Case Letter

To the Editor:

A 3-year-old boy with a history of tuberous sclerosis presented to our clinic for evaluation of bumps on the second and third fingers of the left hand. Physical examination revealed firm rubbery nodules on the palmar third metacarpophalangeal joint extending to the palm and the lateral aspect of the distal third dorsal finger. There also was asymmetric overgrowth of the left second and third digits consistent with bony segmental overgrowth (Figure).

Tuberous sclerosis and overgrowth syndromes including Proteus syndrome have mutations that share a common pathway, namely the PI3K/AKT/mTOR (phosphoinositide 3-kinase/alpha serine/threonine-protein kinase/mammalian target of rapamycin) pathway.¹ The mutations in tuberous sclerosis involve the loss of TSC1 (TSC complex subunit 1) on chromosome 9 or TSC2 (TSC complex subunit 2) on chromosome 16.² The protein products of these genes, hamartin and tuberin, act together as a tumor suppressor complex.³ The inheritance pattern of tuberous sclerosis is autosomal dominant, though two-thirds of cases are due to de novo germline mutations.⁴ The second copy of the gene must be lost spontaneously in any particular cell for the deleterious effects of the disease to manifest. The mutation in overgrowth syndromes including Proteus syndrome involves the activation of AKT1 (AKT serine/threonine kinase 1) on chromosome 14. This mutation occurs in somatic cells as opposed to germ cells, as in tuberous sclerosis. This difference accounts for the mosaic expression of segmental overgrowth syndromes. This concept has been demonstrated in overgrowth syndromes such as Proteus syndrome, with cells from unaffected areas having different genetic makeup than those from affected tissues.⁵ These mutations, though different, result in the downstream effects of unchecked messenger RNA translation and dysregulated cellular growth.

In our patient, we hypothesized that a small proportion of his postfertilization somatic cells underwent a second de novo mutation in the AKT1 pathway, resulting in the bony overgrowth seen on the left hand. We suspected that this second mutation could be an activation of AKT1, the mutation seen in Proteus syndrome. Sequencing of the tissue may be performed in the future, especially if segmental overgrowth continues and necessitates therapy.

To the Editor:

A 3-year-old boy with a history of tuberous sclerosis presented to our clinic for evaluation of bumps on the second and third fingers of the left hand. Physical examination revealed firm rubbery nodules on the palmar third metacarpophalangeal joint extending to the palm and the lateral aspect of the distal third dorsal finger. There also was asymmetric overgrowth of the left second and third digits consistent with bony segmental overgrowth (Figure).

Tuberous sclerosis and overgrowth syndromes including Proteus syndrome have mutations that share a common pathway, namely the PI3K/AKT/mTOR (phosphoinositide 3-kinase/alpha serine/threonine-protein kinase/mammalian target of rapamycin) pathway.¹ The mutations in tuberous sclerosis involve the loss of TSC1 (TSC complex subunit 1) on chromosome 9 or TSC2 (TSC complex subunit 2) on chromosome 16.² The protein products of these genes, hamartin and tuberin, act together as a tumor suppressor complex.³ The inheritance pattern of tuberous sclerosis is autosomal dominant, though two-thirds of cases are due to de novo germline mutations.⁴ The second copy of the gene must be lost spontaneously in any particular cell for the deleterious effects of the disease to manifest. The mutation in overgrowth syndromes including Proteus syndrome involves the activation of AKT1 (AKT serine/threonine kinase 1) on chromosome 14. This mutation occurs in somatic cells as opposed to germ cells, as in tuberous sclerosis. This difference accounts for the mosaic expression of segmental overgrowth syndromes. This concept has been demonstrated in overgrowth syndromes such as Proteus syndrome, with cells from unaffected areas having different genetic makeup than those from affected tissues.⁵ These mutations, though different, result in the downstream effects of unchecked messenger RNA translation and dysregulated cellular growth.

In our patient, we hypothesized that a small proportion of his postfertilization somatic cells underwent a second de novo mutation in the AKT1 pathway, resulting in the bony overgrowth seen on the left hand. We suspected that this second mutation could be an activation of AKT1, the mutation seen in Proteus syndrome. Sequencing of the tissue may be performed in the future, especially if segmental overgrowth continues and necessitates therapy.

To the Editor:

A 3-year-old boy with a history of tuberous sclerosis presented to our clinic for evaluation of bumps on the second and third fingers of the left hand. Physical examination revealed firm rubbery nodules on the palmar third metacarpophalangeal joint extending to the palm and the lateral aspect of the distal third dorsal finger. There also was asymmetric overgrowth of the left second and third digits consistent with bony segmental overgrowth (Figure).

Tuberous sclerosis and overgrowth syndromes including Proteus syndrome have mutations that share a common pathway, namely the PI3K/AKT/mTOR (phosphoinositide 3-kinase/alpha serine/threonine-protein kinase/mammalian target of rapamycin) pathway.¹ The mutations in tuberous sclerosis involve the loss of TSC1 (TSC complex subunit 1) on chromosome 9 or TSC2 (TSC complex subunit 2) on chromosome 16.² The protein products of these genes, hamartin and tuberin, act together as a tumor suppressor complex.³ The inheritance pattern of tuberous sclerosis is autosomal dominant, though two-thirds of cases are due to de novo germline mutations.⁴ The second copy of the gene must be lost spontaneously in any particular cell for the deleterious effects of the disease to manifest. The mutation in overgrowth syndromes including Proteus syndrome involves the activation of AKT1 (AKT serine/threonine kinase 1) on chromosome 14. This mutation occurs in somatic cells as opposed to germ cells, as in tuberous sclerosis. This difference accounts for the mosaic expression of segmental overgrowth syndromes. This concept has been demonstrated in overgrowth syndromes such as Proteus syndrome, with cells from unaffected areas having different genetic makeup than those from affected tissues.⁵ These mutations, though different, result in the downstream effects of unchecked messenger RNA translation and dysregulated cellular growth.

In our patient, we hypothesized that a small proportion of his postfertilization somatic cells underwent a second de novo mutation in the AKT1 pathway, resulting in the bony overgrowth seen on the left hand. We suspected that this second mutation could be an activation of AKT1, the mutation seen in Proteus syndrome. Sequencing of the tissue may be performed in the future, especially if segmental overgrowth continues and necessitates therapy.

To the Editor:

A 59-year-old man presented with a lesion on the right frontal scalp of 4 months’ duration and a lesion on the left frontal scalp of 1 month’s duration. Both lesions were tender, bleeding, nonhealing, and growing in size. The patient reported no improvement with the use of triple antibiotic ointment. He denied any associated symptoms or trauma to the affected areas. He had a history of stage IV esophageal adenocarcinoma that initially had been surgically removed 6 years prior but metastasized to the lungs and bone. The patient subsequently underwent treatment with FOLFOX (folinic acid, fluorouracil, oxaliplatin), trastuzumab, and radiation therapy.

Physical examination revealed a hyperkeratotic pink nodule with a central erosion and crust on the right frontal scalp measuring 1.5×2 cm in diameter (Figure 1A). The left frontal scalp lesion was a smooth pearly papule measuring 5×5 mm in diameter (Figure 1B). The differential diagnosis included basal cell carcinoma, squamous cell carcinoma, and cutaneous metastases from esophageal adenocarcinoma. Shave biopsies were taken of both scalp lesions.

Our case highlights multiple cutaneous metastases of the scalp from a primary esophageal adenocarcinoma. Although cutaneous scalp metastasis of esophageal adenocarcinoma is rare, it is essential to provide a full-body skin examination, including the scalp, in patients with a history of esophageal cancer and to biopsy any suspicious nodules or plaques. The 1-year survival rate after diagnosis of esophageal carcinoma is less than 50%, and the 5-year survival rate is less than 10%.¹³ Identifying cutaneous metastasis of an esophageal adenocarcinoma can either change the staging of the cancer (if it was the first distant metastasis noted) or indicate an insufficient response to treatment in a patient with known metastatic disease, prompting a potential change in treatment.⁷

This case illustrates a rare site of metastasis of a fairly common cancer and highlights the histopathology and accompanying immunohistochemical stains that can be useful in diagnosis as well as the spectrum of its clinical presentation.

To the Editor:

A 59-year-old man presented with a lesion on the right frontal scalp of 4 months’ duration and a lesion on the left frontal scalp of 1 month’s duration. Both lesions were tender, bleeding, nonhealing, and growing in size. The patient reported no improvement with the use of triple antibiotic ointment. He denied any associated symptoms or trauma to the affected areas. He had a history of stage IV esophageal adenocarcinoma that initially had been surgically removed 6 years prior but metastasized to the lungs and bone. The patient subsequently underwent treatment with FOLFOX (folinic acid, fluorouracil, oxaliplatin), trastuzumab, and radiation therapy.

Physical examination revealed a hyperkeratotic pink nodule with a central erosion and crust on the right frontal scalp measuring 1.5×2 cm in diameter (Figure 1A). The left frontal scalp lesion was a smooth pearly papule measuring 5×5 mm in diameter (Figure 1B). The differential diagnosis included basal cell carcinoma, squamous cell carcinoma, and cutaneous metastases from esophageal adenocarcinoma. Shave biopsies were taken of both scalp lesions.

Our case highlights multiple cutaneous metastases of the scalp from a primary esophageal adenocarcinoma. Although cutaneous scalp metastasis of esophageal adenocarcinoma is rare, it is essential to provide a full-body skin examination, including the scalp, in patients with a history of esophageal cancer and to biopsy any suspicious nodules or plaques. The 1-year survival rate after diagnosis of esophageal carcinoma is less than 50%, and the 5-year survival rate is less than 10%.¹³ Identifying cutaneous metastasis of an esophageal adenocarcinoma can either change the staging of the cancer (if it was the first distant metastasis noted) or indicate an insufficient response to treatment in a patient with known metastatic disease, prompting a potential change in treatment.⁷

This case illustrates a rare site of metastasis of a fairly common cancer and highlights the histopathology and accompanying immunohistochemical stains that can be useful in diagnosis as well as the spectrum of its clinical presentation.

To the Editor:

A 59-year-old man presented with a lesion on the right frontal scalp of 4 months’ duration and a lesion on the left frontal scalp of 1 month’s duration. Both lesions were tender, bleeding, nonhealing, and growing in size. The patient reported no improvement with the use of triple antibiotic ointment. He denied any associated symptoms or trauma to the affected areas. He had a history of stage IV esophageal adenocarcinoma that initially had been surgically removed 6 years prior but metastasized to the lungs and bone. The patient subsequently underwent treatment with FOLFOX (folinic acid, fluorouracil, oxaliplatin), trastuzumab, and radiation therapy.

Physical examination revealed a hyperkeratotic pink nodule with a central erosion and crust on the right frontal scalp measuring 1.5×2 cm in diameter (Figure 1A). The left frontal scalp lesion was a smooth pearly papule measuring 5×5 mm in diameter (Figure 1B). The differential diagnosis included basal cell carcinoma, squamous cell carcinoma, and cutaneous metastases from esophageal adenocarcinoma. Shave biopsies were taken of both scalp lesions.

Our case highlights multiple cutaneous metastases of the scalp from a primary esophageal adenocarcinoma. Although cutaneous scalp metastasis of esophageal adenocarcinoma is rare, it is essential to provide a full-body skin examination, including the scalp, in patients with a history of esophageal cancer and to biopsy any suspicious nodules or plaques. The 1-year survival rate after diagnosis of esophageal carcinoma is less than 50%, and the 5-year survival rate is less than 10%.¹³ Identifying cutaneous metastasis of an esophageal adenocarcinoma can either change the staging of the cancer (if it was the first distant metastasis noted) or indicate an insufficient response to treatment in a patient with known metastatic disease, prompting a potential change in treatment.⁷

This case illustrates a rare site of metastasis of a fairly common cancer and highlights the histopathology and accompanying immunohistochemical stains that can be useful in diagnosis as well as the spectrum of its clinical presentation.

To the Editor:

Calciphylaxis (also known as calcific uremic arteriolopathy and calcifying panniculitis) is a rare vasculopathy affecting the small vessels.¹ It is characterized by cutaneous ischemia and necrosis secondary to calcification. It is most commonly seen in patients with end-stage renal disease (ESRD) and hyperparathyroidism.^1-3 Histopathologic features that are consistent with the diagnosis of calciphylaxis include calcification of medium-sized vessels in the deep dermis or subcutaneous fat as well as smaller distal vessels that supply the papillary dermis and epidermis.^4,5 Although it commonly presents as well-demarcated, painful, purplish lesions that evolve into necrotic eschars, calciphylaxis rarely can present with hemorrhagic or serous bullous lesions followed by ulceration, as was seen in our patient.^1,5,6 We report this uncommon presentation to highlight the variety in clinical appearance of calciphylaxis and the importance of early diagnosis.

A 43-year-old woman presented to the emergency department for evaluation of chest and abdominal pain that began 1 day prior to presentation. She had a history of systemic lupus erythematosus and ESRD secondary to poststreptococcal glomerulonephritis and was currently on peritoneal dialysis. The patient was admitted for peritonitis and treated with broad-spectrum antibiotics. At the time of admission, the patient also was noted to have several painful bullae on the legs. Her medical history also was remarkable for cerebral infarction, fibromyalgia, cerebral artery occlusion with cerebral infarction, sciatica, hyperlipidemia, deep vein thrombosis, and seizures. She had no history of herpes simplex virus. Surgical history was remarkable for tubal ligation, nephrectomy and kidney transplant, parathyroidectomy, and cholecystectomy. The patient’s medications included sevelamer carbonate, prednisone, epogen, calcium carbonate, esomeprazole, ondansetron, topical gentamicin, and atorvastatin.

Skin examination was performed by the inpatient dermatology service and revealed several tense, 1- to 5-cm, nonhemorrhagic bullae on the thighs and lower legs, some that had ruptured. The lesions were notably tender to palpation. No surrounding erythema, ecchymosis, or warmth was appreciated. The Nikolsky sign was negative. The patient also was noted to have at least grade 2 to 3+ pitting edema of the bilateral legs. The oral and conjunctival mucosae were unremarkable.

Antinuclear antibody, double-stranded DNA, and anti-Smith antibody levels were negative. A punch biopsy of the left lateral thigh revealed intraepidermal vesicular dermatitis with dermal edema suggestive of edema bullae and direct immunofluorescence was negative for immune complex and complement deposition.

Conservative therapy with wound care was recommended. The patient continued to report persistent severe skin pain and developed a subcutaneous nodule on the right inner thigh 1 week later, prompting a second biopsy. Results of the excisional biopsy were nondiagnostic but were suggestive of calciphylaxis, revealing subepidermal bullae with epidermal necrosis, a scant perivascular lymphocytic infiltrate, and extravasated erythrocytes. No evidence of calcification was seen within the vessels. The patient was then started on sodium thiosulfate with hemodialysis for treatment of presumed calciphylaxis.

Despite meticulous wound care and treatment with sodium thiosulfate, the patient developed ulcerations with necrotic eschars on the bilateral buttocks, hips, and thighs 1 month later (Figure 1). She subsequently worsened over the next few weeks. She developed sepsis and was transferred to the intensive care unit. A third biopsy was performed, finally confirming the diagnosis of calciphylaxis. Histopathology revealed small blood vessels with basophilic granular deposits in the walls consistent with calcium in the subcutaneous tissue (highlighted with the von Kossa stain), as well as thrombi in the lumens of some vessels; early fat necrosis; focal epidermal necrosis with underlying congested blood vessels with deposits in their walls; a perivascular infiltrate predominately of lymphocytes and neutrophils with scattered nuclear dust; and thick, hyalinized, closely crowded collagen bundles in the reticular dermis and in a widened subcutaneous septum (Figures 2 and 3).

Supportive care and pain control were continued, but the overall prognosis was determined to be very poor, and the patient eventually was discharged to hospice and died.

Although calciphylaxis is commonly seen in patients with ESRD and hyperparathyroidism, patients without renal disease also may develop the condition.^2,3 Prior epidemiologic studies have shown a prevalence of 1% in patients with chronic kidney disease and up to 4% in those receiving dialysis.^2-5 The average age at presentation is 48 years.^6,7 Although calciphylaxis has been noted to affect males and females equally, some studies have suggested a female predominance.^5-8

The etiology of calciphylaxis is unknown, but ESRD requiring dialysis, primary or secondary hyperparathyroidism, obesity, diabetes mellitus, skin trauma, and/or a hypercoagulable state may put patients at increased risk for developing this disease.^2,3 Other risk factors include systemic corticosteroids, liver disease, increased serum aluminum, and increased erythrocyte sedimentation rate. Although high calcium-phosphate product has been noted as a risk factor in prior studies, one retrospective study found that it does not reliably confirm or exclude a diagnosis of calciphylaxis.⁸

The pathogenesis of calciphylaxis is not well understood; however, some researchers suggest that an imbalance in calcium-phosphate homeostasis may lead to calciphylaxis; that is, elevated calcium and phosphate levels exceed their solubility and deposit in the walls of small- and medium-sized arteries, which consequently leads to ischemic necrosis and gangrene of the surrounding tissue.⁹

Clinically, calciphylaxis has an indolent onset and usually presents as well-demarcated, painful, purplish, mottled lesions that evolve into necrotic gray-black eschars and gangrene in adjacent tissues.^1,5,6 The ischemic process may even extend to the muscle layer.⁵ Other common presentations include mild erythematous patches; livedo reticularis; painful nodules; necrotic ulcerating lesions; and more rarely flaccid, hemorrhagic, or serous bullous lesions followed by ulceration, as was seen in our patient.^6,9,10 Lesions usually begin at sites of trauma and seem to be distributed symmetrically.^5,6 The most commonly affected locations are the legs, specifically the medial thighs, as well as the abdomen and buttocks, but lesions also can be found at more distal sites such as the breasts, tongue, vulva, penis, fingers, and toes.^5,6,10 The head and neck region rarely is affected. Although uncommon, calciphylaxis may affect other organs, including the lungs, stomach, kidneys, and adrenal glands.⁵ The accompanying systemic symptoms and findings may include muscle weakness, tenderness, or myositis with rhabdomyolysis; calcific cerebral embolism; dementia and infarction of the central nervous system; acute respiratory failure; heart disease; atrioventricular block; and calcification of the cardiac conduction system.⁶ Unlike other forms of peripheral vascular disease, distal pulses are present in calciphylaxis, as blood flow usually is preserved distal and deep to the areas of necrosis.^5,6

A careful history and thorough physical examination are important first steps in the diagnosis of this condition.^2,10 Although there are no definitive laboratory tests, elevated serum calcium, phosphorous, and calcium-phosphate product levels, as well as parathyroid hormone level, may be suggestive of calciphylaxis.^2,5 Leukocytosis may occur if an infection is present.⁵

The most accurate method to confirm the diagnosis is a deep incisional biopsy from an erythematous, slightly purpuric area adjacent to the necrotic lesion.^2,10,11 The histopathologic features used to make the diagnosis include calcification of medium-sized vessels, particularly the intimal or medial layers, in the deep dermis and subcutaneous fat in addition to lobular capillaries of the subcutaneous fat.^5,10 These vessels, including the smaller distal vessels that supply the papillary dermis and epidermis, also may be thrombosed due to calcification, leading to vascular occlusion and subsequently ischemic necrosis of the overlying epidermis.¹⁰ Other findings may include pseudoxanthoma elasticum changes, panniculitis, and subcutaneous fat necrosis.^4,10

The differential diagnosis for calciphylaxis includes peripheral vascular disease, vasculitis, juvenile dermatomyositis, proteins C and S deficiencies, cryofibrinogenemia, calcinosis cutis, and tumoral calcinosis.² Polyarteritis nodosa, Sjögren syndrome, atherosclerotic peripheral vascular disease, pyoderma gangrenosum, systemic lupus erythematosus, necrotizing fasciitis, septic embolism, and necrosis secondary to warfarin and heparin may mimic calciphylaxis.⁵

Treatment of calciphylaxis is multidimensional but primarily is supportive.^6,11 Controlling calcium and phosphate levels and secondary hyperparathyroidism through diet and phosphate binders (eg, sevelamer hydrochloride) has been shown to be effective.⁶ Pamidronate, a bisphosphonate, inhibits arterial calcification in animal models and has been reported to treat calciphylaxis, resulting in marked pain reduction and ulcer healing.^4,6 Cinacalcet, which functions as a calcimimetic, has been implicated in the treatment of calciphylaxis. It has been used to treat primary and secondary hyperparathyroidism and to normalize serum calcium levels; it also may be used as an alternative to parathyroidectomy.^4,6 Intravenous administration of sodium thiosulfate, a potent antioxidant and chelator of calcium, has been helpful in reversing signs and symptoms of calciphylaxis.^6,12 It also has been shown to effectively remove extra calcium during peritoneal dialysis.⁶ Parathyroidectomy has been useful in patients with markedly elevated parathyroid hormone levels, as it suppresses or eliminates the sensitizing agent causing hypercalcemia, elevated calcium-phosphate product, and hyperparathyroidism.^1,2,6,13

Wound care and prevention of sepsis are essential in the treatment of calciphylaxis. Management options include surgical debridement, hydrocolloid and biologic dressings, skin grafts, systemic antibiotics, oral pentoxifylline combined with maggot therapy, nutritional support, hyperbaric oxygen therapy, and revascularization and amputation when other interventions have failed. Pain control with analgesics and correction of thrombosis in the skin and blood vessels via anticoagulation therapy also are important complementary treatments.⁶

The clinical outcome of calciphylaxis is dependent on early diagnosis, antimicrobial therapy, and wound management,⁹ but overall, the prognosis usually is poor and has a high mortality rate. The most common causes of death are infection and sepsis.^1,9 A study of 7 cases reported 100% mortality,¹⁴ but other studies have suggested a mortality rate of 60% to 80%.^4,10 Female sex and obesity are poor prognostic indicators.² A better prognosis has been appreciated in cases in which lesions occur at distal sites (eg, lower legs, hands) compared to more proximal sites (eg, abdomen), where 25% and 75% mortalities have been noted, respectively.^10,14,15 In one study, the overall mortality rate was 45% in patients with calciphylaxis at 1 year.⁶ The rate was 41% in patients with plaques only and 67% in those who presented with ulceration. Patients who survive often experience a high degree of morbidity and prolonged hospitalization; these patients often are severely debilitated, especially in the case of limb amputation.⁶

Our report of calciphylaxis demonstrates the diversity in clinical presentation and emphasizes the importance of early and accurate diagnosis in reducing morbidity and mortality. In our case, the patient presented with skin pain and tense nonhemorrhagic bullae without underlying ecchymotic or erythematous lesions as the earliest sign of calciphylaxis. Physicians should have a high degree of suspicion in the setting of dialysis-dependent ESRD patients with bullae, extreme pain, and continuous decline. We hope that this case will help increase awareness of the varying presentations of this condition.

To the Editor:

Calciphylaxis (also known as calcific uremic arteriolopathy and calcifying panniculitis) is a rare vasculopathy affecting the small vessels.¹ It is characterized by cutaneous ischemia and necrosis secondary to calcification. It is most commonly seen in patients with end-stage renal disease (ESRD) and hyperparathyroidism.^1-3 Histopathologic features that are consistent with the diagnosis of calciphylaxis include calcification of medium-sized vessels in the deep dermis or subcutaneous fat as well as smaller distal vessels that supply the papillary dermis and epidermis.^4,5 Although it commonly presents as well-demarcated, painful, purplish lesions that evolve into necrotic eschars, calciphylaxis rarely can present with hemorrhagic or serous bullous lesions followed by ulceration, as was seen in our patient.^1,5,6 We report this uncommon presentation to highlight the variety in clinical appearance of calciphylaxis and the importance of early diagnosis.

A 43-year-old woman presented to the emergency department for evaluation of chest and abdominal pain that began 1 day prior to presentation. She had a history of systemic lupus erythematosus and ESRD secondary to poststreptococcal glomerulonephritis and was currently on peritoneal dialysis. The patient was admitted for peritonitis and treated with broad-spectrum antibiotics. At the time of admission, the patient also was noted to have several painful bullae on the legs. Her medical history also was remarkable for cerebral infarction, fibromyalgia, cerebral artery occlusion with cerebral infarction, sciatica, hyperlipidemia, deep vein thrombosis, and seizures. She had no history of herpes simplex virus. Surgical history was remarkable for tubal ligation, nephrectomy and kidney transplant, parathyroidectomy, and cholecystectomy. The patient’s medications included sevelamer carbonate, prednisone, epogen, calcium carbonate, esomeprazole, ondansetron, topical gentamicin, and atorvastatin.

Skin examination was performed by the inpatient dermatology service and revealed several tense, 1- to 5-cm, nonhemorrhagic bullae on the thighs and lower legs, some that had ruptured. The lesions were notably tender to palpation. No surrounding erythema, ecchymosis, or warmth was appreciated. The Nikolsky sign was negative. The patient also was noted to have at least grade 2 to 3+ pitting edema of the bilateral legs. The oral and conjunctival mucosae were unremarkable.

Antinuclear antibody, double-stranded DNA, and anti-Smith antibody levels were negative. A punch biopsy of the left lateral thigh revealed intraepidermal vesicular dermatitis with dermal edema suggestive of edema bullae and direct immunofluorescence was negative for immune complex and complement deposition.

Conservative therapy with wound care was recommended. The patient continued to report persistent severe skin pain and developed a subcutaneous nodule on the right inner thigh 1 week later, prompting a second biopsy. Results of the excisional biopsy were nondiagnostic but were suggestive of calciphylaxis, revealing subepidermal bullae with epidermal necrosis, a scant perivascular lymphocytic infiltrate, and extravasated erythrocytes. No evidence of calcification was seen within the vessels. The patient was then started on sodium thiosulfate with hemodialysis for treatment of presumed calciphylaxis.

Despite meticulous wound care and treatment with sodium thiosulfate, the patient developed ulcerations with necrotic eschars on the bilateral buttocks, hips, and thighs 1 month later (Figure 1). She subsequently worsened over the next few weeks. She developed sepsis and was transferred to the intensive care unit. A third biopsy was performed, finally confirming the diagnosis of calciphylaxis. Histopathology revealed small blood vessels with basophilic granular deposits in the walls consistent with calcium in the subcutaneous tissue (highlighted with the von Kossa stain), as well as thrombi in the lumens of some vessels; early fat necrosis; focal epidermal necrosis with underlying congested blood vessels with deposits in their walls; a perivascular infiltrate predominately of lymphocytes and neutrophils with scattered nuclear dust; and thick, hyalinized, closely crowded collagen bundles in the reticular dermis and in a widened subcutaneous septum (Figures 2 and 3).

Supportive care and pain control were continued, but the overall prognosis was determined to be very poor, and the patient eventually was discharged to hospice and died.

Although calciphylaxis is commonly seen in patients with ESRD and hyperparathyroidism, patients without renal disease also may develop the condition.^2,3 Prior epidemiologic studies have shown a prevalence of 1% in patients with chronic kidney disease and up to 4% in those receiving dialysis.^2-5 The average age at presentation is 48 years.^6,7 Although calciphylaxis has been noted to affect males and females equally, some studies have suggested a female predominance.^5-8

The etiology of calciphylaxis is unknown, but ESRD requiring dialysis, primary or secondary hyperparathyroidism, obesity, diabetes mellitus, skin trauma, and/or a hypercoagulable state may put patients at increased risk for developing this disease.^2,3 Other risk factors include systemic corticosteroids, liver disease, increased serum aluminum, and increased erythrocyte sedimentation rate. Although high calcium-phosphate product has been noted as a risk factor in prior studies, one retrospective study found that it does not reliably confirm or exclude a diagnosis of calciphylaxis.⁸

The pathogenesis of calciphylaxis is not well understood; however, some researchers suggest that an imbalance in calcium-phosphate homeostasis may lead to calciphylaxis; that is, elevated calcium and phosphate levels exceed their solubility and deposit in the walls of small- and medium-sized arteries, which consequently leads to ischemic necrosis and gangrene of the surrounding tissue.⁹

Clinically, calciphylaxis has an indolent onset and usually presents as well-demarcated, painful, purplish, mottled lesions that evolve into necrotic gray-black eschars and gangrene in adjacent tissues.^1,5,6 The ischemic process may even extend to the muscle layer.⁵ Other common presentations include mild erythematous patches; livedo reticularis; painful nodules; necrotic ulcerating lesions; and more rarely flaccid, hemorrhagic, or serous bullous lesions followed by ulceration, as was seen in our patient.^6,9,10 Lesions usually begin at sites of trauma and seem to be distributed symmetrically.^5,6 The most commonly affected locations are the legs, specifically the medial thighs, as well as the abdomen and buttocks, but lesions also can be found at more distal sites such as the breasts, tongue, vulva, penis, fingers, and toes.^5,6,10 The head and neck region rarely is affected. Although uncommon, calciphylaxis may affect other organs, including the lungs, stomach, kidneys, and adrenal glands.⁵ The accompanying systemic symptoms and findings may include muscle weakness, tenderness, or myositis with rhabdomyolysis; calcific cerebral embolism; dementia and infarction of the central nervous system; acute respiratory failure; heart disease; atrioventricular block; and calcification of the cardiac conduction system.⁶ Unlike other forms of peripheral vascular disease, distal pulses are present in calciphylaxis, as blood flow usually is preserved distal and deep to the areas of necrosis.^5,6

A careful history and thorough physical examination are important first steps in the diagnosis of this condition.^2,10 Although there are no definitive laboratory tests, elevated serum calcium, phosphorous, and calcium-phosphate product levels, as well as parathyroid hormone level, may be suggestive of calciphylaxis.^2,5 Leukocytosis may occur if an infection is present.⁵

The most accurate method to confirm the diagnosis is a deep incisional biopsy from an erythematous, slightly purpuric area adjacent to the necrotic lesion.^2,10,11 The histopathologic features used to make the diagnosis include calcification of medium-sized vessels, particularly the intimal or medial layers, in the deep dermis and subcutaneous fat in addition to lobular capillaries of the subcutaneous fat.^5,10 These vessels, including the smaller distal vessels that supply the papillary dermis and epidermis, also may be thrombosed due to calcification, leading to vascular occlusion and subsequently ischemic necrosis of the overlying epidermis.¹⁰ Other findings may include pseudoxanthoma elasticum changes, panniculitis, and subcutaneous fat necrosis.^4,10

The differential diagnosis for calciphylaxis includes peripheral vascular disease, vasculitis, juvenile dermatomyositis, proteins C and S deficiencies, cryofibrinogenemia, calcinosis cutis, and tumoral calcinosis.² Polyarteritis nodosa, Sjögren syndrome, atherosclerotic peripheral vascular disease, pyoderma gangrenosum, systemic lupus erythematosus, necrotizing fasciitis, septic embolism, and necrosis secondary to warfarin and heparin may mimic calciphylaxis.⁵

Treatment of calciphylaxis is multidimensional but primarily is supportive.^6,11 Controlling calcium and phosphate levels and secondary hyperparathyroidism through diet and phosphate binders (eg, sevelamer hydrochloride) has been shown to be effective.⁶ Pamidronate, a bisphosphonate, inhibits arterial calcification in animal models and has been reported to treat calciphylaxis, resulting in marked pain reduction and ulcer healing.^4,6 Cinacalcet, which functions as a calcimimetic, has been implicated in the treatment of calciphylaxis. It has been used to treat primary and secondary hyperparathyroidism and to normalize serum calcium levels; it also may be used as an alternative to parathyroidectomy.^4,6 Intravenous administration of sodium thiosulfate, a potent antioxidant and chelator of calcium, has been helpful in reversing signs and symptoms of calciphylaxis.^6,12 It also has been shown to effectively remove extra calcium during peritoneal dialysis.⁶ Parathyroidectomy has been useful in patients with markedly elevated parathyroid hormone levels, as it suppresses or eliminates the sensitizing agent causing hypercalcemia, elevated calcium-phosphate product, and hyperparathyroidism.^1,2,6,13

Wound care and prevention of sepsis are essential in the treatment of calciphylaxis. Management options include surgical debridement, hydrocolloid and biologic dressings, skin grafts, systemic antibiotics, oral pentoxifylline combined with maggot therapy, nutritional support, hyperbaric oxygen therapy, and revascularization and amputation when other interventions have failed. Pain control with analgesics and correction of thrombosis in the skin and blood vessels via anticoagulation therapy also are important complementary treatments.⁶

The clinical outcome of calciphylaxis is dependent on early diagnosis, antimicrobial therapy, and wound management,⁹ but overall, the prognosis usually is poor and has a high mortality rate. The most common causes of death are infection and sepsis.^1,9 A study of 7 cases reported 100% mortality,¹⁴ but other studies have suggested a mortality rate of 60% to 80%.^4,10 Female sex and obesity are poor prognostic indicators.² A better prognosis has been appreciated in cases in which lesions occur at distal sites (eg, lower legs, hands) compared to more proximal sites (eg, abdomen), where 25% and 75% mortalities have been noted, respectively.^10,14,15 In one study, the overall mortality rate was 45% in patients with calciphylaxis at 1 year.⁶ The rate was 41% in patients with plaques only and 67% in those who presented with ulceration. Patients who survive often experience a high degree of morbidity and prolonged hospitalization; these patients often are severely debilitated, especially in the case of limb amputation.⁶

Our report of calciphylaxis demonstrates the diversity in clinical presentation and emphasizes the importance of early and accurate diagnosis in reducing morbidity and mortality. In our case, the patient presented with skin pain and tense nonhemorrhagic bullae without underlying ecchymotic or erythematous lesions as the earliest sign of calciphylaxis. Physicians should have a high degree of suspicion in the setting of dialysis-dependent ESRD patients with bullae, extreme pain, and continuous decline. We hope that this case will help increase awareness of the varying presentations of this condition.

To the Editor:

Calciphylaxis (also known as calcific uremic arteriolopathy and calcifying panniculitis) is a rare vasculopathy affecting the small vessels.¹ It is characterized by cutaneous ischemia and necrosis secondary to calcification. It is most commonly seen in patients with end-stage renal disease (ESRD) and hyperparathyroidism.^1-3 Histopathologic features that are consistent with the diagnosis of calciphylaxis include calcification of medium-sized vessels in the deep dermis or subcutaneous fat as well as smaller distal vessels that supply the papillary dermis and epidermis.^4,5 Although it commonly presents as well-demarcated, painful, purplish lesions that evolve into necrotic eschars, calciphylaxis rarely can present with hemorrhagic or serous bullous lesions followed by ulceration, as was seen in our patient.^1,5,6 We report this uncommon presentation to highlight the variety in clinical appearance of calciphylaxis and the importance of early diagnosis.

A 43-year-old woman presented to the emergency department for evaluation of chest and abdominal pain that began 1 day prior to presentation. She had a history of systemic lupus erythematosus and ESRD secondary to poststreptococcal glomerulonephritis and was currently on peritoneal dialysis. The patient was admitted for peritonitis and treated with broad-spectrum antibiotics. At the time of admission, the patient also was noted to have several painful bullae on the legs. Her medical history also was remarkable for cerebral infarction, fibromyalgia, cerebral artery occlusion with cerebral infarction, sciatica, hyperlipidemia, deep vein thrombosis, and seizures. She had no history of herpes simplex virus. Surgical history was remarkable for tubal ligation, nephrectomy and kidney transplant, parathyroidectomy, and cholecystectomy. The patient’s medications included sevelamer carbonate, prednisone, epogen, calcium carbonate, esomeprazole, ondansetron, topical gentamicin, and atorvastatin.

Skin examination was performed by the inpatient dermatology service and revealed several tense, 1- to 5-cm, nonhemorrhagic bullae on the thighs and lower legs, some that had ruptured. The lesions were notably tender to palpation. No surrounding erythema, ecchymosis, or warmth was appreciated. The Nikolsky sign was negative. The patient also was noted to have at least grade 2 to 3+ pitting edema of the bilateral legs. The oral and conjunctival mucosae were unremarkable.

Antinuclear antibody, double-stranded DNA, and anti-Smith antibody levels were negative. A punch biopsy of the left lateral thigh revealed intraepidermal vesicular dermatitis with dermal edema suggestive of edema bullae and direct immunofluorescence was negative for immune complex and complement deposition.

Conservative therapy with wound care was recommended. The patient continued to report persistent severe skin pain and developed a subcutaneous nodule on the right inner thigh 1 week later, prompting a second biopsy. Results of the excisional biopsy were nondiagnostic but were suggestive of calciphylaxis, revealing subepidermal bullae with epidermal necrosis, a scant perivascular lymphocytic infiltrate, and extravasated erythrocytes. No evidence of calcification was seen within the vessels. The patient was then started on sodium thiosulfate with hemodialysis for treatment of presumed calciphylaxis.

Despite meticulous wound care and treatment with sodium thiosulfate, the patient developed ulcerations with necrotic eschars on the bilateral buttocks, hips, and thighs 1 month later (Figure 1). She subsequently worsened over the next few weeks. She developed sepsis and was transferred to the intensive care unit. A third biopsy was performed, finally confirming the diagnosis of calciphylaxis. Histopathology revealed small blood vessels with basophilic granular deposits in the walls consistent with calcium in the subcutaneous tissue (highlighted with the von Kossa stain), as well as thrombi in the lumens of some vessels; early fat necrosis; focal epidermal necrosis with underlying congested blood vessels with deposits in their walls; a perivascular infiltrate predominately of lymphocytes and neutrophils with scattered nuclear dust; and thick, hyalinized, closely crowded collagen bundles in the reticular dermis and in a widened subcutaneous septum (Figures 2 and 3).

Supportive care and pain control were continued, but the overall prognosis was determined to be very poor, and the patient eventually was discharged to hospice and died.

Although calciphylaxis is commonly seen in patients with ESRD and hyperparathyroidism, patients without renal disease also may develop the condition.^2,3 Prior epidemiologic studies have shown a prevalence of 1% in patients with chronic kidney disease and up to 4% in those receiving dialysis.^2-5 The average age at presentation is 48 years.^6,7 Although calciphylaxis has been noted to affect males and females equally, some studies have suggested a female predominance.^5-8

The etiology of calciphylaxis is unknown, but ESRD requiring dialysis, primary or secondary hyperparathyroidism, obesity, diabetes mellitus, skin trauma, and/or a hypercoagulable state may put patients at increased risk for developing this disease.^2,3 Other risk factors include systemic corticosteroids, liver disease, increased serum aluminum, and increased erythrocyte sedimentation rate. Although high calcium-phosphate product has been noted as a risk factor in prior studies, one retrospective study found that it does not reliably confirm or exclude a diagnosis of calciphylaxis.⁸

The pathogenesis of calciphylaxis is not well understood; however, some researchers suggest that an imbalance in calcium-phosphate homeostasis may lead to calciphylaxis; that is, elevated calcium and phosphate levels exceed their solubility and deposit in the walls of small- and medium-sized arteries, which consequently leads to ischemic necrosis and gangrene of the surrounding tissue.⁹

Clinically, calciphylaxis has an indolent onset and usually presents as well-demarcated, painful, purplish, mottled lesions that evolve into necrotic gray-black eschars and gangrene in adjacent tissues.^1,5,6 The ischemic process may even extend to the muscle layer.⁵ Other common presentations include mild erythematous patches; livedo reticularis; painful nodules; necrotic ulcerating lesions; and more rarely flaccid, hemorrhagic, or serous bullous lesions followed by ulceration, as was seen in our patient.^6,9,10 Lesions usually begin at sites of trauma and seem to be distributed symmetrically.^5,6 The most commonly affected locations are the legs, specifically the medial thighs, as well as the abdomen and buttocks, but lesions also can be found at more distal sites such as the breasts, tongue, vulva, penis, fingers, and toes.^5,6,10 The head and neck region rarely is affected. Although uncommon, calciphylaxis may affect other organs, including the lungs, stomach, kidneys, and adrenal glands.⁵ The accompanying systemic symptoms and findings may include muscle weakness, tenderness, or myositis with rhabdomyolysis; calcific cerebral embolism; dementia and infarction of the central nervous system; acute respiratory failure; heart disease; atrioventricular block; and calcification of the cardiac conduction system.⁶ Unlike other forms of peripheral vascular disease, distal pulses are present in calciphylaxis, as blood flow usually is preserved distal and deep to the areas of necrosis.^5,6

A careful history and thorough physical examination are important first steps in the diagnosis of this condition.^2,10 Although there are no definitive laboratory tests, elevated serum calcium, phosphorous, and calcium-phosphate product levels, as well as parathyroid hormone level, may be suggestive of calciphylaxis.^2,5 Leukocytosis may occur if an infection is present.⁵

The most accurate method to confirm the diagnosis is a deep incisional biopsy from an erythematous, slightly purpuric area adjacent to the necrotic lesion.^2,10,11 The histopathologic features used to make the diagnosis include calcification of medium-sized vessels, particularly the intimal or medial layers, in the deep dermis and subcutaneous fat in addition to lobular capillaries of the subcutaneous fat.^5,10 These vessels, including the smaller distal vessels that supply the papillary dermis and epidermis, also may be thrombosed due to calcification, leading to vascular occlusion and subsequently ischemic necrosis of the overlying epidermis.¹⁰ Other findings may include pseudoxanthoma elasticum changes, panniculitis, and subcutaneous fat necrosis.^4,10

The differential diagnosis for calciphylaxis includes peripheral vascular disease, vasculitis, juvenile dermatomyositis, proteins C and S deficiencies, cryofibrinogenemia, calcinosis cutis, and tumoral calcinosis.² Polyarteritis nodosa, Sjögren syndrome, atherosclerotic peripheral vascular disease, pyoderma gangrenosum, systemic lupus erythematosus, necrotizing fasciitis, septic embolism, and necrosis secondary to warfarin and heparin may mimic calciphylaxis.⁵

Treatment of calciphylaxis is multidimensional but primarily is supportive.^6,11 Controlling calcium and phosphate levels and secondary hyperparathyroidism through diet and phosphate binders (eg, sevelamer hydrochloride) has been shown to be effective.⁶ Pamidronate, a bisphosphonate, inhibits arterial calcification in animal models and has been reported to treat calciphylaxis, resulting in marked pain reduction and ulcer healing.^4,6 Cinacalcet, which functions as a calcimimetic, has been implicated in the treatment of calciphylaxis. It has been used to treat primary and secondary hyperparathyroidism and to normalize serum calcium levels; it also may be used as an alternative to parathyroidectomy.^4,6 Intravenous administration of sodium thiosulfate, a potent antioxidant and chelator of calcium, has been helpful in reversing signs and symptoms of calciphylaxis.^6,12 It also has been shown to effectively remove extra calcium during peritoneal dialysis.⁶ Parathyroidectomy has been useful in patients with markedly elevated parathyroid hormone levels, as it suppresses or eliminates the sensitizing agent causing hypercalcemia, elevated calcium-phosphate product, and hyperparathyroidism.^1,2,6,13

Wound care and prevention of sepsis are essential in the treatment of calciphylaxis. Management options include surgical debridement, hydrocolloid and biologic dressings, skin grafts, systemic antibiotics, oral pentoxifylline combined with maggot therapy, nutritional support, hyperbaric oxygen therapy, and revascularization and amputation when other interventions have failed. Pain control with analgesics and correction of thrombosis in the skin and blood vessels via anticoagulation therapy also are important complementary treatments.⁶

The clinical outcome of calciphylaxis is dependent on early diagnosis, antimicrobial therapy, and wound management,⁹ but overall, the prognosis usually is poor and has a high mortality rate. The most common causes of death are infection and sepsis.^1,9 A study of 7 cases reported 100% mortality,¹⁴ but other studies have suggested a mortality rate of 60% to 80%.^4,10 Female sex and obesity are poor prognostic indicators.² A better prognosis has been appreciated in cases in which lesions occur at distal sites (eg, lower legs, hands) compared to more proximal sites (eg, abdomen), where 25% and 75% mortalities have been noted, respectively.^10,14,15 In one study, the overall mortality rate was 45% in patients with calciphylaxis at 1 year.⁶ The rate was 41% in patients with plaques only and 67% in those who presented with ulceration. Patients who survive often experience a high degree of morbidity and prolonged hospitalization; these patients often are severely debilitated, especially in the case of limb amputation.⁶

Our report of calciphylaxis demonstrates the diversity in clinical presentation and emphasizes the importance of early and accurate diagnosis in reducing morbidity and mortality. In our case, the patient presented with skin pain and tense nonhemorrhagic bullae without underlying ecchymotic or erythematous lesions as the earliest sign of calciphylaxis. Physicians should have a high degree of suspicion in the setting of dialysis-dependent ESRD patients with bullae, extreme pain, and continuous decline. We hope that this case will help increase awareness of the varying presentations of this condition.

To the Editor:

In recent years, noninvasive brain stimulation techniques have gained growing importance in the treatment of psychiatric¹ and neurologic disorders as well as in neurologic rehabilitation (eg, after a stroke).² One of these techniques is transcranial electrical stimulation (tES), which includes transcranial direct current stimulation (tDCS), transcranial random noise stimulation, and transcranial alternating current stimulation. The current is administered through rubber electrodes covered by saline-soaked sponges that are attached to the skull over the dysfunctional brain areas using broad rubber bands.

Transcranial direct current stimulation ameliorates brain function by anodal stimulation after a series of 5 to 10 stimulations.¹ Recently, commercially available brain stimulation devices have been developed to improve working memory for online/video gaming³; however, application of a direct current (eg, 1–2 mA) over longer periods of time (15–20 minutes) can cause skin burns due to drying out of the electrode.⁴ Inhomogeneities in skin-electrode contact can lead to current bridges, resulting in quick evaporation of the contact medium (sodium chloride solution) and subsequent thermic damage of the skin. Another possible cause of skin lesions associated with tES is skin contact with the rubber electrode due to incorrect positioning of the electrode in the sponge covering. We report 2 cases of burns caused by tDCS.

A 55-year-old woman who was treated with tDCS (2 mA; 20 minutes) for recurrent depressive disorder developed a 0.5-cm, round, erosive, second-degree burn with hemorrhagic crust on the skin in the middle of the area where a 5×7-cm electrode (cathode) was positioned over the right orbit (Figure 1). It was the fifth stimulation with tDCS. The anode was positioned over the left dorsolateral prefrontal cortex. It was determined that the saline-soaked sponge covering the rubber electrode dried out during treatment and caused the burn. Transcranial direct current stimulation subsequently was stopped, and the lesion healed without intervention within 4 to 5 weeks, resulting in a small scar.

To the Editor:

In recent years, noninvasive brain stimulation techniques have gained growing importance in the treatment of psychiatric¹ and neurologic disorders as well as in neurologic rehabilitation (eg, after a stroke).² One of these techniques is transcranial electrical stimulation (tES), which includes transcranial direct current stimulation (tDCS), transcranial random noise stimulation, and transcranial alternating current stimulation. The current is administered through rubber electrodes covered by saline-soaked sponges that are attached to the skull over the dysfunctional brain areas using broad rubber bands.

Transcranial direct current stimulation ameliorates brain function by anodal stimulation after a series of 5 to 10 stimulations.¹ Recently, commercially available brain stimulation devices have been developed to improve working memory for online/video gaming³; however, application of a direct current (eg, 1–2 mA) over longer periods of time (15–20 minutes) can cause skin burns due to drying out of the electrode.⁴ Inhomogeneities in skin-electrode contact can lead to current bridges, resulting in quick evaporation of the contact medium (sodium chloride solution) and subsequent thermic damage of the skin. Another possible cause of skin lesions associated with tES is skin contact with the rubber electrode due to incorrect positioning of the electrode in the sponge covering. We report 2 cases of burns caused by tDCS.

A 55-year-old woman who was treated with tDCS (2 mA; 20 minutes) for recurrent depressive disorder developed a 0.5-cm, round, erosive, second-degree burn with hemorrhagic crust on the skin in the middle of the area where a 5×7-cm electrode (cathode) was positioned over the right orbit (Figure 1). It was the fifth stimulation with tDCS. The anode was positioned over the left dorsolateral prefrontal cortex. It was determined that the saline-soaked sponge covering the rubber electrode dried out during treatment and caused the burn. Transcranial direct current stimulation subsequently was stopped, and the lesion healed without intervention within 4 to 5 weeks, resulting in a small scar.

To the Editor:

In recent years, noninvasive brain stimulation techniques have gained growing importance in the treatment of psychiatric¹ and neurologic disorders as well as in neurologic rehabilitation (eg, after a stroke).² One of these techniques is transcranial electrical stimulation (tES), which includes transcranial direct current stimulation (tDCS), transcranial random noise stimulation, and transcranial alternating current stimulation. The current is administered through rubber electrodes covered by saline-soaked sponges that are attached to the skull over the dysfunctional brain areas using broad rubber bands.

Transcranial direct current stimulation ameliorates brain function by anodal stimulation after a series of 5 to 10 stimulations.¹ Recently, commercially available brain stimulation devices have been developed to improve working memory for online/video gaming³; however, application of a direct current (eg, 1–2 mA) over longer periods of time (15–20 minutes) can cause skin burns due to drying out of the electrode.⁴ Inhomogeneities in skin-electrode contact can lead to current bridges, resulting in quick evaporation of the contact medium (sodium chloride solution) and subsequent thermic damage of the skin. Another possible cause of skin lesions associated with tES is skin contact with the rubber electrode due to incorrect positioning of the electrode in the sponge covering. We report 2 cases of burns caused by tDCS.

A 55-year-old woman who was treated with tDCS (2 mA; 20 minutes) for recurrent depressive disorder developed a 0.5-cm, round, erosive, second-degree burn with hemorrhagic crust on the skin in the middle of the area where a 5×7-cm electrode (cathode) was positioned over the right orbit (Figure 1). It was the fifth stimulation with tDCS. The anode was positioned over the left dorsolateral prefrontal cortex. It was determined that the saline-soaked sponge covering the rubber electrode dried out during treatment and caused the burn. Transcranial direct current stimulation subsequently was stopped, and the lesion healed without intervention within 4 to 5 weeks, resulting in a small scar.

To the Editor:

Afatinib is a small molecule covalently binding and inhibiting the epidermal growth factor receptor (EGFR) as well as HER2 and HER4 receptor tyrosine kinases.¹ The EGFR family is part of a complex signal transduction network that is central to several critical cellular processes.² The human EGFR family is dysregulated in many solid tumors, making it an attractive target for anticancer therapy.² In 2013, the US Food and Drug Administration approved afatinib as a first-line treatment of patients with metastatic non–small cell lung cancer whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.³

Treatment with afatinib and other EGFR inhibitors is frequently associated with cutaneous adverse effects that occur in up to 90% of patients. These cutaneous reactions are typical for this drug family and distinct from the skin adverse effects related to other types of anticancer chemotherapy.⁴ The most frequent skin manifestations following afatinib treatment consist of an acneform pustular eruption in up to 90% of patients.^5,6 Other dermatologic reactions include nonspecific maculopapular rashes (90%), stomatitis (71%), paronychia with some nail changes (58%), xerosis (31%), pruritus (21%), and hand-foot syndrome (7%)^5,6; however, grade 3 dermatologic reactions occurred in only 0.15% of patients.

Inflammatory changes in both preexisting and undetected actinic keratoses (AKs) and even progression to squamous cell carcinoma (SCC) have been previously described as uncommon dermatologic adverse effects of 2 EGFR inhibitors, sorafenib and erlotinib.^7-9 Seven of 131 patients with metastatic renal cell carcinoma treated with single-agent sorafenib developed cutaneous SCC and 3 more had AKs.⁹ One patient demonstrated self-limited inflammatory flare-up of AKs during erlotinib treatment.⁸ We report acute inflammation of AKs from afatinib treatment.

A 78-year-old woman with fair skin who was previously treated for several AKs in sun-exposed areas presented with inflammatory changes that appeared at the site of AKs on photoexposed areas 110 days after initiating afatinib therapy (40 mg/d). Physical examination revealed multiple erythematous scaly plaques on the face, neck, chest, and forearms (Figure 1).

Eighteen months prior to the current presentation, the patient was diagnosed with locally advanced, inoperable, stage IIIA adenocarcinoma of the lung with deletion in exon 19 of the EGFR gene. She received definitive concomitant chemoradiation with the carboplatin-vinorelbine regimen and 60-Gy radiation. Four months later, a positron emission tomography (PET)–fludeoxyglucose scan revealed a single bone lesion in the L5 vertebra leading to irradiation to the lumbar spine. Subsequently, new metastases to the neck, right lung, T5 vertebra, and left acetabulum were detected by PET–computed tomography. One year later, afatinib 40 mg/d was initiated. A PET scan after 2 months of treatment showed excellent response.

At the current presentation, a punch biopsy obtained from an inflammatory lesion on the left dorsal forearm revealed findings consistent with an eroded and inflamed AK; the biopsy showed marked dysplasia of the keratinocytes that was predominately located in the basal layer of the epidermis. The lesion was accompanied by a dense mixed inflammatory cell infiltrate that was centered in the papillary dermis and extended to the epidermis (Figure 2). Because of this grade 3 skin toxicity, the afatinib dosage was reduced to 20 mg/d, and betamethasone cream 0.1% and emollients were applied locally for 2 weeks. A reduction in the number of AKs and clinical regression of the inflammatory changes was observed 2 weeks later (Figure 3).

There are many strategies for treating AKs. Physical procedures for destroying the lesions are commonly used. Some topical drugs, including imiquimod, 5-fluorouracil, and diclofenac sodium, also have proven efficacy.¹⁷

Conventional chemotherapeutic agents that have been described to be associated with the inflammation of AKs include docetaxel; doxorubicin; capecitabine; pentostatin; and the combination of dactinomycin, vincristine, dacarbazine and doxorubicin, cytarabine, and 6-thioguanine.^7,18 The mechanism leading to this effect is unknown, though abnormal DNA synthesis and a type of radiation recall phenomenon have been postulated.⁷

We described inflammatory changes in AKs associated with afatinib treatment. The precise mechanism by which afatinib induces inflammation in AK has not been elucidated; however, it is known that EGFR normally downregulates chemokine expression in keratinocytes. Conversely, EGFR signaling blockade produces opposite effects, with increased CCL2, CCL5, and CXCL10, as well as reduced CXCL8 expression, leading to enhanced skin inflammation.¹⁹ Afatinib is a targeted agent that modulates the Ras/Raf/MEK/ERK signaling circuit, which is a key intracellular signal transduction pathway.²⁰ This pathway and its downstream effectors have been implicated in cutaneous squamous cell carcinogenesis that might be accompanied by inflammatory changes.^21,22 The remarkable clinical improvement of the AKs in our patient following the inflammatory flare-up supports the notion that the anticancer effect on intraepidermal neoplasms might be mediated by inflammation.²³

To the Editor:

Afatinib is a small molecule covalently binding and inhibiting the epidermal growth factor receptor (EGFR) as well as HER2 and HER4 receptor tyrosine kinases.¹ The EGFR family is part of a complex signal transduction network that is central to several critical cellular processes.² The human EGFR family is dysregulated in many solid tumors, making it an attractive target for anticancer therapy.² In 2013, the US Food and Drug Administration approved afatinib as a first-line treatment of patients with metastatic non–small cell lung cancer whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.³

Treatment with afatinib and other EGFR inhibitors is frequently associated with cutaneous adverse effects that occur in up to 90% of patients. These cutaneous reactions are typical for this drug family and distinct from the skin adverse effects related to other types of anticancer chemotherapy.⁴ The most frequent skin manifestations following afatinib treatment consist of an acneform pustular eruption in up to 90% of patients.^5,6 Other dermatologic reactions include nonspecific maculopapular rashes (90%), stomatitis (71%), paronychia with some nail changes (58%), xerosis (31%), pruritus (21%), and hand-foot syndrome (7%)^5,6; however, grade 3 dermatologic reactions occurred in only 0.15% of patients.

Inflammatory changes in both preexisting and undetected actinic keratoses (AKs) and even progression to squamous cell carcinoma (SCC) have been previously described as uncommon dermatologic adverse effects of 2 EGFR inhibitors, sorafenib and erlotinib.^7-9 Seven of 131 patients with metastatic renal cell carcinoma treated with single-agent sorafenib developed cutaneous SCC and 3 more had AKs.⁹ One patient demonstrated self-limited inflammatory flare-up of AKs during erlotinib treatment.⁸ We report acute inflammation of AKs from afatinib treatment.

A 78-year-old woman with fair skin who was previously treated for several AKs in sun-exposed areas presented with inflammatory changes that appeared at the site of AKs on photoexposed areas 110 days after initiating afatinib therapy (40 mg/d). Physical examination revealed multiple erythematous scaly plaques on the face, neck, chest, and forearms (Figure 1).

Eighteen months prior to the current presentation, the patient was diagnosed with locally advanced, inoperable, stage IIIA adenocarcinoma of the lung with deletion in exon 19 of the EGFR gene. She received definitive concomitant chemoradiation with the carboplatin-vinorelbine regimen and 60-Gy radiation. Four months later, a positron emission tomography (PET)–fludeoxyglucose scan revealed a single bone lesion in the L5 vertebra leading to irradiation to the lumbar spine. Subsequently, new metastases to the neck, right lung, T5 vertebra, and left acetabulum were detected by PET–computed tomography. One year later, afatinib 40 mg/d was initiated. A PET scan after 2 months of treatment showed excellent response.

At the current presentation, a punch biopsy obtained from an inflammatory lesion on the left dorsal forearm revealed findings consistent with an eroded and inflamed AK; the biopsy showed marked dysplasia of the keratinocytes that was predominately located in the basal layer of the epidermis. The lesion was accompanied by a dense mixed inflammatory cell infiltrate that was centered in the papillary dermis and extended to the epidermis (Figure 2). Because of this grade 3 skin toxicity, the afatinib dosage was reduced to 20 mg/d, and betamethasone cream 0.1% and emollients were applied locally for 2 weeks. A reduction in the number of AKs and clinical regression of the inflammatory changes was observed 2 weeks later (Figure 3).

There are many strategies for treating AKs. Physical procedures for destroying the lesions are commonly used. Some topical drugs, including imiquimod, 5-fluorouracil, and diclofenac sodium, also have proven efficacy.¹⁷

Conventional chemotherapeutic agents that have been described to be associated with the inflammation of AKs include docetaxel; doxorubicin; capecitabine; pentostatin; and the combination of dactinomycin, vincristine, dacarbazine and doxorubicin, cytarabine, and 6-thioguanine.^7,18 The mechanism leading to this effect is unknown, though abnormal DNA synthesis and a type of radiation recall phenomenon have been postulated.⁷

We described inflammatory changes in AKs associated with afatinib treatment. The precise mechanism by which afatinib induces inflammation in AK has not been elucidated; however, it is known that EGFR normally downregulates chemokine expression in keratinocytes. Conversely, EGFR signaling blockade produces opposite effects, with increased CCL2, CCL5, and CXCL10, as well as reduced CXCL8 expression, leading to enhanced skin inflammation.¹⁹ Afatinib is a targeted agent that modulates the Ras/Raf/MEK/ERK signaling circuit, which is a key intracellular signal transduction pathway.²⁰ This pathway and its downstream effectors have been implicated in cutaneous squamous cell carcinogenesis that might be accompanied by inflammatory changes.^21,22 The remarkable clinical improvement of the AKs in our patient following the inflammatory flare-up supports the notion that the anticancer effect on intraepidermal neoplasms might be mediated by inflammation.²³

To the Editor:

Afatinib is a small molecule covalently binding and inhibiting the epidermal growth factor receptor (EGFR) as well as HER2 and HER4 receptor tyrosine kinases.¹ The EGFR family is part of a complex signal transduction network that is central to several critical cellular processes.² The human EGFR family is dysregulated in many solid tumors, making it an attractive target for anticancer therapy.² In 2013, the US Food and Drug Administration approved afatinib as a first-line treatment of patients with metastatic non–small cell lung cancer whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.³

Treatment with afatinib and other EGFR inhibitors is frequently associated with cutaneous adverse effects that occur in up to 90% of patients. These cutaneous reactions are typical for this drug family and distinct from the skin adverse effects related to other types of anticancer chemotherapy.⁴ The most frequent skin manifestations following afatinib treatment consist of an acneform pustular eruption in up to 90% of patients.^5,6 Other dermatologic reactions include nonspecific maculopapular rashes (90%), stomatitis (71%), paronychia with some nail changes (58%), xerosis (31%), pruritus (21%), and hand-foot syndrome (7%)^5,6; however, grade 3 dermatologic reactions occurred in only 0.15% of patients.

Inflammatory changes in both preexisting and undetected actinic keratoses (AKs) and even progression to squamous cell carcinoma (SCC) have been previously described as uncommon dermatologic adverse effects of 2 EGFR inhibitors, sorafenib and erlotinib.^7-9 Seven of 131 patients with metastatic renal cell carcinoma treated with single-agent sorafenib developed cutaneous SCC and 3 more had AKs.⁹ One patient demonstrated self-limited inflammatory flare-up of AKs during erlotinib treatment.⁸ We report acute inflammation of AKs from afatinib treatment.

A 78-year-old woman with fair skin who was previously treated for several AKs in sun-exposed areas presented with inflammatory changes that appeared at the site of AKs on photoexposed areas 110 days after initiating afatinib therapy (40 mg/d). Physical examination revealed multiple erythematous scaly plaques on the face, neck, chest, and forearms (Figure 1).

Eighteen months prior to the current presentation, the patient was diagnosed with locally advanced, inoperable, stage IIIA adenocarcinoma of the lung with deletion in exon 19 of the EGFR gene. She received definitive concomitant chemoradiation with the carboplatin-vinorelbine regimen and 60-Gy radiation. Four months later, a positron emission tomography (PET)–fludeoxyglucose scan revealed a single bone lesion in the L5 vertebra leading to irradiation to the lumbar spine. Subsequently, new metastases to the neck, right lung, T5 vertebra, and left acetabulum were detected by PET–computed tomography. One year later, afatinib 40 mg/d was initiated. A PET scan after 2 months of treatment showed excellent response.

At the current presentation, a punch biopsy obtained from an inflammatory lesion on the left dorsal forearm revealed findings consistent with an eroded and inflamed AK; the biopsy showed marked dysplasia of the keratinocytes that was predominately located in the basal layer of the epidermis. The lesion was accompanied by a dense mixed inflammatory cell infiltrate that was centered in the papillary dermis and extended to the epidermis (Figure 2). Because of this grade 3 skin toxicity, the afatinib dosage was reduced to 20 mg/d, and betamethasone cream 0.1% and emollients were applied locally for 2 weeks. A reduction in the number of AKs and clinical regression of the inflammatory changes was observed 2 weeks later (Figure 3).

There are many strategies for treating AKs. Physical procedures for destroying the lesions are commonly used. Some topical drugs, including imiquimod, 5-fluorouracil, and diclofenac sodium, also have proven efficacy.¹⁷

Conventional chemotherapeutic agents that have been described to be associated with the inflammation of AKs include docetaxel; doxorubicin; capecitabine; pentostatin; and the combination of dactinomycin, vincristine, dacarbazine and doxorubicin, cytarabine, and 6-thioguanine.^7,18 The mechanism leading to this effect is unknown, though abnormal DNA synthesis and a type of radiation recall phenomenon have been postulated.⁷

We described inflammatory changes in AKs associated with afatinib treatment. The precise mechanism by which afatinib induces inflammation in AK has not been elucidated; however, it is known that EGFR normally downregulates chemokine expression in keratinocytes. Conversely, EGFR signaling blockade produces opposite effects, with increased CCL2, CCL5, and CXCL10, as well as reduced CXCL8 expression, leading to enhanced skin inflammation.¹⁹ Afatinib is a targeted agent that modulates the Ras/Raf/MEK/ERK signaling circuit, which is a key intracellular signal transduction pathway.²⁰ This pathway and its downstream effectors have been implicated in cutaneous squamous cell carcinogenesis that might be accompanied by inflammatory changes.^21,22 The remarkable clinical improvement of the AKs in our patient following the inflammatory flare-up supports the notion that the anticancer effect on intraepidermal neoplasms might be mediated by inflammation.²³

To the Editor:

In 1998, 2-octyl-cyanoacrylate (2-CA) tissue adhesive gained US Food and Drug Administration approval for topical application to easily hold closed approximated skin edges from surgical excisions and simple trauma-induced lacerations.¹ It has since been employed for a number of off-label indications, including sutureless circumcision,² skin graft fixation,³ pericatheter leakage,⁴ and intracorporeal use to control air leaks during lung resection.⁵ Animal investigations additionally have attempted to elucidate potential future uses of 2-CA for procedures such as inguinal hernia repair,⁶ bowel anastomosis,⁷ incisional hernia repair with mesh,⁸ and microvascular anastomosis.⁹ Compared to sutures, 2-CA offers ease and rapidity of application, a water-resistant barrier, and equivalent cosmetic results, as well as eliminates the need for suture removal.¹⁰ As 2-CA is used with increasing frequency across a variety of settings, there arises a greater need to be mindful of the potential complications of its use, such as irritant contact dermatitis (ICD), allergic contact dermatitis (ACD), and cutaneous id reaction.

A 14-year-old adolescent boy with no notable medical history and no known allergies underwent a minimally invasive Nuss procedure¹¹ (performed by P.L.G.) for the repair of severe pectus excavatum. Two 4-cm incisions were made—one in each lateral chest wall at the approximately eighth intercostal space—to facilitate the introduction of the Nuss bar. The surgical wounds were closed with 2 layers of running polyglactin 910 suture before 2-CA was applied topically to the incision sites. The surgery was well tolerated, and the patient’s wounds healed without incident. When the patient was evaluated for Nuss bar removal 3 years later, incision sites were noted to be well healed, and he exhibited no other skin lesions. The original incision sites (bilateral chest walls) were utilized to facilitate surgical Nuss bar removal. The wounds were closed in 4 layers and 2-CA was again applied topically to the incision sites. There were no intraoperative complications; no devices, drains, or tissue implants were left in the patient at the conclusion of the procedure.

One week later, via text message and digital photographs, the patient reported intense pruritus at the bilateral chest wall incision sites, which were now surrounded by symmetric 1-cm erythematous plaques and associated sparse erythematous satellite papules (Figure 1). The patient denied any fevers, pain, swelling, or purulent discharge from the wounds. He was started on hydrocortisone cream 1% twice daily as well as oral diphenhydramine 25 mg at bedtime with initial good effect.

Allergic contact dermatitis is a type IV hypersensitivity reaction that appears after initial sensitization to an allergen followed by re-exposure. Our patient presented with symmetric erythematous plaques at the surgical incision sites 1 week after 2-CA had been applied. During this interval, sensitization to the inciting allergen occurred. The allergen is taken up by antigen-presenting cells, which then migrate to lymph nodes where they encounter naïve T lymphocytes that subsequently undergo clonal expansion to produce a cohort of T cells that are capable of recognizing the allergen. If subsequent exposure to the specific allergen takes place, an elicitation phase occurs in which primed T cells are incited to release mediators of inflammation that engender the manifestations of ACD within 24 to 72 hours.^18,20 Sensitization may be promoted by skin barrier impairments such as dermatitis or a frank wound.^12,20 In most cases, the patient is unaware that sensitization has occurred, though a primary ACD within 5 to 15 days after initial exposure to the inciting allergen rarely may be observed.¹⁸ Although our patient had 2-CA applied to his surgical wounds at 14 years of age, it was unlikely that sensitization took place at that time, as it was 1 week rather than 1 to 3 days before he experienced the cutaneous eruption associated with his second 2-CA exposure at 17 years of age.

Cyanoacrylate tissue adhesive also may cause ICD resulting from histotoxic degradation products such as formaldehyde and cyanoacetate that are capable of compromising cutaneous barrier function. Keratinocytes that have had their membranes disturbed release proinflammatory cytokines, which recruit cells of the innate immune system as well as T lymphocytes to the site of insult to facilitate the inflammatory response. The manifestations of ICD include erythema, edema, and local necrosis that can compromise wound healing.²⁰ The speed at which a given cyanoacrylate adhesive degrades is proportional to the length of its carbon side chain. Those with shorter side chains—ethyl and methyl cyanoacrylate—degrade more rapidly into formaldehyde and cyanoacetate; 2-CA possesses a longer side chain and therefore degrades more slowly, which should, in theory, lessen its potential to cause ICD.²⁰ Because it may take 7 to 14 days before 2-CA will spontaneously peel from the application site, however, its potential to evoke ICD nevertheless exists.

Treatment of ICD entails removing the irritant while concurrently working to restore the skin’s barrier with emollients. Although topical corticosteroids often are reflexively prescribed to treat rashes, some believe that their use should be avoided in cases of ICD, as their inhibitory effects on epidermal lipid synthesis may further impair the skin’s barrier.²¹ For cases of ACD, with or without an accompanying id reaction, topical corticosteroids are the mainstay of therapy. It is customary to start with a higher-potency topical steroid such as clobetasol and taper to lower-potency steroids as the patient’s condition improves. Steroid ointments are petroleum based and are capable of causing 2-CA to separate from the skin.¹⁰ As a result, they should be used with care when being applied to an area where 2-CA is maintaining dermal closure. Systemic corticosteroids may be warranted in cases with involvement of more than 20% of the body surface area and should start to provide relief within 12 to 24 hours.²² Oral antihistamines and cold water compresses can be added to help address pruritus and discomfort in both ACD and ICD.

Instances of contact dermatitis caused by 2-CA are rare, and progression to an id reaction is rarer still. Physicians should be aware of the possibility of encountering a patient that manifests one or both of these complications whenever 2-CA is employed for skin closure. Physicians who employ 2-CA for skin closure should first ask patients about prior cutaneous reactions to cyanoacrylates including 2-CA and other commonly encountered acrylate-containing products including adhesive wound dressings, dental cements and prostheses, superglue, artificial nails, and adhesives for wigs and false eyelashes. Still, many patients who exhibit acrylate-induced contact dermatitis, with or without an associated id reaction, will not attest to a history of adverse reactions; they simply may not recognize acrylate as the inciting agent. Practitioners across a range of specialties outside of dermatology—surgeons, emergency physicians, and primary care providers—should be prepared to both recognize contact dermatitis and id reaction arising from the use of 2-CA and implement a basic treatment plan that will bring the patient relief without compromising wound closure.

To the Editor:

In 1998, 2-octyl-cyanoacrylate (2-CA) tissue adhesive gained US Food and Drug Administration approval for topical application to easily hold closed approximated skin edges from surgical excisions and simple trauma-induced lacerations.¹ It has since been employed for a number of off-label indications, including sutureless circumcision,² skin graft fixation,³ pericatheter leakage,⁴ and intracorporeal use to control air leaks during lung resection.⁵ Animal investigations additionally have attempted to elucidate potential future uses of 2-CA for procedures such as inguinal hernia repair,⁶ bowel anastomosis,⁷ incisional hernia repair with mesh,⁸ and microvascular anastomosis.⁹ Compared to sutures, 2-CA offers ease and rapidity of application, a water-resistant barrier, and equivalent cosmetic results, as well as eliminates the need for suture removal.¹⁰ As 2-CA is used with increasing frequency across a variety of settings, there arises a greater need to be mindful of the potential complications of its use, such as irritant contact dermatitis (ICD), allergic contact dermatitis (ACD), and cutaneous id reaction.

A 14-year-old adolescent boy with no notable medical history and no known allergies underwent a minimally invasive Nuss procedure¹¹ (performed by P.L.G.) for the repair of severe pectus excavatum. Two 4-cm incisions were made—one in each lateral chest wall at the approximately eighth intercostal space—to facilitate the introduction of the Nuss bar. The surgical wounds were closed with 2 layers of running polyglactin 910 suture before 2-CA was applied topically to the incision sites. The surgery was well tolerated, and the patient’s wounds healed without incident. When the patient was evaluated for Nuss bar removal 3 years later, incision sites were noted to be well healed, and he exhibited no other skin lesions. The original incision sites (bilateral chest walls) were utilized to facilitate surgical Nuss bar removal. The wounds were closed in 4 layers and 2-CA was again applied topically to the incision sites. There were no intraoperative complications; no devices, drains, or tissue implants were left in the patient at the conclusion of the procedure.

One week later, via text message and digital photographs, the patient reported intense pruritus at the bilateral chest wall incision sites, which were now surrounded by symmetric 1-cm erythematous plaques and associated sparse erythematous satellite papules (Figure 1). The patient denied any fevers, pain, swelling, or purulent discharge from the wounds. He was started on hydrocortisone cream 1% twice daily as well as oral diphenhydramine 25 mg at bedtime with initial good effect.

Allergic contact dermatitis is a type IV hypersensitivity reaction that appears after initial sensitization to an allergen followed by re-exposure. Our patient presented with symmetric erythematous plaques at the surgical incision sites 1 week after 2-CA had been applied. During this interval, sensitization to the inciting allergen occurred. The allergen is taken up by antigen-presenting cells, which then migrate to lymph nodes where they encounter naïve T lymphocytes that subsequently undergo clonal expansion to produce a cohort of T cells that are capable of recognizing the allergen. If subsequent exposure to the specific allergen takes place, an elicitation phase occurs in which primed T cells are incited to release mediators of inflammation that engender the manifestations of ACD within 24 to 72 hours.^18,20 Sensitization may be promoted by skin barrier impairments such as dermatitis or a frank wound.^12,20 In most cases, the patient is unaware that sensitization has occurred, though a primary ACD within 5 to 15 days after initial exposure to the inciting allergen rarely may be observed.¹⁸ Although our patient had 2-CA applied to his surgical wounds at 14 years of age, it was unlikely that sensitization took place at that time, as it was 1 week rather than 1 to 3 days before he experienced the cutaneous eruption associated with his second 2-CA exposure at 17 years of age.

Cyanoacrylate tissue adhesive also may cause ICD resulting from histotoxic degradation products such as formaldehyde and cyanoacetate that are capable of compromising cutaneous barrier function. Keratinocytes that have had their membranes disturbed release proinflammatory cytokines, which recruit cells of the innate immune system as well as T lymphocytes to the site of insult to facilitate the inflammatory response. The manifestations of ICD include erythema, edema, and local necrosis that can compromise wound healing.²⁰ The speed at which a given cyanoacrylate adhesive degrades is proportional to the length of its carbon side chain. Those with shorter side chains—ethyl and methyl cyanoacrylate—degrade more rapidly into formaldehyde and cyanoacetate; 2-CA possesses a longer side chain and therefore degrades more slowly, which should, in theory, lessen its potential to cause ICD.²⁰ Because it may take 7 to 14 days before 2-CA will spontaneously peel from the application site, however, its potential to evoke ICD nevertheless exists.

Treatment of ICD entails removing the irritant while concurrently working to restore the skin’s barrier with emollients. Although topical corticosteroids often are reflexively prescribed to treat rashes, some believe that their use should be avoided in cases of ICD, as their inhibitory effects on epidermal lipid synthesis may further impair the skin’s barrier.²¹ For cases of ACD, with or without an accompanying id reaction, topical corticosteroids are the mainstay of therapy. It is customary to start with a higher-potency topical steroid such as clobetasol and taper to lower-potency steroids as the patient’s condition improves. Steroid ointments are petroleum based and are capable of causing 2-CA to separate from the skin.¹⁰ As a result, they should be used with care when being applied to an area where 2-CA is maintaining dermal closure. Systemic corticosteroids may be warranted in cases with involvement of more than 20% of the body surface area and should start to provide relief within 12 to 24 hours.²² Oral antihistamines and cold water compresses can be added to help address pruritus and discomfort in both ACD and ICD.

Instances of contact dermatitis caused by 2-CA are rare, and progression to an id reaction is rarer still. Physicians should be aware of the possibility of encountering a patient that manifests one or both of these complications whenever 2-CA is employed for skin closure. Physicians who employ 2-CA for skin closure should first ask patients about prior cutaneous reactions to cyanoacrylates including 2-CA and other commonly encountered acrylate-containing products including adhesive wound dressings, dental cements and prostheses, superglue, artificial nails, and adhesives for wigs and false eyelashes. Still, many patients who exhibit acrylate-induced contact dermatitis, with or without an associated id reaction, will not attest to a history of adverse reactions; they simply may not recognize acrylate as the inciting agent. Practitioners across a range of specialties outside of dermatology—surgeons, emergency physicians, and primary care providers—should be prepared to both recognize contact dermatitis and id reaction arising from the use of 2-CA and implement a basic treatment plan that will bring the patient relief without compromising wound closure.

To the Editor:

In 1998, 2-octyl-cyanoacrylate (2-CA) tissue adhesive gained US Food and Drug Administration approval for topical application to easily hold closed approximated skin edges from surgical excisions and simple trauma-induced lacerations.¹ It has since been employed for a number of off-label indications, including sutureless circumcision,² skin graft fixation,³ pericatheter leakage,⁴ and intracorporeal use to control air leaks during lung resection.⁵ Animal investigations additionally have attempted to elucidate potential future uses of 2-CA for procedures such as inguinal hernia repair,⁶ bowel anastomosis,⁷ incisional hernia repair with mesh,⁸ and microvascular anastomosis.⁹ Compared to sutures, 2-CA offers ease and rapidity of application, a water-resistant barrier, and equivalent cosmetic results, as well as eliminates the need for suture removal.¹⁰ As 2-CA is used with increasing frequency across a variety of settings, there arises a greater need to be mindful of the potential complications of its use, such as irritant contact dermatitis (ICD), allergic contact dermatitis (ACD), and cutaneous id reaction.

A 14-year-old adolescent boy with no notable medical history and no known allergies underwent a minimally invasive Nuss procedure¹¹ (performed by P.L.G.) for the repair of severe pectus excavatum. Two 4-cm incisions were made—one in each lateral chest wall at the approximately eighth intercostal space—to facilitate the introduction of the Nuss bar. The surgical wounds were closed with 2 layers of running polyglactin 910 suture before 2-CA was applied topically to the incision sites. The surgery was well tolerated, and the patient’s wounds healed without incident. When the patient was evaluated for Nuss bar removal 3 years later, incision sites were noted to be well healed, and he exhibited no other skin lesions. The original incision sites (bilateral chest walls) were utilized to facilitate surgical Nuss bar removal. The wounds were closed in 4 layers and 2-CA was again applied topically to the incision sites. There were no intraoperative complications; no devices, drains, or tissue implants were left in the patient at the conclusion of the procedure.

One week later, via text message and digital photographs, the patient reported intense pruritus at the bilateral chest wall incision sites, which were now surrounded by symmetric 1-cm erythematous plaques and associated sparse erythematous satellite papules (Figure 1). The patient denied any fevers, pain, swelling, or purulent discharge from the wounds. He was started on hydrocortisone cream 1% twice daily as well as oral diphenhydramine 25 mg at bedtime with initial good effect.

Allergic contact dermatitis is a type IV hypersensitivity reaction that appears after initial sensitization to an allergen followed by re-exposure. Our patient presented with symmetric erythematous plaques at the surgical incision sites 1 week after 2-CA had been applied. During this interval, sensitization to the inciting allergen occurred. The allergen is taken up by antigen-presenting cells, which then migrate to lymph nodes where they encounter naïve T lymphocytes that subsequently undergo clonal expansion to produce a cohort of T cells that are capable of recognizing the allergen. If subsequent exposure to the specific allergen takes place, an elicitation phase occurs in which primed T cells are incited to release mediators of inflammation that engender the manifestations of ACD within 24 to 72 hours.^18,20 Sensitization may be promoted by skin barrier impairments such as dermatitis or a frank wound.^12,20 In most cases, the patient is unaware that sensitization has occurred, though a primary ACD within 5 to 15 days after initial exposure to the inciting allergen rarely may be observed.¹⁸ Although our patient had 2-CA applied to his surgical wounds at 14 years of age, it was unlikely that sensitization took place at that time, as it was 1 week rather than 1 to 3 days before he experienced the cutaneous eruption associated with his second 2-CA exposure at 17 years of age.

Cyanoacrylate tissue adhesive also may cause ICD resulting from histotoxic degradation products such as formaldehyde and cyanoacetate that are capable of compromising cutaneous barrier function. Keratinocytes that have had their membranes disturbed release proinflammatory cytokines, which recruit cells of the innate immune system as well as T lymphocytes to the site of insult to facilitate the inflammatory response. The manifestations of ICD include erythema, edema, and local necrosis that can compromise wound healing.²⁰ The speed at which a given cyanoacrylate adhesive degrades is proportional to the length of its carbon side chain. Those with shorter side chains—ethyl and methyl cyanoacrylate—degrade more rapidly into formaldehyde and cyanoacetate; 2-CA possesses a longer side chain and therefore degrades more slowly, which should, in theory, lessen its potential to cause ICD.²⁰ Because it may take 7 to 14 days before 2-CA will spontaneously peel from the application site, however, its potential to evoke ICD nevertheless exists.

Treatment of ICD entails removing the irritant while concurrently working to restore the skin’s barrier with emollients. Although topical corticosteroids often are reflexively prescribed to treat rashes, some believe that their use should be avoided in cases of ICD, as their inhibitory effects on epidermal lipid synthesis may further impair the skin’s barrier.²¹ For cases of ACD, with or without an accompanying id reaction, topical corticosteroids are the mainstay of therapy. It is customary to start with a higher-potency topical steroid such as clobetasol and taper to lower-potency steroids as the patient’s condition improves. Steroid ointments are petroleum based and are capable of causing 2-CA to separate from the skin.¹⁰ As a result, they should be used with care when being applied to an area where 2-CA is maintaining dermal closure. Systemic corticosteroids may be warranted in cases with involvement of more than 20% of the body surface area and should start to provide relief within 12 to 24 hours.²² Oral antihistamines and cold water compresses can be added to help address pruritus and discomfort in both ACD and ICD.

Instances of contact dermatitis caused by 2-CA are rare, and progression to an id reaction is rarer still. Physicians should be aware of the possibility of encountering a patient that manifests one or both of these complications whenever 2-CA is employed for skin closure. Physicians who employ 2-CA for skin closure should first ask patients about prior cutaneous reactions to cyanoacrylates including 2-CA and other commonly encountered acrylate-containing products including adhesive wound dressings, dental cements and prostheses, superglue, artificial nails, and adhesives for wigs and false eyelashes. Still, many patients who exhibit acrylate-induced contact dermatitis, with or without an associated id reaction, will not attest to a history of adverse reactions; they simply may not recognize acrylate as the inciting agent. Practitioners across a range of specialties outside of dermatology—surgeons, emergency physicians, and primary care providers—should be prepared to both recognize contact dermatitis and id reaction arising from the use of 2-CA and implement a basic treatment plan that will bring the patient relief without compromising wound closure.

To the Editor:

Mesotherapy, also known as intradermotherapy, is a cosmetic procedure in which multiple intradermal or subcutaneous injections of homeopathic substances, vitamins, chemicals, and plant extracts are administered.¹ First conceived in Europe, mesotherapy is not approved by the US Food and Drug Administration but is gaining popularity in the United States as an alternative cosmetic procedure for various purposes, including lipolysis, body contouring, stretch marks, acne scars, actinic damage, and skin rejuvenation.^1,2 We report a case of a healthy woman who developed perifolliculitis, transaminitis, and neutropenia 2 weeks after mesotherapy administration to the face, neck, and chest. We also review other potential side effects of this procedure.

A 36-year-old woman with no notable medical history presented to the emergency department with a worsening pruritic and painful rash on the face, chest, and neck of 2 weeks’ duration. The rash had developed 3 days after the patient received mesotherapy with an unknown substance for cosmetic rejuvenation; the rash was localized only to the injection sites. She did not note any fever, chills, nausea, vomiting, diarrhea, headache, arthralgia, or upper respiratory tract symptoms. She further denied starting any new medications, herbal products, or topical therapies apart from the procedure she had received 2 weeks prior.

The patient was found to be in no acute distress and vital signs were stable. Laboratory testing was remarkable for elevations in alanine aminotransferase (62 U/L [reference range, 10–40 U/L]) and aspartate aminotransferase (72 U/L [reference range 10–30 U/L]). Moreover, she had an absolute neutrophil count of 0.5×10³ cells/µL (reference range 1.8–8.0×10³ cells/µL). An electrolyte panel, creatinine level, and urinalysis were normal. Physical examination revealed numerous 4- to 5-mm erythematous papules in a gridlike distribution across the face, neck, and chest (Figure 1). No pustules or nodules were present. There was no discharge, crust, excoriations, or secondary lesions. Additionally, there was no lymphadenopathy and no mucous membrane or ocular involvement.

Mesotherapy promises aesthetic benefits through a minimally invasive procedure and therefore is rapidly gaining popularity in aesthetic spas and treatment centers. Due to the lack of regulation in treatment protocols and substances used, there have been numerous reported cases of adverse side effects following mesotherapy, such as pain, allergic reactions, urticaria, panniculitis, ulceration, hair loss, necrosis, paraffinoma, cutaneous tuberculosis, and rapidly growing nontuberculous mycobacterial infections.^1-5 More serious side effects also have been reported, such as permanent scarring, deformities, delirium, and massive subcutaneous emphysema (Table).^2,4-18

To the Editor:

Mesotherapy, also known as intradermotherapy, is a cosmetic procedure in which multiple intradermal or subcutaneous injections of homeopathic substances, vitamins, chemicals, and plant extracts are administered.¹ First conceived in Europe, mesotherapy is not approved by the US Food and Drug Administration but is gaining popularity in the United States as an alternative cosmetic procedure for various purposes, including lipolysis, body contouring, stretch marks, acne scars, actinic damage, and skin rejuvenation.^1,2 We report a case of a healthy woman who developed perifolliculitis, transaminitis, and neutropenia 2 weeks after mesotherapy administration to the face, neck, and chest. We also review other potential side effects of this procedure.

A 36-year-old woman with no notable medical history presented to the emergency department with a worsening pruritic and painful rash on the face, chest, and neck of 2 weeks’ duration. The rash had developed 3 days after the patient received mesotherapy with an unknown substance for cosmetic rejuvenation; the rash was localized only to the injection sites. She did not note any fever, chills, nausea, vomiting, diarrhea, headache, arthralgia, or upper respiratory tract symptoms. She further denied starting any new medications, herbal products, or topical therapies apart from the procedure she had received 2 weeks prior.

The patient was found to be in no acute distress and vital signs were stable. Laboratory testing was remarkable for elevations in alanine aminotransferase (62 U/L [reference range, 10–40 U/L]) and aspartate aminotransferase (72 U/L [reference range 10–30 U/L]). Moreover, she had an absolute neutrophil count of 0.5×10³ cells/µL (reference range 1.8–8.0×10³ cells/µL). An electrolyte panel, creatinine level, and urinalysis were normal. Physical examination revealed numerous 4- to 5-mm erythematous papules in a gridlike distribution across the face, neck, and chest (Figure 1). No pustules or nodules were present. There was no discharge, crust, excoriations, or secondary lesions. Additionally, there was no lymphadenopathy and no mucous membrane or ocular involvement.

Mesotherapy promises aesthetic benefits through a minimally invasive procedure and therefore is rapidly gaining popularity in aesthetic spas and treatment centers. Due to the lack of regulation in treatment protocols and substances used, there have been numerous reported cases of adverse side effects following mesotherapy, such as pain, allergic reactions, urticaria, panniculitis, ulceration, hair loss, necrosis, paraffinoma, cutaneous tuberculosis, and rapidly growing nontuberculous mycobacterial infections.^1-5 More serious side effects also have been reported, such as permanent scarring, deformities, delirium, and massive subcutaneous emphysema (Table).^2,4-18

To the Editor:

Mesotherapy, also known as intradermotherapy, is a cosmetic procedure in which multiple intradermal or subcutaneous injections of homeopathic substances, vitamins, chemicals, and plant extracts are administered.¹ First conceived in Europe, mesotherapy is not approved by the US Food and Drug Administration but is gaining popularity in the United States as an alternative cosmetic procedure for various purposes, including lipolysis, body contouring, stretch marks, acne scars, actinic damage, and skin rejuvenation.^1,2 We report a case of a healthy woman who developed perifolliculitis, transaminitis, and neutropenia 2 weeks after mesotherapy administration to the face, neck, and chest. We also review other potential side effects of this procedure.

A 36-year-old woman with no notable medical history presented to the emergency department with a worsening pruritic and painful rash on the face, chest, and neck of 2 weeks’ duration. The rash had developed 3 days after the patient received mesotherapy with an unknown substance for cosmetic rejuvenation; the rash was localized only to the injection sites. She did not note any fever, chills, nausea, vomiting, diarrhea, headache, arthralgia, or upper respiratory tract symptoms. She further denied starting any new medications, herbal products, or topical therapies apart from the procedure she had received 2 weeks prior.

The patient was found to be in no acute distress and vital signs were stable. Laboratory testing was remarkable for elevations in alanine aminotransferase (62 U/L [reference range, 10–40 U/L]) and aspartate aminotransferase (72 U/L [reference range 10–30 U/L]). Moreover, she had an absolute neutrophil count of 0.5×10³ cells/µL (reference range 1.8–8.0×10³ cells/µL). An electrolyte panel, creatinine level, and urinalysis were normal. Physical examination revealed numerous 4- to 5-mm erythematous papules in a gridlike distribution across the face, neck, and chest (Figure 1). No pustules or nodules were present. There was no discharge, crust, excoriations, or secondary lesions. Additionally, there was no lymphadenopathy and no mucous membrane or ocular involvement.

Mesotherapy promises aesthetic benefits through a minimally invasive procedure and therefore is rapidly gaining popularity in aesthetic spas and treatment centers. Due to the lack of regulation in treatment protocols and substances used, there have been numerous reported cases of adverse side effects following mesotherapy, such as pain, allergic reactions, urticaria, panniculitis, ulceration, hair loss, necrosis, paraffinoma, cutaneous tuberculosis, and rapidly growing nontuberculous mycobacterial infections.^1-5 More serious side effects also have been reported, such as permanent scarring, deformities, delirium, and massive subcutaneous emphysema (Table).^2,4-18

To the Editor:

The incidence of psoriasis in human immunodeficiency virus (HIV)–infected patients is similar to the general population, but it usually becomes more severe as immunosuppression increases. Additionally, it tends to be more resistant to conventional therapies, and the incidence and severity of psoriatic arthropathy is increased. Psoriasis often worsens at the time of HIV primary infection.¹ We describe a case of a patient with hepatitis B virus (HBV) whose severe plaque psoriasis was controlled on ustekinumab; he was later diagnosed with HIV infection.

A 42-year-old man with HBV treated with entecavir (HBV DNA viral load, <20 copies/mL [inactive carrier, <2000 copies/mL]) presented to our dermatology unit with severe plaque psoriasis (psoriasis area and severity index 23) that caused notable psychologic difficulties such as anxiety and depression. Treatment was attempted with cyclosporine; acitretin; psoralen plus UVA; infliximab; adalimumab; and eventually ustekinumab (45 mg every 3 months), which controlled the condition well (psoriasis area and severity index 0) in an almost completely sustained manner.

Serologic tests requested at one of his analytical control appointments 2 years after initiating treatment with ustekinumab revealed he was HIV positive. The patient reported unprotected sexual intercourse 4 months prior. He was referred to the infectious disease unit and was classified in subtype A1 of HIV infection (CD4 count, 583 cells/µL [reference range, 500-1200 cells/µL]; viral load, 159,268 copies/mL [rapid progression to AIDS, >100,000 copies/mL]). Treatment was initiated with raltegravir, ritonavir, darunavir, and abacavir; tolerance was suitable. Because of the patient’s history of severe psoriasis, treatment with ustekinumab was maintained. Normally, treatment with this drug would be contraindicated in patients with HIV, as it can lead to viral reactivation. Four years after his HIV diagnosis, neither the patient’s cutaneous nor HIV-associated condition had worsened.

For patients with HIV and mild or moderate psoriasis, topical therapies (eg, corticosteroids, vitamin D analogues, tazarotene) are recommended, similar to patients who are HIV negative. Human immunodeficiency virus–positive patients with severe psoriasis who do not respond to topical treatment should receive phototherapy (UVB or psoralen plus UVA) or acitretin along with their antiretroviral drugs.² In refractory cases, immunosuppressants, including cyclosporine, methotrexate, or tumor necrosis factor α inhibitors, might be used, though experience with them is limited.^3,4 Maintaining antiretroviral therapy and prophylaxis against opportunist disease is important in patients who receive such immunosuppressants, as is close monitoring of the viral load.

Ustekinumab is an IL-12/IL-23 monoclonal antibody indicated for the treatment of moderate to severe plaque psoriasis, active psoriatic arthritis, and inflammatory bowel disease. It is contraindicated in patients with clinically important active infections, such as HBV and hepatitis C virus infections.⁵ However, it was shown to be safe in a group of 18 patients with HBV who had received antiviral prophylaxis⁶; a degree of reactivation was observed in similar patients who received no such prophylaxis and in others with hepatitis C virus infection.⁷ The simultaneous use of methotrexate with ustekinumab in the treatment of psoriatic arthritis does not appear to affect the safety of the latter drug.⁸ Paparizos et al⁹ described a patient with HIV controlled with antiretroviral drugs who was treated with ustekinumab for psoriasis; no adverse effects were observed.

We report the case of a patient with HBV and psoriasis who was treated with ustekinumab and later became infected with HIV. His ustekinumab treatment was maintained without subsequent cutaneous or systemic complications.

To the Editor:

The incidence of psoriasis in human immunodeficiency virus (HIV)–infected patients is similar to the general population, but it usually becomes more severe as immunosuppression increases. Additionally, it tends to be more resistant to conventional therapies, and the incidence and severity of psoriatic arthropathy is increased. Psoriasis often worsens at the time of HIV primary infection.¹ We describe a case of a patient with hepatitis B virus (HBV) whose severe plaque psoriasis was controlled on ustekinumab; he was later diagnosed with HIV infection.

A 42-year-old man with HBV treated with entecavir (HBV DNA viral load, <20 copies/mL [inactive carrier, <2000 copies/mL]) presented to our dermatology unit with severe plaque psoriasis (psoriasis area and severity index 23) that caused notable psychologic difficulties such as anxiety and depression. Treatment was attempted with cyclosporine; acitretin; psoralen plus UVA; infliximab; adalimumab; and eventually ustekinumab (45 mg every 3 months), which controlled the condition well (psoriasis area and severity index 0) in an almost completely sustained manner.

Serologic tests requested at one of his analytical control appointments 2 years after initiating treatment with ustekinumab revealed he was HIV positive. The patient reported unprotected sexual intercourse 4 months prior. He was referred to the infectious disease unit and was classified in subtype A1 of HIV infection (CD4 count, 583 cells/µL [reference range, 500-1200 cells/µL]; viral load, 159,268 copies/mL [rapid progression to AIDS, >100,000 copies/mL]). Treatment was initiated with raltegravir, ritonavir, darunavir, and abacavir; tolerance was suitable. Because of the patient’s history of severe psoriasis, treatment with ustekinumab was maintained. Normally, treatment with this drug would be contraindicated in patients with HIV, as it can lead to viral reactivation. Four years after his HIV diagnosis, neither the patient’s cutaneous nor HIV-associated condition had worsened.

For patients with HIV and mild or moderate psoriasis, topical therapies (eg, corticosteroids, vitamin D analogues, tazarotene) are recommended, similar to patients who are HIV negative. Human immunodeficiency virus–positive patients with severe psoriasis who do not respond to topical treatment should receive phototherapy (UVB or psoralen plus UVA) or acitretin along with their antiretroviral drugs.² In refractory cases, immunosuppressants, including cyclosporine, methotrexate, or tumor necrosis factor α inhibitors, might be used, though experience with them is limited.^3,4 Maintaining antiretroviral therapy and prophylaxis against opportunist disease is important in patients who receive such immunosuppressants, as is close monitoring of the viral load.

Ustekinumab is an IL-12/IL-23 monoclonal antibody indicated for the treatment of moderate to severe plaque psoriasis, active psoriatic arthritis, and inflammatory bowel disease. It is contraindicated in patients with clinically important active infections, such as HBV and hepatitis C virus infections.⁵ However, it was shown to be safe in a group of 18 patients with HBV who had received antiviral prophylaxis⁶; a degree of reactivation was observed in similar patients who received no such prophylaxis and in others with hepatitis C virus infection.⁷ The simultaneous use of methotrexate with ustekinumab in the treatment of psoriatic arthritis does not appear to affect the safety of the latter drug.⁸ Paparizos et al⁹ described a patient with HIV controlled with antiretroviral drugs who was treated with ustekinumab for psoriasis; no adverse effects were observed.

We report the case of a patient with HBV and psoriasis who was treated with ustekinumab and later became infected with HIV. His ustekinumab treatment was maintained without subsequent cutaneous or systemic complications.

To the Editor:

The incidence of psoriasis in human immunodeficiency virus (HIV)–infected patients is similar to the general population, but it usually becomes more severe as immunosuppression increases. Additionally, it tends to be more resistant to conventional therapies, and the incidence and severity of psoriatic arthropathy is increased. Psoriasis often worsens at the time of HIV primary infection.¹ We describe a case of a patient with hepatitis B virus (HBV) whose severe plaque psoriasis was controlled on ustekinumab; he was later diagnosed with HIV infection.

A 42-year-old man with HBV treated with entecavir (HBV DNA viral load, <20 copies/mL [inactive carrier, <2000 copies/mL]) presented to our dermatology unit with severe plaque psoriasis (psoriasis area and severity index 23) that caused notable psychologic difficulties such as anxiety and depression. Treatment was attempted with cyclosporine; acitretin; psoralen plus UVA; infliximab; adalimumab; and eventually ustekinumab (45 mg every 3 months), which controlled the condition well (psoriasis area and severity index 0) in an almost completely sustained manner.

Serologic tests requested at one of his analytical control appointments 2 years after initiating treatment with ustekinumab revealed he was HIV positive. The patient reported unprotected sexual intercourse 4 months prior. He was referred to the infectious disease unit and was classified in subtype A1 of HIV infection (CD4 count, 583 cells/µL [reference range, 500-1200 cells/µL]; viral load, 159,268 copies/mL [rapid progression to AIDS, >100,000 copies/mL]). Treatment was initiated with raltegravir, ritonavir, darunavir, and abacavir; tolerance was suitable. Because of the patient’s history of severe psoriasis, treatment with ustekinumab was maintained. Normally, treatment with this drug would be contraindicated in patients with HIV, as it can lead to viral reactivation. Four years after his HIV diagnosis, neither the patient’s cutaneous nor HIV-associated condition had worsened.

For patients with HIV and mild or moderate psoriasis, topical therapies (eg, corticosteroids, vitamin D analogues, tazarotene) are recommended, similar to patients who are HIV negative. Human immunodeficiency virus–positive patients with severe psoriasis who do not respond to topical treatment should receive phototherapy (UVB or psoralen plus UVA) or acitretin along with their antiretroviral drugs.² In refractory cases, immunosuppressants, including cyclosporine, methotrexate, or tumor necrosis factor α inhibitors, might be used, though experience with them is limited.^3,4 Maintaining antiretroviral therapy and prophylaxis against opportunist disease is important in patients who receive such immunosuppressants, as is close monitoring of the viral load.

Ustekinumab is an IL-12/IL-23 monoclonal antibody indicated for the treatment of moderate to severe plaque psoriasis, active psoriatic arthritis, and inflammatory bowel disease. It is contraindicated in patients with clinically important active infections, such as HBV and hepatitis C virus infections.⁵ However, it was shown to be safe in a group of 18 patients with HBV who had received antiviral prophylaxis⁶; a degree of reactivation was observed in similar patients who received no such prophylaxis and in others with hepatitis C virus infection.⁷ The simultaneous use of methotrexate with ustekinumab in the treatment of psoriatic arthritis does not appear to affect the safety of the latter drug.⁸ Paparizos et al⁹ described a patient with HIV controlled with antiretroviral drugs who was treated with ustekinumab for psoriasis; no adverse effects were observed.

We report the case of a patient with HBV and psoriasis who was treated with ustekinumab and later became infected with HIV. His ustekinumab treatment was maintained without subsequent cutaneous or systemic complications.

To the Editor:

Basal cell carcinoma (BCC) is the most common of the nonmelanoma skin cancers and is a highly curable skin growth.^1,2 Conversely, angiosarcomas are aggressive vascular tumors of endothelial origin that classically appear as reddish purple patches or plaques that exhibit rapid growth and invasion.³ Sporadic cutaneous angiosarcomas are the most common type of this soft tissue tumor, occurring most often in the head and neck regions in men older than 70 years.^4,5 Other types of angiosarcomas include those associated with radiation therapy and chronic lymphedema. Postradiation angiosarcomas have been most frequently reported after treatment of breast cancer and appear as infiltrative plaques over the irradiated area.^4,5 Patients with chronic lymphedema, which most commonly is related to axillary lymph node dissection for breast cancer (90% of cases), may develop angiosarcoma presenting as a violaceous indurated plaque.⁵ Although angiosarcomas most often are seen with these distinct clinical characteristics, especially their violaceous color, they have been shown to mimic a few other skin disorders such as eczema and keratoacanthoma, but a limited number of cases of angiosarcoma mimicking BCC have been reported.^1,6,7 We present a case of an elderly man with a unique presentation of a lesion that clinically appeared as a morpheaform BCC but was confirmed to be an angiosarcoma on histopathology.

A 75-year-old man was referred to our dermatology clinic for evaluation of a flesh-colored plaque on the face that initially had developed 2 years prior on the right central malar cheek. Computed tomography of the head and neck 1 year prior, which the patient reported was for workup of the lesion, was found to be negative; however, these medical records were not obtained for confirmation. The lesion had been stable in size and remained flesh colored until 6 months prior to the current presentation when it exhibited a rapid increase in size. An initial biopsy was performed 1 month prior to presentation by an outside dermatology office and had been read as an angiosarcoma.

Physical examination revealed a 6-cm, flesh-colored, indurated, ill-defined plaque distributed on the right malar cheek below the eye and extending to the nasal bridge (Figure 1). There was no cervical or facial lymphadenopathy. The clinical features resembled a morpheaform BCC, and the lesion did not exhibit any reddish or purple color indicating it was of vascular origin. However, due to the prior histopathology report and recent rapid enlargement, a repeat sampling with a larger punch biopsy was performed, which confirmed the diagnosis of angiosarcoma. Histopathology demonstrated multiple atypical vascular channels lined by hyperchromatic cells extending from the upper dermis to the base of the biopsy site (Figure 2). Large, oval, atypical nuclei were present in multiple endothelial cells in the vascular channels, with some forming irregularly contoured and slitlike formations (Figure 3). Immunochemical staining was intensely and uniformly positive for CD31 and CD34, both endothelial markers. Diffuse positive staining with CD31 is considered to have high sensitivity and specificity for the diagnosis of angiosarcoma.⁴ Other pertinent staining demonstrated 2+ positivity for factor VIII and 1+ positivity for D2-40; CD45, AE1/AE3, S-100, and human herpesvirus 8 were negative, consistent with angiosarcoma. The patient was referred to radiation oncology and otolaryngology at our Multidisciplinary Head and Neck Oncology Center for further investigation of the extent of the disease and discussion of treatment. Computed tomography of the head and neck region at this time showed extensive disease extending into the medial canthal area without metastasis. Due to the extent of disease and facial location, he was not deemed a candidate for surgery. He was treated with 6 weeks of targeted radiation therapy with concurrent chemotherapy. He tolerated this treatment with minimal side effects and was found to be free from clinical disease 1 year after diagnosis. He was followed for 20 months by our Multidisciplinary Oncology Clinic without recurrence of his disease but was then lost to follow-up.

This case illustrates a rare presentation of an angiosarcoma clinically mimicking a BCC, which has been described in a small number of case reports and retrospective reviews. One study of 656 patients diagnosed with BCC based on clinical features revealed that 48 of these lesions were proven to be a BCC-mimicking lesion and only 1 was an angiosarcoma.¹ Cutaneous lesions that appear on physical examination to be a highly curable BCC may not induce the same urgency for treatment as an angiosarcoma. Although the clinical presentation may mimic a morpheaform BCC, our case demonstrates that it is imperative to include angiosarcoma in the differential diagnosis and underscores the utility of tissue sampling. Angiosarcoma has a poor overall 5-year survival rate, and patients often are found to have multiple metastatic lesions at diagnosis. However, diagnosis prior to metastasis may improve prognosis.⁸

Our patient’s angiosarcoma did not exhibit metastasis at the time of diagnosis, and he was able to achieve a favorable outcome. However, the 5-year survival rate is only 40%, and close clinical monitoring after diagnosis is required.⁸ Including angiosarcoma in the differential diagnosis for our patient, particularly upon lesion appearance 2 years prior, may have resulted in diagnosis antecedent to local invasion, possibly providing more treatment options. Employing a higher index of clinical suspicion for angiosarcoma may lead to decreased mortality in other patients due to increased detection.

To the Editor:

Basal cell carcinoma (BCC) is the most common of the nonmelanoma skin cancers and is a highly curable skin growth.^1,2 Conversely, angiosarcomas are aggressive vascular tumors of endothelial origin that classically appear as reddish purple patches or plaques that exhibit rapid growth and invasion.³ Sporadic cutaneous angiosarcomas are the most common type of this soft tissue tumor, occurring most often in the head and neck regions in men older than 70 years.^4,5 Other types of angiosarcomas include those associated with radiation therapy and chronic lymphedema. Postradiation angiosarcomas have been most frequently reported after treatment of breast cancer and appear as infiltrative plaques over the irradiated area.^4,5 Patients with chronic lymphedema, which most commonly is related to axillary lymph node dissection for breast cancer (90% of cases), may develop angiosarcoma presenting as a violaceous indurated plaque.⁵ Although angiosarcomas most often are seen with these distinct clinical characteristics, especially their violaceous color, they have been shown to mimic a few other skin disorders such as eczema and keratoacanthoma, but a limited number of cases of angiosarcoma mimicking BCC have been reported.^1,6,7 We present a case of an elderly man with a unique presentation of a lesion that clinically appeared as a morpheaform BCC but was confirmed to be an angiosarcoma on histopathology.

A 75-year-old man was referred to our dermatology clinic for evaluation of a flesh-colored plaque on the face that initially had developed 2 years prior on the right central malar cheek. Computed tomography of the head and neck 1 year prior, which the patient reported was for workup of the lesion, was found to be negative; however, these medical records were not obtained for confirmation. The lesion had been stable in size and remained flesh colored until 6 months prior to the current presentation when it exhibited a rapid increase in size. An initial biopsy was performed 1 month prior to presentation by an outside dermatology office and had been read as an angiosarcoma.

Physical examination revealed a 6-cm, flesh-colored, indurated, ill-defined plaque distributed on the right malar cheek below the eye and extending to the nasal bridge (Figure 1). There was no cervical or facial lymphadenopathy. The clinical features resembled a morpheaform BCC, and the lesion did not exhibit any reddish or purple color indicating it was of vascular origin. However, due to the prior histopathology report and recent rapid enlargement, a repeat sampling with a larger punch biopsy was performed, which confirmed the diagnosis of angiosarcoma. Histopathology demonstrated multiple atypical vascular channels lined by hyperchromatic cells extending from the upper dermis to the base of the biopsy site (Figure 2). Large, oval, atypical nuclei were present in multiple endothelial cells in the vascular channels, with some forming irregularly contoured and slitlike formations (Figure 3). Immunochemical staining was intensely and uniformly positive for CD31 and CD34, both endothelial markers. Diffuse positive staining with CD31 is considered to have high sensitivity and specificity for the diagnosis of angiosarcoma.⁴ Other pertinent staining demonstrated 2+ positivity for factor VIII and 1+ positivity for D2-40; CD45, AE1/AE3, S-100, and human herpesvirus 8 were negative, consistent with angiosarcoma. The patient was referred to radiation oncology and otolaryngology at our Multidisciplinary Head and Neck Oncology Center for further investigation of the extent of the disease and discussion of treatment. Computed tomography of the head and neck region at this time showed extensive disease extending into the medial canthal area without metastasis. Due to the extent of disease and facial location, he was not deemed a candidate for surgery. He was treated with 6 weeks of targeted radiation therapy with concurrent chemotherapy. He tolerated this treatment with minimal side effects and was found to be free from clinical disease 1 year after diagnosis. He was followed for 20 months by our Multidisciplinary Oncology Clinic without recurrence of his disease but was then lost to follow-up.

This case illustrates a rare presentation of an angiosarcoma clinically mimicking a BCC, which has been described in a small number of case reports and retrospective reviews. One study of 656 patients diagnosed with BCC based on clinical features revealed that 48 of these lesions were proven to be a BCC-mimicking lesion and only 1 was an angiosarcoma.¹ Cutaneous lesions that appear on physical examination to be a highly curable BCC may not induce the same urgency for treatment as an angiosarcoma. Although the clinical presentation may mimic a morpheaform BCC, our case demonstrates that it is imperative to include angiosarcoma in the differential diagnosis and underscores the utility of tissue sampling. Angiosarcoma has a poor overall 5-year survival rate, and patients often are found to have multiple metastatic lesions at diagnosis. However, diagnosis prior to metastasis may improve prognosis.⁸

Our patient’s angiosarcoma did not exhibit metastasis at the time of diagnosis, and he was able to achieve a favorable outcome. However, the 5-year survival rate is only 40%, and close clinical monitoring after diagnosis is required.⁸ Including angiosarcoma in the differential diagnosis for our patient, particularly upon lesion appearance 2 years prior, may have resulted in diagnosis antecedent to local invasion, possibly providing more treatment options. Employing a higher index of clinical suspicion for angiosarcoma may lead to decreased mortality in other patients due to increased detection.

To the Editor:

Basal cell carcinoma (BCC) is the most common of the nonmelanoma skin cancers and is a highly curable skin growth.^1,2 Conversely, angiosarcomas are aggressive vascular tumors of endothelial origin that classically appear as reddish purple patches or plaques that exhibit rapid growth and invasion.³ Sporadic cutaneous angiosarcomas are the most common type of this soft tissue tumor, occurring most often in the head and neck regions in men older than 70 years.^4,5 Other types of angiosarcomas include those associated with radiation therapy and chronic lymphedema. Postradiation angiosarcomas have been most frequently reported after treatment of breast cancer and appear as infiltrative plaques over the irradiated area.^4,5 Patients with chronic lymphedema, which most commonly is related to axillary lymph node dissection for breast cancer (90% of cases), may develop angiosarcoma presenting as a violaceous indurated plaque.⁵ Although angiosarcomas most often are seen with these distinct clinical characteristics, especially their violaceous color, they have been shown to mimic a few other skin disorders such as eczema and keratoacanthoma, but a limited number of cases of angiosarcoma mimicking BCC have been reported.^1,6,7 We present a case of an elderly man with a unique presentation of a lesion that clinically appeared as a morpheaform BCC but was confirmed to be an angiosarcoma on histopathology.

A 75-year-old man was referred to our dermatology clinic for evaluation of a flesh-colored plaque on the face that initially had developed 2 years prior on the right central malar cheek. Computed tomography of the head and neck 1 year prior, which the patient reported was for workup of the lesion, was found to be negative; however, these medical records were not obtained for confirmation. The lesion had been stable in size and remained flesh colored until 6 months prior to the current presentation when it exhibited a rapid increase in size. An initial biopsy was performed 1 month prior to presentation by an outside dermatology office and had been read as an angiosarcoma.

Physical examination revealed a 6-cm, flesh-colored, indurated, ill-defined plaque distributed on the right malar cheek below the eye and extending to the nasal bridge (Figure 1). There was no cervical or facial lymphadenopathy. The clinical features resembled a morpheaform BCC, and the lesion did not exhibit any reddish or purple color indicating it was of vascular origin. However, due to the prior histopathology report and recent rapid enlargement, a repeat sampling with a larger punch biopsy was performed, which confirmed the diagnosis of angiosarcoma. Histopathology demonstrated multiple atypical vascular channels lined by hyperchromatic cells extending from the upper dermis to the base of the biopsy site (Figure 2). Large, oval, atypical nuclei were present in multiple endothelial cells in the vascular channels, with some forming irregularly contoured and slitlike formations (Figure 3). Immunochemical staining was intensely and uniformly positive for CD31 and CD34, both endothelial markers. Diffuse positive staining with CD31 is considered to have high sensitivity and specificity for the diagnosis of angiosarcoma.⁴ Other pertinent staining demonstrated 2+ positivity for factor VIII and 1+ positivity for D2-40; CD45, AE1/AE3, S-100, and human herpesvirus 8 were negative, consistent with angiosarcoma. The patient was referred to radiation oncology and otolaryngology at our Multidisciplinary Head and Neck Oncology Center for further investigation of the extent of the disease and discussion of treatment. Computed tomography of the head and neck region at this time showed extensive disease extending into the medial canthal area without metastasis. Due to the extent of disease and facial location, he was not deemed a candidate for surgery. He was treated with 6 weeks of targeted radiation therapy with concurrent chemotherapy. He tolerated this treatment with minimal side effects and was found to be free from clinical disease 1 year after diagnosis. He was followed for 20 months by our Multidisciplinary Oncology Clinic without recurrence of his disease but was then lost to follow-up.

This case illustrates a rare presentation of an angiosarcoma clinically mimicking a BCC, which has been described in a small number of case reports and retrospective reviews. One study of 656 patients diagnosed with BCC based on clinical features revealed that 48 of these lesions were proven to be a BCC-mimicking lesion and only 1 was an angiosarcoma.¹ Cutaneous lesions that appear on physical examination to be a highly curable BCC may not induce the same urgency for treatment as an angiosarcoma. Although the clinical presentation may mimic a morpheaform BCC, our case demonstrates that it is imperative to include angiosarcoma in the differential diagnosis and underscores the utility of tissue sampling. Angiosarcoma has a poor overall 5-year survival rate, and patients often are found to have multiple metastatic lesions at diagnosis. However, diagnosis prior to metastasis may improve prognosis.⁸

Our patient’s angiosarcoma did not exhibit metastasis at the time of diagnosis, and he was able to achieve a favorable outcome. However, the 5-year survival rate is only 40%, and close clinical monitoring after diagnosis is required.⁸ Including angiosarcoma in the differential diagnosis for our patient, particularly upon lesion appearance 2 years prior, may have resulted in diagnosis antecedent to local invasion, possibly providing more treatment options. Employing a higher index of clinical suspicion for angiosarcoma may lead to decreased mortality in other patients due to increased detection.

To the Editor:

Cutaneous collagenous vasculopathy (CCV) is a rare idiopathic microangiopathy characterized by diffuse blanchable telangiectases that usually develop in late adulthood. It appears morphologically identical to generalized essential telangiectasia (GET), but skin biopsy characteristically shows dilated superficial blood vessels in the papillary dermis that are surrounded by a thickened layer of type IV collagen.¹ We report a case of CCV occurring in an elderly white man.

A 72-year-old man presented with an asymptomatic rash on the arms, legs, and abdomen of 3 years’ duration. His medical history was remarkable for hypothyroidism, hypertension, reflex sympathetic dystrophy syndrome, coronary artery disease, and nonmelanoma skin cancer. He denied any changes in medications or illnesses prior to onset of the rash. Physical examination revealed diffuse, erythematous, blanchable telangiectases on the arms, legs, and trunk (Figure 1). No petechiae, atrophy, or epidermal changes were appreciated. Darier sign was negative.

Skin biopsy is essential to differentiate CCV from GET, which appears morphologically identical. Cutaneous collagenous vasculopathy may be underreported as a result of clinician choice not to biopsy due to a presumptive diagnosis of GET.³ Successful treatment with a pulsed dye laser has been reported,⁷ though the extent of disease may make complete destruction of the lesions difficult to accomplish. Although it is theorized that CCV may be a marker for underlying systemic disease or even a genetic defect causing abnormal collagen deposition, its cause has yet to be ascertained.⁵ Previously reported patients have had a variety of comorbidities, including several cases of type 2 diabetes mellitus.⁶ Another patient was reported to have recently started treatment with an angiotensin receptor blocker prior to onset of CCV.⁵

Our case contributes to the small series of reported patients with this rare diagnosis and further suggests that it may be underreported at this time. Similar to previously reported cases, our patient was an elderly white individual. Although our patient had long-standing iatrogenic hypothyroidism, no recent medication changes or underlying comorbidities could be tied to the development of CCV. Further studies are needed to determine if this disease process is associated with any underlying systemic illnesses, medications, or family history.

To the Editor:

Cutaneous collagenous vasculopathy (CCV) is a rare idiopathic microangiopathy characterized by diffuse blanchable telangiectases that usually develop in late adulthood. It appears morphologically identical to generalized essential telangiectasia (GET), but skin biopsy characteristically shows dilated superficial blood vessels in the papillary dermis that are surrounded by a thickened layer of type IV collagen.¹ We report a case of CCV occurring in an elderly white man.

A 72-year-old man presented with an asymptomatic rash on the arms, legs, and abdomen of 3 years’ duration. His medical history was remarkable for hypothyroidism, hypertension, reflex sympathetic dystrophy syndrome, coronary artery disease, and nonmelanoma skin cancer. He denied any changes in medications or illnesses prior to onset of the rash. Physical examination revealed diffuse, erythematous, blanchable telangiectases on the arms, legs, and trunk (Figure 1). No petechiae, atrophy, or epidermal changes were appreciated. Darier sign was negative.

Skin biopsy is essential to differentiate CCV from GET, which appears morphologically identical. Cutaneous collagenous vasculopathy may be underreported as a result of clinician choice not to biopsy due to a presumptive diagnosis of GET.³ Successful treatment with a pulsed dye laser has been reported,⁷ though the extent of disease may make complete destruction of the lesions difficult to accomplish. Although it is theorized that CCV may be a marker for underlying systemic disease or even a genetic defect causing abnormal collagen deposition, its cause has yet to be ascertained.⁵ Previously reported patients have had a variety of comorbidities, including several cases of type 2 diabetes mellitus.⁶ Another patient was reported to have recently started treatment with an angiotensin receptor blocker prior to onset of CCV.⁵

Our case contributes to the small series of reported patients with this rare diagnosis and further suggests that it may be underreported at this time. Similar to previously reported cases, our patient was an elderly white individual. Although our patient had long-standing iatrogenic hypothyroidism, no recent medication changes or underlying comorbidities could be tied to the development of CCV. Further studies are needed to determine if this disease process is associated with any underlying systemic illnesses, medications, or family history.

To the Editor:

Cutaneous collagenous vasculopathy (CCV) is a rare idiopathic microangiopathy characterized by diffuse blanchable telangiectases that usually develop in late adulthood. It appears morphologically identical to generalized essential telangiectasia (GET), but skin biopsy characteristically shows dilated superficial blood vessels in the papillary dermis that are surrounded by a thickened layer of type IV collagen.¹ We report a case of CCV occurring in an elderly white man.

A 72-year-old man presented with an asymptomatic rash on the arms, legs, and abdomen of 3 years’ duration. His medical history was remarkable for hypothyroidism, hypertension, reflex sympathetic dystrophy syndrome, coronary artery disease, and nonmelanoma skin cancer. He denied any changes in medications or illnesses prior to onset of the rash. Physical examination revealed diffuse, erythematous, blanchable telangiectases on the arms, legs, and trunk (Figure 1). No petechiae, atrophy, or epidermal changes were appreciated. Darier sign was negative.

Skin biopsy is essential to differentiate CCV from GET, which appears morphologically identical. Cutaneous collagenous vasculopathy may be underreported as a result of clinician choice not to biopsy due to a presumptive diagnosis of GET.³ Successful treatment with a pulsed dye laser has been reported,⁷ though the extent of disease may make complete destruction of the lesions difficult to accomplish. Although it is theorized that CCV may be a marker for underlying systemic disease or even a genetic defect causing abnormal collagen deposition, its cause has yet to be ascertained.⁵ Previously reported patients have had a variety of comorbidities, including several cases of type 2 diabetes mellitus.⁶ Another patient was reported to have recently started treatment with an angiotensin receptor blocker prior to onset of CCV.⁵

Our case contributes to the small series of reported patients with this rare diagnosis and further suggests that it may be underreported at this time. Similar to previously reported cases, our patient was an elderly white individual. Although our patient had long-standing iatrogenic hypothyroidism, no recent medication changes or underlying comorbidities could be tied to the development of CCV. Further studies are needed to determine if this disease process is associated with any underlying systemic illnesses, medications, or family history.