaneously preclude certain cases from neatly following the predefined rules. These atypical presentations, while diagnostically challenging, can in turn offer a unique opportunity to reexamine the current state of disease understanding to better allow for appropriate classification.

Despite its rarity, SDRIFE should be considered in the differential of undiagnosed drug eruptions, particularly as new clinical presentations emerge. Careful documentation and timely declaration of future cases will prove invaluable for diagnostic and therapeutic advancements should this once-benign condition develop a more destructive potential.

To the Editor:

Symmetric drug-related intertriginous and flexural exanthema (SDRIFE) is a curious disorder that has undergone many clinical transformations since first being described by Andersen et al¹ in 1984 using the term baboon syndrome. Initially described as a mercury hypersensitivity reaction resulting in an eruption resembling the red-bottomed baboon, this exanthema has expanded in definition with inciting agents, clinical features, and diagnostic criteria. Its prognosis, however, has remained stable and favorable throughout the decades. The condition is almost universally benign and self-limited.^1-3 As new cases are reported in the literature and the paradigm of SDRIFE continues to shift, its prognosis also may warrant reconsideration and respect as a potentially destructive reaction.

A 39-year-old woman who was otherwise healthy presented to the emergency department after developing a rapidly evolving and blistering rash on the left flank. Hours later, the rash had progressed to a sharply demarcated, confluent, erythematous plaque with central ulceration and large flaccid bullae peripherally, encompassing 18% of total body surface area and extending from the gluteal cleft to the tip of the scapula along the left flank (Figure 1) with no vaginal or mucosal involvement. The patient recently had completed a 10-day course of amoxicillin–clavulanic acid 2 days prior for a cat bite on the right dorsal wrist. Additional history confirmed the absence of prodromal fever, fatigue, or chills. Inciting trauma, including chemical and thermal burns, was denied. Potential underlying psychosocial cofounders were explored and were unrevealing.

In the undifferentiated patient, categorization of the clinical syndrome proves helpful in prognostication and therapeutic approach. The complexities and commonalities intrinsic to these syndromes, however, may simultaneously preclude certain cases from neatly following the predefined rules. These atypical presentations, while diagnostically challenging, can in turn offer a unique opportunity to reexamine the current state of disease understanding to better allow for appropriate classification.

Despite its rarity, SDRIFE should be considered in the differential of undiagnosed drug eruptions, particularly as new clinical presentations emerge. Careful documentation and timely declaration of future cases will prove invaluable for diagnostic and therapeutic advancements should this once-benign condition develop a more destructive potential.

To the Editor:

Symmetric drug-related intertriginous and flexural exanthema (SDRIFE) is a curious disorder that has undergone many clinical transformations since first being described by Andersen et al¹ in 1984 using the term baboon syndrome. Initially described as a mercury hypersensitivity reaction resulting in an eruption resembling the red-bottomed baboon, this exanthema has expanded in definition with inciting agents, clinical features, and diagnostic criteria. Its prognosis, however, has remained stable and favorable throughout the decades. The condition is almost universally benign and self-limited.^1-3 As new cases are reported in the literature and the paradigm of SDRIFE continues to shift, its prognosis also may warrant reconsideration and respect as a potentially destructive reaction.

A 39-year-old woman who was otherwise healthy presented to the emergency department after developing a rapidly evolving and blistering rash on the left flank. Hours later, the rash had progressed to a sharply demarcated, confluent, erythematous plaque with central ulceration and large flaccid bullae peripherally, encompassing 18% of total body surface area and extending from the gluteal cleft to the tip of the scapula along the left flank (Figure 1) with no vaginal or mucosal involvement. The patient recently had completed a 10-day course of amoxicillin–clavulanic acid 2 days prior for a cat bite on the right dorsal wrist. Additional history confirmed the absence of prodromal fever, fatigue, or chills. Inciting trauma, including chemical and thermal burns, was denied. Potential underlying psychosocial cofounders were explored and were unrevealing.

In the undifferentiated patient, categorization of the clinical syndrome proves helpful in prognostication and therapeutic approach. The complexities and commonalities intrinsic to these syndromes, however, may simultaneously preclude certain cases from neatly following the predefined rules. These atypical presentations, while diagnostically challenging, can in turn offer a unique opportunity to reexamine the current state of disease understanding to better allow for appropriate classification.

Despite its rarity, SDRIFE should be considered in the differential of undiagnosed drug eruptions, particularly as new clinical presentations emerge. Careful documentation and timely declaration of future cases will prove invaluable for diagnostic and therapeutic advancements should this once-benign condition develop a more destructive potential.

To the Editor:

A 32-year-old man presented to the dermatology clinic with multiple asymptomatic blue lesions on the arms and upper torso of 15 years’ duration. His medical history was notable for a recent diagnosis of malignant melanoma following excision of a mole on the upper back 4 months prior. He reported that the mole had been present since childhood, but his sister noticed that it increased in size and changed in color over the course of a year. Physical examination showed multiple blue subcutaneous nodules on the bilateral arms and lower back. The nodules were soft and nontender, and some had telangiectasia on the overlying skin.

Given the atypical distribution of nodules and the patient’s recent history of melanoma, there was concern for cutaneous metastases. A punch biopsy of one of the nodules on the right upper arm was performed. Microscopic examination of the biopsy specimen revealed a proliferation of multiple cavernous vessels surrounded by several rows of monotonous round cells with moderate eosinophilic cytoplasm and monomorphic nuclei, which was consistent with a diagnosis of glomangioma (Figure 1). Immunohistochemical analysis showed diffuse positive staining for smooth muscle actin (Figure 2); CD34 immunostain was positive in endothelial cells and negative in tumor cells (Figure 3).

Glomus tumors arise from modified smooth muscle cells located in glomus bodies. The glomus body is a component of the dermis involved in regulation of body temperature that is composed of an afferent arteriole and an efferent venule. The arterial end of this apparatus, known as the Sucquet-Hoyer canal, is surrounded by glomus cells that have a contractile capability similar to smooth muscle cells. Glomus tumors usually present as painful masses on the fingers with a typical subungual location and almost always are solitary.¹ Glomangiomas, sometimes known as glomuvenous malformations, tend to be larger and usually are painless. They mostly are found on the trunk and extremities and can appear in groups.^2,3 Histopathologically, glomus tumors are circumscribed lesions that show a predominance of glomus cells surrounding inconspicuous blood vessels. Glomangiomas are less well-circumscribed and show a more vascular architecture with prominent dilated vessels and a smaller number of glomus cells.⁴

We present a case of a patient with multiple glomangiomas. There are few reports of multiple glomangiomas in the literature. This case is particularly interesting in that our patient had a history of malignant melanoma, and there was a concern for skin metastases. Despite the patient’s personal history of blue lesions that predated the diagnosis of melanoma for many years, we could not exclude the possibility of cutaneous metastases without performing biopsies.

Tumors of glomus cell origin usually are benign. It has been suggested to replace the term glomangioma with glomuvenous malformations to emphasize the hamartomatous nature of these lesions.⁵ Glomuvenous malformations, or glomangiomas, can occur sporadically or can be inherited as a familial disorder. Inheritable glomangioma has been linked to the chromosome 1p21-22 locus and mutations in the glomulin gene, GLMN, with variable penetrance.⁶ Our patient did not report a family history of such lesions.

Glomangiomas typically are solitary but rarely can present as multiple lesions in fewer than 10% of cases.⁷ Multiple glomangiomas are classified into 3 subtypes: localized, disseminated, and congenital plaque type. Localized multiple glomangiomas present as blue nodules confined to 1 anatomic location such as the hand or arm. Disseminated glomangiomas are more widely distributed and involve more than 1 anatomic location.⁸ Plaque-type glomangiomas consist of numerous confluent lesions occurring either as solitary or multiple plaques.² Clinically, glomangiomas manifest as painless to mildly painful cutaneous nodules. Compared to venous malformations, glomangiomas are less compressible under external pressure.

Histopathologically, glomangiomas appear as nonencapsulated tumors with large, irregular, prominent vessels lined by glomus cells. Glomus cells may be so sparse that the distinction from venous malformations and hemangiomas becomes difficult. Immunohistochemistry can play an important role in diagnosis. As modified smooth muscle cells, glomus cells stain positive with a-smooth muscle actin, while CD34 highlights the vascular endothelium.¹The clinical differential diagnosis of multiple blue or violaceous subcutaneous nodules includes blue rubber bleb nevus syndrome, Maffucci syndrome, glomus tumor, pyogenic granuloma, hemangioma, spiradenoma, angiolipoma, leiomyoma, or hemangiopericytoma.^9-12

Different treatment modalities are available for solitary glomangiomas, including surgical excision, sclerotherapy, and laser application. Treatment of multiple glomangiomas may not be feasible, and excision of isolated symptomatic lesions may be the only option; however, it is crucial to reach the correct diagnosis in these patients to avoid improper treatments and interventions.

To the Editor:

A 32-year-old man presented to the dermatology clinic with multiple asymptomatic blue lesions on the arms and upper torso of 15 years’ duration. His medical history was notable for a recent diagnosis of malignant melanoma following excision of a mole on the upper back 4 months prior. He reported that the mole had been present since childhood, but his sister noticed that it increased in size and changed in color over the course of a year. Physical examination showed multiple blue subcutaneous nodules on the bilateral arms and lower back. The nodules were soft and nontender, and some had telangiectasia on the overlying skin.

Given the atypical distribution of nodules and the patient’s recent history of melanoma, there was concern for cutaneous metastases. A punch biopsy of one of the nodules on the right upper arm was performed. Microscopic examination of the biopsy specimen revealed a proliferation of multiple cavernous vessels surrounded by several rows of monotonous round cells with moderate eosinophilic cytoplasm and monomorphic nuclei, which was consistent with a diagnosis of glomangioma (Figure 1). Immunohistochemical analysis showed diffuse positive staining for smooth muscle actin (Figure 2); CD34 immunostain was positive in endothelial cells and negative in tumor cells (Figure 3).

Glomus tumors arise from modified smooth muscle cells located in glomus bodies. The glomus body is a component of the dermis involved in regulation of body temperature that is composed of an afferent arteriole and an efferent venule. The arterial end of this apparatus, known as the Sucquet-Hoyer canal, is surrounded by glomus cells that have a contractile capability similar to smooth muscle cells. Glomus tumors usually present as painful masses on the fingers with a typical subungual location and almost always are solitary.¹ Glomangiomas, sometimes known as glomuvenous malformations, tend to be larger and usually are painless. They mostly are found on the trunk and extremities and can appear in groups.^2,3 Histopathologically, glomus tumors are circumscribed lesions that show a predominance of glomus cells surrounding inconspicuous blood vessels. Glomangiomas are less well-circumscribed and show a more vascular architecture with prominent dilated vessels and a smaller number of glomus cells.⁴

We present a case of a patient with multiple glomangiomas. There are few reports of multiple glomangiomas in the literature. This case is particularly interesting in that our patient had a history of malignant melanoma, and there was a concern for skin metastases. Despite the patient’s personal history of blue lesions that predated the diagnosis of melanoma for many years, we could not exclude the possibility of cutaneous metastases without performing biopsies.

Tumors of glomus cell origin usually are benign. It has been suggested to replace the term glomangioma with glomuvenous malformations to emphasize the hamartomatous nature of these lesions.⁵ Glomuvenous malformations, or glomangiomas, can occur sporadically or can be inherited as a familial disorder. Inheritable glomangioma has been linked to the chromosome 1p21-22 locus and mutations in the glomulin gene, GLMN, with variable penetrance.⁶ Our patient did not report a family history of such lesions.

Glomangiomas typically are solitary but rarely can present as multiple lesions in fewer than 10% of cases.⁷ Multiple glomangiomas are classified into 3 subtypes: localized, disseminated, and congenital plaque type. Localized multiple glomangiomas present as blue nodules confined to 1 anatomic location such as the hand or arm. Disseminated glomangiomas are more widely distributed and involve more than 1 anatomic location.⁸ Plaque-type glomangiomas consist of numerous confluent lesions occurring either as solitary or multiple plaques.² Clinically, glomangiomas manifest as painless to mildly painful cutaneous nodules. Compared to venous malformations, glomangiomas are less compressible under external pressure.

Histopathologically, glomangiomas appear as nonencapsulated tumors with large, irregular, prominent vessels lined by glomus cells. Glomus cells may be so sparse that the distinction from venous malformations and hemangiomas becomes difficult. Immunohistochemistry can play an important role in diagnosis. As modified smooth muscle cells, glomus cells stain positive with a-smooth muscle actin, while CD34 highlights the vascular endothelium.¹The clinical differential diagnosis of multiple blue or violaceous subcutaneous nodules includes blue rubber bleb nevus syndrome, Maffucci syndrome, glomus tumor, pyogenic granuloma, hemangioma, spiradenoma, angiolipoma, leiomyoma, or hemangiopericytoma.^9-12

Different treatment modalities are available for solitary glomangiomas, including surgical excision, sclerotherapy, and laser application. Treatment of multiple glomangiomas may not be feasible, and excision of isolated symptomatic lesions may be the only option; however, it is crucial to reach the correct diagnosis in these patients to avoid improper treatments and interventions.

To the Editor:

A 32-year-old man presented to the dermatology clinic with multiple asymptomatic blue lesions on the arms and upper torso of 15 years’ duration. His medical history was notable for a recent diagnosis of malignant melanoma following excision of a mole on the upper back 4 months prior. He reported that the mole had been present since childhood, but his sister noticed that it increased in size and changed in color over the course of a year. Physical examination showed multiple blue subcutaneous nodules on the bilateral arms and lower back. The nodules were soft and nontender, and some had telangiectasia on the overlying skin.

Given the atypical distribution of nodules and the patient’s recent history of melanoma, there was concern for cutaneous metastases. A punch biopsy of one of the nodules on the right upper arm was performed. Microscopic examination of the biopsy specimen revealed a proliferation of multiple cavernous vessels surrounded by several rows of monotonous round cells with moderate eosinophilic cytoplasm and monomorphic nuclei, which was consistent with a diagnosis of glomangioma (Figure 1). Immunohistochemical analysis showed diffuse positive staining for smooth muscle actin (Figure 2); CD34 immunostain was positive in endothelial cells and negative in tumor cells (Figure 3).

Glomus tumors arise from modified smooth muscle cells located in glomus bodies. The glomus body is a component of the dermis involved in regulation of body temperature that is composed of an afferent arteriole and an efferent venule. The arterial end of this apparatus, known as the Sucquet-Hoyer canal, is surrounded by glomus cells that have a contractile capability similar to smooth muscle cells. Glomus tumors usually present as painful masses on the fingers with a typical subungual location and almost always are solitary.¹ Glomangiomas, sometimes known as glomuvenous malformations, tend to be larger and usually are painless. They mostly are found on the trunk and extremities and can appear in groups.^2,3 Histopathologically, glomus tumors are circumscribed lesions that show a predominance of glomus cells surrounding inconspicuous blood vessels. Glomangiomas are less well-circumscribed and show a more vascular architecture with prominent dilated vessels and a smaller number of glomus cells.⁴

We present a case of a patient with multiple glomangiomas. There are few reports of multiple glomangiomas in the literature. This case is particularly interesting in that our patient had a history of malignant melanoma, and there was a concern for skin metastases. Despite the patient’s personal history of blue lesions that predated the diagnosis of melanoma for many years, we could not exclude the possibility of cutaneous metastases without performing biopsies.

Tumors of glomus cell origin usually are benign. It has been suggested to replace the term glomangioma with glomuvenous malformations to emphasize the hamartomatous nature of these lesions.⁵ Glomuvenous malformations, or glomangiomas, can occur sporadically or can be inherited as a familial disorder. Inheritable glomangioma has been linked to the chromosome 1p21-22 locus and mutations in the glomulin gene, GLMN, with variable penetrance.⁶ Our patient did not report a family history of such lesions.

Glomangiomas typically are solitary but rarely can present as multiple lesions in fewer than 10% of cases.⁷ Multiple glomangiomas are classified into 3 subtypes: localized, disseminated, and congenital plaque type. Localized multiple glomangiomas present as blue nodules confined to 1 anatomic location such as the hand or arm. Disseminated glomangiomas are more widely distributed and involve more than 1 anatomic location.⁸ Plaque-type glomangiomas consist of numerous confluent lesions occurring either as solitary or multiple plaques.² Clinically, glomangiomas manifest as painless to mildly painful cutaneous nodules. Compared to venous malformations, glomangiomas are less compressible under external pressure.

Histopathologically, glomangiomas appear as nonencapsulated tumors with large, irregular, prominent vessels lined by glomus cells. Glomus cells may be so sparse that the distinction from venous malformations and hemangiomas becomes difficult. Immunohistochemistry can play an important role in diagnosis. As modified smooth muscle cells, glomus cells stain positive with a-smooth muscle actin, while CD34 highlights the vascular endothelium.¹The clinical differential diagnosis of multiple blue or violaceous subcutaneous nodules includes blue rubber bleb nevus syndrome, Maffucci syndrome, glomus tumor, pyogenic granuloma, hemangioma, spiradenoma, angiolipoma, leiomyoma, or hemangiopericytoma.^9-12

Different treatment modalities are available for solitary glomangiomas, including surgical excision, sclerotherapy, and laser application. Treatment of multiple glomangiomas may not be feasible, and excision of isolated symptomatic lesions may be the only option; however, it is crucial to reach the correct diagnosis in these patients to avoid improper treatments and interventions.

To the Editor:

Cutaneous reactions to implantable devices, such as dental implants, intracoronary stents, prosthetic valves, endovascular prostheses, gynecologic devices, and spinal cord stimulator devices, occur with varying frequency and include infectious, hypersensitivity, allergic, and foreign-body reactions. Manifestations have included contact dermatitis; urticarial, vasculitic, and bullous eruptions; extrusion; and granuloma formation.^1,2 Immune complex reactions around implants causing pain, inflammation, and loosening of hardwarealso have been reported.^3,4 Most reported cutaneous reactions typically occur within the first weeks or months after implantation; a reaction rarely presents several years after implantation. We report a cutaneous reaction to an orthopedic appliance almost 10 years after implantation.

A 67-year-old man presented with 2 painful nodules on the right clavicle that were present for several months. The patient denied fever, chills, weight loss, enlarged lymph nodes, or night sweats. Approximately 10 years prior to the appearance of the nodules, the patient fractured the right clavicle and underwent placement of a metal plate. His medical history included resection of the right tonsil and soft-palate carcinoma with radical neck dissection and postoperative radiation, which was completed approximately 4 years prior to placement of the metal plate. The patient recently completed 4 to 6 weeks of fluorouracil for shave biopsy–proven actinic keratosis overlying the entire irradiated area.

Physical examination revealed 2 pink friable nodules measuring 1.5 to 2.5 cm in diameter and leaking serous fluid within the irradiated area (Figure 1). The differential diagnosis included pyogenic granuloma, cutaneous recurrent metastasis, and atypical basal cell carcinoma. A skin biopsy specimen showed hemorrhagic ulcerated skin with acute and chronic inflammation and abscess.

To the Editor:

Cutaneous reactions to implantable devices, such as dental implants, intracoronary stents, prosthetic valves, endovascular prostheses, gynecologic devices, and spinal cord stimulator devices, occur with varying frequency and include infectious, hypersensitivity, allergic, and foreign-body reactions. Manifestations have included contact dermatitis; urticarial, vasculitic, and bullous eruptions; extrusion; and granuloma formation.^1,2 Immune complex reactions around implants causing pain, inflammation, and loosening of hardwarealso have been reported.^3,4 Most reported cutaneous reactions typically occur within the first weeks or months after implantation; a reaction rarely presents several years after implantation. We report a cutaneous reaction to an orthopedic appliance almost 10 years after implantation.

A 67-year-old man presented with 2 painful nodules on the right clavicle that were present for several months. The patient denied fever, chills, weight loss, enlarged lymph nodes, or night sweats. Approximately 10 years prior to the appearance of the nodules, the patient fractured the right clavicle and underwent placement of a metal plate. His medical history included resection of the right tonsil and soft-palate carcinoma with radical neck dissection and postoperative radiation, which was completed approximately 4 years prior to placement of the metal plate. The patient recently completed 4 to 6 weeks of fluorouracil for shave biopsy–proven actinic keratosis overlying the entire irradiated area.

Physical examination revealed 2 pink friable nodules measuring 1.5 to 2.5 cm in diameter and leaking serous fluid within the irradiated area (Figure 1). The differential diagnosis included pyogenic granuloma, cutaneous recurrent metastasis, and atypical basal cell carcinoma. A skin biopsy specimen showed hemorrhagic ulcerated skin with acute and chronic inflammation and abscess.

To the Editor:

Cutaneous reactions to implantable devices, such as dental implants, intracoronary stents, prosthetic valves, endovascular prostheses, gynecologic devices, and spinal cord stimulator devices, occur with varying frequency and include infectious, hypersensitivity, allergic, and foreign-body reactions. Manifestations have included contact dermatitis; urticarial, vasculitic, and bullous eruptions; extrusion; and granuloma formation.^1,2 Immune complex reactions around implants causing pain, inflammation, and loosening of hardwarealso have been reported.^3,4 Most reported cutaneous reactions typically occur within the first weeks or months after implantation; a reaction rarely presents several years after implantation. We report a cutaneous reaction to an orthopedic appliance almost 10 years after implantation.

A 67-year-old man presented with 2 painful nodules on the right clavicle that were present for several months. The patient denied fever, chills, weight loss, enlarged lymph nodes, or night sweats. Approximately 10 years prior to the appearance of the nodules, the patient fractured the right clavicle and underwent placement of a metal plate. His medical history included resection of the right tonsil and soft-palate carcinoma with radical neck dissection and postoperative radiation, which was completed approximately 4 years prior to placement of the metal plate. The patient recently completed 4 to 6 weeks of fluorouracil for shave biopsy–proven actinic keratosis overlying the entire irradiated area.

Physical examination revealed 2 pink friable nodules measuring 1.5 to 2.5 cm in diameter and leaking serous fluid within the irradiated area (Figure 1). The differential diagnosis included pyogenic granuloma, cutaneous recurrent metastasis, and atypical basal cell carcinoma. A skin biopsy specimen showed hemorrhagic ulcerated skin with acute and chronic inflammation and abscess.

To the Editor:

A 73-year-old man presented with a 2.5-cm, recurrent, fluctuant, multiloculated nodule on the left forearm. The lesion was nontender with occasional chalky, white to yellow discharge from multiple sinus tracts. He was otherwise well appearing without signs of systemic infection. He reported similar lesions in slightly different anatomic locations on the left forearm both 7 and 4 years prior to the current presentation. In both instances, the nodules were excised at an outside hospital without any additional treatment. Histopathology of the excised tissue from both prior occasions demonstrated brown septate hyphae surrounded by suppurative and granulomatous inflammation consistent with dematiaceous fungal infection of the dermis (Figures 1 and 2); the organisms were highlighted with periodic acid–Schiff stain.

The patient’s medical history was notable for advanced heart failure with an ejection fraction of 25% and autosomal-dominant polycystic kidney disease. He received an orthotopic kidney transplant 17 years prior to the current presentation. Medications included tacrolimus, mycophenolate mofetil, and prednisone. He denied any trauma or notable exposures to vegetation, and his travel history was unremarkable. A review of systems was negative.

At the current presentation, a sterile fungal culture was performed and found positive for Exophiala species, while bacterial and mycobacterial cultures were negative. A diagnosis of phaeohyphomycosis was made, and he was scheduled for re-excision. Out of concern for interactions with his immunosuppressive regimen, he chose to forgo any systemic antifungal therapy. He died from hospital-acquired pneumonia and volume overload unresponsive to diuretics or dialysis.

Phaeohyphomycosis is a rare fungal infection caused by several genera of dematiaceous fungi that are characterized by the presence of melaninlike cell wall pigments thought to locally hinder immune clearance by scavenging phagocyte-derived free radicals. These fungi are ubiquitous in soil and vegetation and usually penetrate the skin at sites of minor trauma.¹ Phaeohyphomycosis typically affects immunosuppressed hosts, and its incidence among organ transplant recipients currently is 9%.² The incidence in this population has been rising, however, as recent advances in immunosuppressive therapies have increased posttransplant survival.³

Subcutaneous phaeohyphomycosis can present with nodules, cysts, tumors, and/or verrucous plaques, and the diagnosis almost always requires clinicopathologic correlation.³ Rapid diagnosis can be made when septate brown hyphae and/or yeast forms are observed on hematoxylin and eosin stain. Rarely, patients present with disseminated infection, characterized by fungemia; central nervous system involvement; and/or infection of multiple deep structures including the eyes, lungs, bones, and sinuses.⁴ The risk for dissemination from the skin likely is related to the culprit organism’s genus; Lomentospora, Cladophialophora, and Verruconis often are associated with dissemination, while Alternaria, Exophiala, and Fonsecaea typically remain confined to the skin and subcutis.⁵ Due to this difference and its potential to impact management, obtaining a tissue fungal culture is advisable when phaeohyphomycosis is suspected.

There is no standard treatment of phaeohyphomycosis. Regimens typically consist of excision and prolonged courses of azole therapy, though excision alone with close follow-up may be a reasonable alternative.⁶ The latter is a particularly important consideration when managing phaeohyphomycosis in organ transplant recipients, as azoles are known cytochrome P450 3A4 inhibitors that can affect serum levels of common immunosuppressive medications including calcineurin inhibitors and mammalian target of rapamycin inhibitors.³ Local recurrence is common regardless of whether azole therapy is pursued,⁷ and dissemination of localized Exophiala infections is exceedingly rare.⁸ There is a strong argument to be made for our patient’s decision to forgo antifungal therapy.

This case underscores the difficulty inherent to eradicating local subcutaneous Exophiala phaeohyphomycosis while providing reassurance that with treatment, the risk of life-threatening complications is low. Obtaining tissue for both hematoxylin and eosin stain and sterile culture is crucial to ensuring prompt diagnosis and tailoring the optimal treatment and surveillance strategy to the culprit organism. To avoid delays in diagnosis and treatment, it is important for clinicians to consider phaeohyphomycosis in the differential diagnosis for recurrent nodulocystic lesions in immunosuppressed patients and to recognize that presentations may span many years.

To the Editor:

A 73-year-old man presented with a 2.5-cm, recurrent, fluctuant, multiloculated nodule on the left forearm. The lesion was nontender with occasional chalky, white to yellow discharge from multiple sinus tracts. He was otherwise well appearing without signs of systemic infection. He reported similar lesions in slightly different anatomic locations on the left forearm both 7 and 4 years prior to the current presentation. In both instances, the nodules were excised at an outside hospital without any additional treatment. Histopathology of the excised tissue from both prior occasions demonstrated brown septate hyphae surrounded by suppurative and granulomatous inflammation consistent with dematiaceous fungal infection of the dermis (Figures 1 and 2); the organisms were highlighted with periodic acid–Schiff stain.

The patient’s medical history was notable for advanced heart failure with an ejection fraction of 25% and autosomal-dominant polycystic kidney disease. He received an orthotopic kidney transplant 17 years prior to the current presentation. Medications included tacrolimus, mycophenolate mofetil, and prednisone. He denied any trauma or notable exposures to vegetation, and his travel history was unremarkable. A review of systems was negative.

At the current presentation, a sterile fungal culture was performed and found positive for Exophiala species, while bacterial and mycobacterial cultures were negative. A diagnosis of phaeohyphomycosis was made, and he was scheduled for re-excision. Out of concern for interactions with his immunosuppressive regimen, he chose to forgo any systemic antifungal therapy. He died from hospital-acquired pneumonia and volume overload unresponsive to diuretics or dialysis.

Phaeohyphomycosis is a rare fungal infection caused by several genera of dematiaceous fungi that are characterized by the presence of melaninlike cell wall pigments thought to locally hinder immune clearance by scavenging phagocyte-derived free radicals. These fungi are ubiquitous in soil and vegetation and usually penetrate the skin at sites of minor trauma.¹ Phaeohyphomycosis typically affects immunosuppressed hosts, and its incidence among organ transplant recipients currently is 9%.² The incidence in this population has been rising, however, as recent advances in immunosuppressive therapies have increased posttransplant survival.³

Subcutaneous phaeohyphomycosis can present with nodules, cysts, tumors, and/or verrucous plaques, and the diagnosis almost always requires clinicopathologic correlation.³ Rapid diagnosis can be made when septate brown hyphae and/or yeast forms are observed on hematoxylin and eosin stain. Rarely, patients present with disseminated infection, characterized by fungemia; central nervous system involvement; and/or infection of multiple deep structures including the eyes, lungs, bones, and sinuses.⁴ The risk for dissemination from the skin likely is related to the culprit organism’s genus; Lomentospora, Cladophialophora, and Verruconis often are associated with dissemination, while Alternaria, Exophiala, and Fonsecaea typically remain confined to the skin and subcutis.⁵ Due to this difference and its potential to impact management, obtaining a tissue fungal culture is advisable when phaeohyphomycosis is suspected.

There is no standard treatment of phaeohyphomycosis. Regimens typically consist of excision and prolonged courses of azole therapy, though excision alone with close follow-up may be a reasonable alternative.⁶ The latter is a particularly important consideration when managing phaeohyphomycosis in organ transplant recipients, as azoles are known cytochrome P450 3A4 inhibitors that can affect serum levels of common immunosuppressive medications including calcineurin inhibitors and mammalian target of rapamycin inhibitors.³ Local recurrence is common regardless of whether azole therapy is pursued,⁷ and dissemination of localized Exophiala infections is exceedingly rare.⁸ There is a strong argument to be made for our patient’s decision to forgo antifungal therapy.

This case underscores the difficulty inherent to eradicating local subcutaneous Exophiala phaeohyphomycosis while providing reassurance that with treatment, the risk of life-threatening complications is low. Obtaining tissue for both hematoxylin and eosin stain and sterile culture is crucial to ensuring prompt diagnosis and tailoring the optimal treatment and surveillance strategy to the culprit organism. To avoid delays in diagnosis and treatment, it is important for clinicians to consider phaeohyphomycosis in the differential diagnosis for recurrent nodulocystic lesions in immunosuppressed patients and to recognize that presentations may span many years.

To the Editor:

A 73-year-old man presented with a 2.5-cm, recurrent, fluctuant, multiloculated nodule on the left forearm. The lesion was nontender with occasional chalky, white to yellow discharge from multiple sinus tracts. He was otherwise well appearing without signs of systemic infection. He reported similar lesions in slightly different anatomic locations on the left forearm both 7 and 4 years prior to the current presentation. In both instances, the nodules were excised at an outside hospital without any additional treatment. Histopathology of the excised tissue from both prior occasions demonstrated brown septate hyphae surrounded by suppurative and granulomatous inflammation consistent with dematiaceous fungal infection of the dermis (Figures 1 and 2); the organisms were highlighted with periodic acid–Schiff stain.

The patient’s medical history was notable for advanced heart failure with an ejection fraction of 25% and autosomal-dominant polycystic kidney disease. He received an orthotopic kidney transplant 17 years prior to the current presentation. Medications included tacrolimus, mycophenolate mofetil, and prednisone. He denied any trauma or notable exposures to vegetation, and his travel history was unremarkable. A review of systems was negative.

At the current presentation, a sterile fungal culture was performed and found positive for Exophiala species, while bacterial and mycobacterial cultures were negative. A diagnosis of phaeohyphomycosis was made, and he was scheduled for re-excision. Out of concern for interactions with his immunosuppressive regimen, he chose to forgo any systemic antifungal therapy. He died from hospital-acquired pneumonia and volume overload unresponsive to diuretics or dialysis.

Phaeohyphomycosis is a rare fungal infection caused by several genera of dematiaceous fungi that are characterized by the presence of melaninlike cell wall pigments thought to locally hinder immune clearance by scavenging phagocyte-derived free radicals. These fungi are ubiquitous in soil and vegetation and usually penetrate the skin at sites of minor trauma.¹ Phaeohyphomycosis typically affects immunosuppressed hosts, and its incidence among organ transplant recipients currently is 9%.² The incidence in this population has been rising, however, as recent advances in immunosuppressive therapies have increased posttransplant survival.³

Subcutaneous phaeohyphomycosis can present with nodules, cysts, tumors, and/or verrucous plaques, and the diagnosis almost always requires clinicopathologic correlation.³ Rapid diagnosis can be made when septate brown hyphae and/or yeast forms are observed on hematoxylin and eosin stain. Rarely, patients present with disseminated infection, characterized by fungemia; central nervous system involvement; and/or infection of multiple deep structures including the eyes, lungs, bones, and sinuses.⁴ The risk for dissemination from the skin likely is related to the culprit organism’s genus; Lomentospora, Cladophialophora, and Verruconis often are associated with dissemination, while Alternaria, Exophiala, and Fonsecaea typically remain confined to the skin and subcutis.⁵ Due to this difference and its potential to impact management, obtaining a tissue fungal culture is advisable when phaeohyphomycosis is suspected.

There is no standard treatment of phaeohyphomycosis. Regimens typically consist of excision and prolonged courses of azole therapy, though excision alone with close follow-up may be a reasonable alternative.⁶ The latter is a particularly important consideration when managing phaeohyphomycosis in organ transplant recipients, as azoles are known cytochrome P450 3A4 inhibitors that can affect serum levels of common immunosuppressive medications including calcineurin inhibitors and mammalian target of rapamycin inhibitors.³ Local recurrence is common regardless of whether azole therapy is pursued,⁷ and dissemination of localized Exophiala infections is exceedingly rare.⁸ There is a strong argument to be made for our patient’s decision to forgo antifungal therapy.

This case underscores the difficulty inherent to eradicating local subcutaneous Exophiala phaeohyphomycosis while providing reassurance that with treatment, the risk of life-threatening complications is low. Obtaining tissue for both hematoxylin and eosin stain and sterile culture is crucial to ensuring prompt diagnosis and tailoring the optimal treatment and surveillance strategy to the culprit organism. To avoid delays in diagnosis and treatment, it is important for clinicians to consider phaeohyphomycosis in the differential diagnosis for recurrent nodulocystic lesions in immunosuppressed patients and to recognize that presentations may span many years.

To the Editor:

A 71-year-old man presented with a nodule on the vertex of the scalp of 1 year’s duration. The lesion had become soft and tender during the week prior to presentation. He noted that he was experiencing headaches and a buzzing sound in his head. He denied all other neurologic symptoms. The patient was given amoxicillin from a primary care physician and was referred to our institution for evaluation of a presumed inflamed cyst.

The patient’s medical history included an intracranial arteriovenous fistula (AVF) treated with endovascular embolization 1 year prior to presentation, 2 substantial falls in childhood with head trauma and loss of consciousness, essential hypertension, and an aortic aneurysm. His medications included amlodipine, lisinopril, amoxicillin, a multivitamin, and grape seed extract.

Physical examination revealed a 2-cm, pink, somewhat rubbery, subcutaneous, nonmobile nodule on the vertex of the scalp (Figure 1). The lesion was not consistent with a common pilar cyst, and an excisional biopsy was performed to exclude malignancy. Upon superficial incision, the lesion bled moderately, and the procedure was immediately discontinued. Hemostasis was obtained, and the patient was sent for ultrasonography of the lesion.

The diagnosis of an S-AVF is confirmed with imaging studies. Doppler ultrasonography initially will help to detect that a lesion is vascular in nature. Intra-arterial digital subtraction angiography is the gold-standard imaging technique and is necessary to delineate the feeding arteries and the draining channels as well as possible communication with intracranial vasculature.^1,2 There is controversy regarding the appropriate treatment of S-AVFs.² Each S-AVF possesses unique anatomic features that dictate appropriate management. The prognosis for an S-AVF is extremely variable, and the decision to treat is based on the patient’s symptoms and risk for exsanguinating hemorrhage.^2,4 Neurosurgical approaches include ligation of the feeding arteries, surgical resection, electrothrombosis, direct intralesional injection of sclerosing agents, and endovascular embolization. Endovascular intervention increasingly is utilized as a primary treatment or as a preoperative adjunct to surgery.^2,4 Large S-AVFs have a high risk for recurrence after treatment with endovascular embolization alone. In cases with intracranial communication, the intracranial component is treated first.²

This case emphasizes the importance of including S-AVFs on the dermatologic differential diagnosis of a scalp nodule, especially in patients with any history of intracranial AVF. A thorough history, detailed intake of potential signs and symptoms of AVF, and palpation for bruits is recommended as part of the surgical evaluation of a scalp nodule. Imaging of scalp nodules also should be considered for patients with any history of intracranial AVF; S-AVFs should be referred to neurosurgery or interventional neuroradiology for evaluation and possible treatment.

To the Editor:

A 71-year-old man presented with a nodule on the vertex of the scalp of 1 year’s duration. The lesion had become soft and tender during the week prior to presentation. He noted that he was experiencing headaches and a buzzing sound in his head. He denied all other neurologic symptoms. The patient was given amoxicillin from a primary care physician and was referred to our institution for evaluation of a presumed inflamed cyst.

The patient’s medical history included an intracranial arteriovenous fistula (AVF) treated with endovascular embolization 1 year prior to presentation, 2 substantial falls in childhood with head trauma and loss of consciousness, essential hypertension, and an aortic aneurysm. His medications included amlodipine, lisinopril, amoxicillin, a multivitamin, and grape seed extract.

Physical examination revealed a 2-cm, pink, somewhat rubbery, subcutaneous, nonmobile nodule on the vertex of the scalp (Figure 1). The lesion was not consistent with a common pilar cyst, and an excisional biopsy was performed to exclude malignancy. Upon superficial incision, the lesion bled moderately, and the procedure was immediately discontinued. Hemostasis was obtained, and the patient was sent for ultrasonography of the lesion.

The diagnosis of an S-AVF is confirmed with imaging studies. Doppler ultrasonography initially will help to detect that a lesion is vascular in nature. Intra-arterial digital subtraction angiography is the gold-standard imaging technique and is necessary to delineate the feeding arteries and the draining channels as well as possible communication with intracranial vasculature.^1,2 There is controversy regarding the appropriate treatment of S-AVFs.² Each S-AVF possesses unique anatomic features that dictate appropriate management. The prognosis for an S-AVF is extremely variable, and the decision to treat is based on the patient’s symptoms and risk for exsanguinating hemorrhage.^2,4 Neurosurgical approaches include ligation of the feeding arteries, surgical resection, electrothrombosis, direct intralesional injection of sclerosing agents, and endovascular embolization. Endovascular intervention increasingly is utilized as a primary treatment or as a preoperative adjunct to surgery.^2,4 Large S-AVFs have a high risk for recurrence after treatment with endovascular embolization alone. In cases with intracranial communication, the intracranial component is treated first.²

This case emphasizes the importance of including S-AVFs on the dermatologic differential diagnosis of a scalp nodule, especially in patients with any history of intracranial AVF. A thorough history, detailed intake of potential signs and symptoms of AVF, and palpation for bruits is recommended as part of the surgical evaluation of a scalp nodule. Imaging of scalp nodules also should be considered for patients with any history of intracranial AVF; S-AVFs should be referred to neurosurgery or interventional neuroradiology for evaluation and possible treatment.

To the Editor:

A 71-year-old man presented with a nodule on the vertex of the scalp of 1 year’s duration. The lesion had become soft and tender during the week prior to presentation. He noted that he was experiencing headaches and a buzzing sound in his head. He denied all other neurologic symptoms. The patient was given amoxicillin from a primary care physician and was referred to our institution for evaluation of a presumed inflamed cyst.

The patient’s medical history included an intracranial arteriovenous fistula (AVF) treated with endovascular embolization 1 year prior to presentation, 2 substantial falls in childhood with head trauma and loss of consciousness, essential hypertension, and an aortic aneurysm. His medications included amlodipine, lisinopril, amoxicillin, a multivitamin, and grape seed extract.

Physical examination revealed a 2-cm, pink, somewhat rubbery, subcutaneous, nonmobile nodule on the vertex of the scalp (Figure 1). The lesion was not consistent with a common pilar cyst, and an excisional biopsy was performed to exclude malignancy. Upon superficial incision, the lesion bled moderately, and the procedure was immediately discontinued. Hemostasis was obtained, and the patient was sent for ultrasonography of the lesion.

The diagnosis of an S-AVF is confirmed with imaging studies. Doppler ultrasonography initially will help to detect that a lesion is vascular in nature. Intra-arterial digital subtraction angiography is the gold-standard imaging technique and is necessary to delineate the feeding arteries and the draining channels as well as possible communication with intracranial vasculature.^1,2 There is controversy regarding the appropriate treatment of S-AVFs.² Each S-AVF possesses unique anatomic features that dictate appropriate management. The prognosis for an S-AVF is extremely variable, and the decision to treat is based on the patient’s symptoms and risk for exsanguinating hemorrhage.^2,4 Neurosurgical approaches include ligation of the feeding arteries, surgical resection, electrothrombosis, direct intralesional injection of sclerosing agents, and endovascular embolization. Endovascular intervention increasingly is utilized as a primary treatment or as a preoperative adjunct to surgery.^2,4 Large S-AVFs have a high risk for recurrence after treatment with endovascular embolization alone. In cases with intracranial communication, the intracranial component is treated first.²

This case emphasizes the importance of including S-AVFs on the dermatologic differential diagnosis of a scalp nodule, especially in patients with any history of intracranial AVF. A thorough history, detailed intake of potential signs and symptoms of AVF, and palpation for bruits is recommended as part of the surgical evaluation of a scalp nodule. Imaging of scalp nodules also should be considered for patients with any history of intracranial AVF; S-AVFs should be referred to neurosurgery or interventional neuroradiology for evaluation and possible treatment.

To the Editor:

Oral hairy leukoplakia (OHL) is an Epstein-Barr virus (EBV)–mediated mucocutaneous disease that often involves the lingual epithelium. The lateral portions of the tongue are the most commonly affected sites. The lesions often are described as asymptomatic, white, corrugated patches or plaques that are unable to be scraped off.¹ Oral hairy leukoplakia was first identified in 1984 and was considered to be associated with AIDS.² An association between the presence of OHL and the degree of immunosuppression as well as the severity of human immunodeficiency virus (HIV) has been reported.³ Although OHL initially was considered to be pathognomonic for HIV, it has since been described in multiple other immunosuppressive conditions.⁴ Numerous medical conditions and combinations of immunosuppressive medications have been associated with OHL in patients who were HIV negative.⁵

Adalimumab is an injectable human IgG1 recombinant antibody to tumor necrosis factor α (TNF-α).⁶ It currently is approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult and pediatric Crohn disease, ulcerative colitis, noninfectious uveitis, hidradenitis suppurativa, and plaque psoriasis.⁷ We report a case of OHL associated with the use of adalimumab.

A 47-year-old woman initially presented with chronic plaque-type psoriasis. Her medical history was notable for bipolar disorder, migraines, hypertension, and tobacco use. The patient’s psoriasis initially was well controlled on a regimen of topical steroids and methotrexate; however, methotrexate was stopped after 2.5 years due to a mildly elevated alanine aminotransferase level, as well as an abnormal liver biopsy showing mildly active (grade 1 of 3) steatohepatitis with portal chronic inflammation, pericellular fibrosis, and portal and focal periportal fibrosis (stage 1-2 of 4). The patient and her dermatologist were uncomfortable continuing methotrexate with these findings. After baseline screening including a negative purified protein derivative skin test, adalimumab was initiated. A loading dose of 80 mg subcutaneously (SQ) was given, followed by adalimumab 40 mg SQ 1 week later and 40 mg every other week as maintenance.

The patient’s psoriasis was well controlled with adalimumab for 22 months, but she then developed a thin white plaque on the right lateral tongue (Figure 1). An incisional biopsy of the tongue performed by an oral surgeon revealed hyperkeratosis with Candida colonization and viral cytopathic effect (Figure 2). An EBV DNA in situ hybridization stain revealed focal positivity within these cells (Figure 3), leading to a diagnosis of OHL. Laboratory evaluation demonstrated a normal complete blood cell count with differential and liver panel as well as a negative HIV test. The patient otherwise felt well and denied fevers, lymphadenopathy, and weight loss.

Oral hairy leukoplakia is associated with upregulated EBV replication and EBV-encoded proteins such as latent membrane protein 1.² It often presents as white or gray patches on the lateral lingual margins with prominent folds and/or projections, giving a shaggy appearance. Oral hairy leukoplakia often is specific for HIV infection and rarely is associated with other immunodeficiencies.² Prasad and Bilodeau⁵ performed a literature review of medical conditions and immunosuppressive medications associated with OHL in patients without HIV. Allogeneic transplant was associated with the highest incidence of OHL in HIV-negative patients (59.2% [45/76]).⁵ Various combinations of immunosuppressive medications (eg, prednisone, cyclosporine, azathioprine) also may be implicated in cases of HIV-negative patients with OHL. A case of OHL also has been reported with long-standing use of inhaled corticosteroids in an immunocompetent, HIV-negative patient.⁶ Another case was reported with long-term use of the aromatic antiepileptic lamotrigine, which resolved once stopping the medication.⁸ Although EBV is an oncovirus and has been associated with lymphoproliferative disorders and nasopharyngeal carcinoma, OHL is not considered to be a premalignant lesion.⁷ Despite the strong association between OHL and HIV, our patient was HIV negative. The only immunocompromising factor in our patient was the use of adalimumab to treat psoriasis. We did not conduct further testing for immunodeficiency states because the OHL spontaneously resolved when the adalimumab was discontinued.

PubMed and Ovid searches of articles indexed for MEDLINE using the terms adalimumab and oral hairy leukoplakia as well as TNF-alpha inhibitor and oral hairy leukoplakia with humans and English language as limitations revealed that no cases have been reported in the literature demonstrating an association between OHL and adalimumab or any other TNF-α inhibitor. However, Cetkovska et al⁹ reported a case of EBV hepatitis and subsequently chronic hepatitis as a complication of infliximab used for the treatment of chronic psoriasis. Because TNF-α and IFN-γ play an important role in controlling viral infections, there is an increased risk for reactivating a viral illness when depleting TNF through pharmacologic measures (ie, adalimumab, infliximab).⁸ Another case of EBV-associated plasmablastic lymphoma was reported after 1 year of adalimumab use in a patient with Crohn disease. The plasmablastic lymphoma resolved after 4 rounds of chemotherapy.¹⁰

The only contraindication for the use of adalimumab is a known hypersensitivity to the drug. Relative contraindications for use of adalimumab include active tuberculosis, demyelinating disease, hematologic diseases (ie, thrombocytopenia, pancytopenia), lymphoma, hepatitis C, and hepatitis B.¹¹ The most common adverse effect of adalimumab is an injection-site reaction. Additional reported adverse effects of TNF-α inhibitors as a class are lymphoma, melanoma, nonmelanoma skin cancer, reactivation of latent tuberculosis, congestive heart failure, autoimmunity, and hematologic toxicity.¹¹

This case demonstrates an association between adalimumab and OHL in an HIV-negative patient. Although the mechanism behind OHL and immunosuppression remains to be elucidated, this association is important to keep in mind when using adalimumab or other TNF-α inhibitors for the treatment of psoriasis or other medical conditions.

To the Editor:

Oral hairy leukoplakia (OHL) is an Epstein-Barr virus (EBV)–mediated mucocutaneous disease that often involves the lingual epithelium. The lateral portions of the tongue are the most commonly affected sites. The lesions often are described as asymptomatic, white, corrugated patches or plaques that are unable to be scraped off.¹ Oral hairy leukoplakia was first identified in 1984 and was considered to be associated with AIDS.² An association between the presence of OHL and the degree of immunosuppression as well as the severity of human immunodeficiency virus (HIV) has been reported.³ Although OHL initially was considered to be pathognomonic for HIV, it has since been described in multiple other immunosuppressive conditions.⁴ Numerous medical conditions and combinations of immunosuppressive medications have been associated with OHL in patients who were HIV negative.⁵

Adalimumab is an injectable human IgG1 recombinant antibody to tumor necrosis factor α (TNF-α).⁶ It currently is approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult and pediatric Crohn disease, ulcerative colitis, noninfectious uveitis, hidradenitis suppurativa, and plaque psoriasis.⁷ We report a case of OHL associated with the use of adalimumab.

A 47-year-old woman initially presented with chronic plaque-type psoriasis. Her medical history was notable for bipolar disorder, migraines, hypertension, and tobacco use. The patient’s psoriasis initially was well controlled on a regimen of topical steroids and methotrexate; however, methotrexate was stopped after 2.5 years due to a mildly elevated alanine aminotransferase level, as well as an abnormal liver biopsy showing mildly active (grade 1 of 3) steatohepatitis with portal chronic inflammation, pericellular fibrosis, and portal and focal periportal fibrosis (stage 1-2 of 4). The patient and her dermatologist were uncomfortable continuing methotrexate with these findings. After baseline screening including a negative purified protein derivative skin test, adalimumab was initiated. A loading dose of 80 mg subcutaneously (SQ) was given, followed by adalimumab 40 mg SQ 1 week later and 40 mg every other week as maintenance.

The patient’s psoriasis was well controlled with adalimumab for 22 months, but she then developed a thin white plaque on the right lateral tongue (Figure 1). An incisional biopsy of the tongue performed by an oral surgeon revealed hyperkeratosis with Candida colonization and viral cytopathic effect (Figure 2). An EBV DNA in situ hybridization stain revealed focal positivity within these cells (Figure 3), leading to a diagnosis of OHL. Laboratory evaluation demonstrated a normal complete blood cell count with differential and liver panel as well as a negative HIV test. The patient otherwise felt well and denied fevers, lymphadenopathy, and weight loss.

Oral hairy leukoplakia is associated with upregulated EBV replication and EBV-encoded proteins such as latent membrane protein 1.² It often presents as white or gray patches on the lateral lingual margins with prominent folds and/or projections, giving a shaggy appearance. Oral hairy leukoplakia often is specific for HIV infection and rarely is associated with other immunodeficiencies.² Prasad and Bilodeau⁵ performed a literature review of medical conditions and immunosuppressive medications associated with OHL in patients without HIV. Allogeneic transplant was associated with the highest incidence of OHL in HIV-negative patients (59.2% [45/76]).⁵ Various combinations of immunosuppressive medications (eg, prednisone, cyclosporine, azathioprine) also may be implicated in cases of HIV-negative patients with OHL. A case of OHL also has been reported with long-standing use of inhaled corticosteroids in an immunocompetent, HIV-negative patient.⁶ Another case was reported with long-term use of the aromatic antiepileptic lamotrigine, which resolved once stopping the medication.⁸ Although EBV is an oncovirus and has been associated with lymphoproliferative disorders and nasopharyngeal carcinoma, OHL is not considered to be a premalignant lesion.⁷ Despite the strong association between OHL and HIV, our patient was HIV negative. The only immunocompromising factor in our patient was the use of adalimumab to treat psoriasis. We did not conduct further testing for immunodeficiency states because the OHL spontaneously resolved when the adalimumab was discontinued.

PubMed and Ovid searches of articles indexed for MEDLINE using the terms adalimumab and oral hairy leukoplakia as well as TNF-alpha inhibitor and oral hairy leukoplakia with humans and English language as limitations revealed that no cases have been reported in the literature demonstrating an association between OHL and adalimumab or any other TNF-α inhibitor. However, Cetkovska et al⁹ reported a case of EBV hepatitis and subsequently chronic hepatitis as a complication of infliximab used for the treatment of chronic psoriasis. Because TNF-α and IFN-γ play an important role in controlling viral infections, there is an increased risk for reactivating a viral illness when depleting TNF through pharmacologic measures (ie, adalimumab, infliximab).⁸ Another case of EBV-associated plasmablastic lymphoma was reported after 1 year of adalimumab use in a patient with Crohn disease. The plasmablastic lymphoma resolved after 4 rounds of chemotherapy.¹⁰

The only contraindication for the use of adalimumab is a known hypersensitivity to the drug. Relative contraindications for use of adalimumab include active tuberculosis, demyelinating disease, hematologic diseases (ie, thrombocytopenia, pancytopenia), lymphoma, hepatitis C, and hepatitis B.¹¹ The most common adverse effect of adalimumab is an injection-site reaction. Additional reported adverse effects of TNF-α inhibitors as a class are lymphoma, melanoma, nonmelanoma skin cancer, reactivation of latent tuberculosis, congestive heart failure, autoimmunity, and hematologic toxicity.¹¹

This case demonstrates an association between adalimumab and OHL in an HIV-negative patient. Although the mechanism behind OHL and immunosuppression remains to be elucidated, this association is important to keep in mind when using adalimumab or other TNF-α inhibitors for the treatment of psoriasis or other medical conditions.

To the Editor:

Oral hairy leukoplakia (OHL) is an Epstein-Barr virus (EBV)–mediated mucocutaneous disease that often involves the lingual epithelium. The lateral portions of the tongue are the most commonly affected sites. The lesions often are described as asymptomatic, white, corrugated patches or plaques that are unable to be scraped off.¹ Oral hairy leukoplakia was first identified in 1984 and was considered to be associated with AIDS.² An association between the presence of OHL and the degree of immunosuppression as well as the severity of human immunodeficiency virus (HIV) has been reported.³ Although OHL initially was considered to be pathognomonic for HIV, it has since been described in multiple other immunosuppressive conditions.⁴ Numerous medical conditions and combinations of immunosuppressive medications have been associated with OHL in patients who were HIV negative.⁵

Adalimumab is an injectable human IgG1 recombinant antibody to tumor necrosis factor α (TNF-α).⁶ It currently is approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult and pediatric Crohn disease, ulcerative colitis, noninfectious uveitis, hidradenitis suppurativa, and plaque psoriasis.⁷ We report a case of OHL associated with the use of adalimumab.

A 47-year-old woman initially presented with chronic plaque-type psoriasis. Her medical history was notable for bipolar disorder, migraines, hypertension, and tobacco use. The patient’s psoriasis initially was well controlled on a regimen of topical steroids and methotrexate; however, methotrexate was stopped after 2.5 years due to a mildly elevated alanine aminotransferase level, as well as an abnormal liver biopsy showing mildly active (grade 1 of 3) steatohepatitis with portal chronic inflammation, pericellular fibrosis, and portal and focal periportal fibrosis (stage 1-2 of 4). The patient and her dermatologist were uncomfortable continuing methotrexate with these findings. After baseline screening including a negative purified protein derivative skin test, adalimumab was initiated. A loading dose of 80 mg subcutaneously (SQ) was given, followed by adalimumab 40 mg SQ 1 week later and 40 mg every other week as maintenance.

The patient’s psoriasis was well controlled with adalimumab for 22 months, but she then developed a thin white plaque on the right lateral tongue (Figure 1). An incisional biopsy of the tongue performed by an oral surgeon revealed hyperkeratosis with Candida colonization and viral cytopathic effect (Figure 2). An EBV DNA in situ hybridization stain revealed focal positivity within these cells (Figure 3), leading to a diagnosis of OHL. Laboratory evaluation demonstrated a normal complete blood cell count with differential and liver panel as well as a negative HIV test. The patient otherwise felt well and denied fevers, lymphadenopathy, and weight loss.

Oral hairy leukoplakia is associated with upregulated EBV replication and EBV-encoded proteins such as latent membrane protein 1.² It often presents as white or gray patches on the lateral lingual margins with prominent folds and/or projections, giving a shaggy appearance. Oral hairy leukoplakia often is specific for HIV infection and rarely is associated with other immunodeficiencies.² Prasad and Bilodeau⁵ performed a literature review of medical conditions and immunosuppressive medications associated with OHL in patients without HIV. Allogeneic transplant was associated with the highest incidence of OHL in HIV-negative patients (59.2% [45/76]).⁵ Various combinations of immunosuppressive medications (eg, prednisone, cyclosporine, azathioprine) also may be implicated in cases of HIV-negative patients with OHL. A case of OHL also has been reported with long-standing use of inhaled corticosteroids in an immunocompetent, HIV-negative patient.⁶ Another case was reported with long-term use of the aromatic antiepileptic lamotrigine, which resolved once stopping the medication.⁸ Although EBV is an oncovirus and has been associated with lymphoproliferative disorders and nasopharyngeal carcinoma, OHL is not considered to be a premalignant lesion.⁷ Despite the strong association between OHL and HIV, our patient was HIV negative. The only immunocompromising factor in our patient was the use of adalimumab to treat psoriasis. We did not conduct further testing for immunodeficiency states because the OHL spontaneously resolved when the adalimumab was discontinued.

PubMed and Ovid searches of articles indexed for MEDLINE using the terms adalimumab and oral hairy leukoplakia as well as TNF-alpha inhibitor and oral hairy leukoplakia with humans and English language as limitations revealed that no cases have been reported in the literature demonstrating an association between OHL and adalimumab or any other TNF-α inhibitor. However, Cetkovska et al⁹ reported a case of EBV hepatitis and subsequently chronic hepatitis as a complication of infliximab used for the treatment of chronic psoriasis. Because TNF-α and IFN-γ play an important role in controlling viral infections, there is an increased risk for reactivating a viral illness when depleting TNF through pharmacologic measures (ie, adalimumab, infliximab).⁸ Another case of EBV-associated plasmablastic lymphoma was reported after 1 year of adalimumab use in a patient with Crohn disease. The plasmablastic lymphoma resolved after 4 rounds of chemotherapy.¹⁰

The only contraindication for the use of adalimumab is a known hypersensitivity to the drug. Relative contraindications for use of adalimumab include active tuberculosis, demyelinating disease, hematologic diseases (ie, thrombocytopenia, pancytopenia), lymphoma, hepatitis C, and hepatitis B.¹¹ The most common adverse effect of adalimumab is an injection-site reaction. Additional reported adverse effects of TNF-α inhibitors as a class are lymphoma, melanoma, nonmelanoma skin cancer, reactivation of latent tuberculosis, congestive heart failure, autoimmunity, and hematologic toxicity.¹¹

This case demonstrates an association between adalimumab and OHL in an HIV-negative patient. Although the mechanism behind OHL and immunosuppression remains to be elucidated, this association is important to keep in mind when using adalimumab or other TNF-α inhibitors for the treatment of psoriasis or other medical conditions.