Case Letter

To the Editor:

A 58-year-old woman presented to our dermatology clinic with a pruritic weeping eruption circumferentially on the distal digits of both hands of 5 weeks’ duration. The patient disclosed that she had been receiving dip powder manicures at a local nail salon approximately every 2 weeks over the last 3 to 6 months. She had received frequent acrylic nail extensions over the last 8 years prior to starting the dip powder manicures. Physical examination revealed well-demarcated eczematous plaques involving the lateral and proximal nail folds of the right thumb with an overlying serous crust and loss of the cuticle (Figure 1A). Erythematous plaques with firm deep-seated microvesicles also were present on the other digits, distributed distal to the distal interphalangeal joints (Figure 1B). She was diagnosed with dyshidroticlike contact dermatitis and paronychia. Treatment included phenol 1.5% colorless solution and clobetasol ointment 0.05% for twice-daily application to the affected areas. The patient also was advised to stop receiving manicures. At 1-month follow-up, the paronychia had resolved and the dermatitis had nearly resolved.

Dip powder manicures use a wet adhesive base coat with acrylic powder and an activator topcoat to initiate a chemical reaction that hardens and sets the nail polish. The colored powder typically is applied by dipping the digit up to the distal interphalangeal joint into a small container of loose powder and then brushing away the excess (Figure 2). Acrylate, a chemical present in dip powders, is a known allergen and has been associated with the development of allergic contact dermatitis and onychodystrophy in patients after receiving acrylic and UV-cured gel polish manicures.^1,2 Inadequate sanitation practices at nail salons also have been associated with infection transmission.^3,4 Additionally, the news media has covered the potential risk of infection due to contamination from reused dip manicure powder and the use of communal powder containers.⁵

To increase clinical awareness of the dip manicure technique, we describe the presentation and successful treatment of dyshidroticlike contact dermatitis and paronychia that occurred in a patient after she received a dip powder manicure. Dermatoses and infection limited to the distal phalanges will present in patients more frequently as dip powder manicures continue to increase in popularity and frequency.

To the Editor:

A 58-year-old woman presented to our dermatology clinic with a pruritic weeping eruption circumferentially on the distal digits of both hands of 5 weeks’ duration. The patient disclosed that she had been receiving dip powder manicures at a local nail salon approximately every 2 weeks over the last 3 to 6 months. She had received frequent acrylic nail extensions over the last 8 years prior to starting the dip powder manicures. Physical examination revealed well-demarcated eczematous plaques involving the lateral and proximal nail folds of the right thumb with an overlying serous crust and loss of the cuticle (Figure 1A). Erythematous plaques with firm deep-seated microvesicles also were present on the other digits, distributed distal to the distal interphalangeal joints (Figure 1B). She was diagnosed with dyshidroticlike contact dermatitis and paronychia. Treatment included phenol 1.5% colorless solution and clobetasol ointment 0.05% for twice-daily application to the affected areas. The patient also was advised to stop receiving manicures. At 1-month follow-up, the paronychia had resolved and the dermatitis had nearly resolved.

Dip powder manicures use a wet adhesive base coat with acrylic powder and an activator topcoat to initiate a chemical reaction that hardens and sets the nail polish. The colored powder typically is applied by dipping the digit up to the distal interphalangeal joint into a small container of loose powder and then brushing away the excess (Figure 2). Acrylate, a chemical present in dip powders, is a known allergen and has been associated with the development of allergic contact dermatitis and onychodystrophy in patients after receiving acrylic and UV-cured gel polish manicures.^1,2 Inadequate sanitation practices at nail salons also have been associated with infection transmission.^3,4 Additionally, the news media has covered the potential risk of infection due to contamination from reused dip manicure powder and the use of communal powder containers.⁵

To increase clinical awareness of the dip manicure technique, we describe the presentation and successful treatment of dyshidroticlike contact dermatitis and paronychia that occurred in a patient after she received a dip powder manicure. Dermatoses and infection limited to the distal phalanges will present in patients more frequently as dip powder manicures continue to increase in popularity and frequency.

To the Editor:

A 58-year-old woman presented to our dermatology clinic with a pruritic weeping eruption circumferentially on the distal digits of both hands of 5 weeks’ duration. The patient disclosed that she had been receiving dip powder manicures at a local nail salon approximately every 2 weeks over the last 3 to 6 months. She had received frequent acrylic nail extensions over the last 8 years prior to starting the dip powder manicures. Physical examination revealed well-demarcated eczematous plaques involving the lateral and proximal nail folds of the right thumb with an overlying serous crust and loss of the cuticle (Figure 1A). Erythematous plaques with firm deep-seated microvesicles also were present on the other digits, distributed distal to the distal interphalangeal joints (Figure 1B). She was diagnosed with dyshidroticlike contact dermatitis and paronychia. Treatment included phenol 1.5% colorless solution and clobetasol ointment 0.05% for twice-daily application to the affected areas. The patient also was advised to stop receiving manicures. At 1-month follow-up, the paronychia had resolved and the dermatitis had nearly resolved.

Dip powder manicures use a wet adhesive base coat with acrylic powder and an activator topcoat to initiate a chemical reaction that hardens and sets the nail polish. The colored powder typically is applied by dipping the digit up to the distal interphalangeal joint into a small container of loose powder and then brushing away the excess (Figure 2). Acrylate, a chemical present in dip powders, is a known allergen and has been associated with the development of allergic contact dermatitis and onychodystrophy in patients after receiving acrylic and UV-cured gel polish manicures.^1,2 Inadequate sanitation practices at nail salons also have been associated with infection transmission.^3,4 Additionally, the news media has covered the potential risk of infection due to contamination from reused dip manicure powder and the use of communal powder containers.⁵

To increase clinical awareness of the dip manicure technique, we describe the presentation and successful treatment of dyshidroticlike contact dermatitis and paronychia that occurred in a patient after she received a dip powder manicure. Dermatoses and infection limited to the distal phalanges will present in patients more frequently as dip powder manicures continue to increase in popularity and frequency.

Scabies is caused by cutaneous ectoparasitic infection by the mite Sarcoptes scabiei var hominis. The infection is highly contagious via direct skin-to-skin contact or indirectly through infested bedding, clothing or fomites.^1,2 Scabies occurs at all ages, in all ethnic groups, and at all socioeconomic levels.¹ Analysis by the Global Burden of Disease estimates that 200 million individuals have been infected with scabies worldwide. The World Health Organization has declared scabies a neglected tropical disease.³

Crusted scabies is a severe and rare form of scabies, with hyperinfestation of thousands to millions of mites, and more commonly is associated with immunosuppressed states, including HIV and hematologic malignancies.^1,2,4 Crusted scabies has a high mortality rate due to sepsis when left untreated.^3,5

Occasionally, iatrogenic immunosuppression contributes to the development of crusted scabies.^1,2 Iatrogenic immunosuppression leading to crusted scabies most commonly occurs secondary to immunosuppression after bone marrow or solid organ transplantation.⁶ Less often, crusted scabies is caused by iatrogenic immunosuppression from other clinical scenarios.^1,2

We describe a patient with iatrogenic immunosuppression due to azathioprine-induced myelosuppression for the treatment of granulomatosis with polyangiitis (GPA) who developed crusted scabies that clinically presented as erythroderma. Crusted scabies should be included in the differential diagnosis of erythroderma, especially in the setting of iatrogenic immunosuppression, for timely and appropriate management.

Case Report

An 84-year-old man presented with worsening pruritus, erythema, and thick yellow scale that progressed to erythroderma over the last 2 weeks. He was diagnosed with GPA 6 months prior to presentation and was treated with azathioprine 150 mg/d, prednisone 10 mg/d, and sulfamethoxazole 800 mg plus trimethoprim 160 mg twice weekly for prophylaxis against Pneumocystis jirovecii pneumonia.

Three weeks prior to presentation, the patient was hospitalized for pancytopenia attributed to azathioprine-induced myelosuppression (hemoglobin, 6.1 g/dL [reference range, 13.5–18.0 g/dL]; hematocrit, 17.5% [reference range, 42%–52%]; white blood cell count, 1.66×10³/μL [reference range, 4.0–10.5×10³/μL]; platelet count, 146×10³/μL [reference range, 150–450×10³/μL]; absolute neutrophil count, 1.29×10³/μL [reference range, 1.4–6.5×10³/μL]). He was transferred to a skilled nursing facility after discharge and referred to dermatology for evaluation of the worsening pruritic rash.

At the current presentation, the patient denied close contact with anyone who had a similar rash at home or at the skilled nursing facility. Physical examination revealed diffuse erythroderma with yellow scale on the scalp, trunk, arms, and legs (Figure 1). The palms showed scattered 2- to 3-mm pustules. The mucosal surfaces did not have lesions. A punch biopsy of a pustule from the right arm revealed focal spongiosis, parakeratosis, and acanthosis, as well as a perivascular and interstitial mixed inflammatory infiltrate with lymphocytes and eosinophils. Organisms morphologically compatible with scabies were found in the stratum corneum (Figure 2). Another punch biopsy of a pustule from the right arm was performed for direct immunofluorescence (DIF) and was negative for immunoglobulin deposition. Mineral oil preparation from pustules on the palm was positive for mites.

The patient was treated with permethrin cream 5% and oral ivermectin 200 μg/kg on day 1 and day 10. The prednisone dosage was increased from 10 mg/d to 50 mg/d and tapered over 2 weeks to treat the symptomatic rash and GPA. He remains on maintenance rituximab for GPA, without recurrence of scabies.

Comment

Pathogenesis—As an obligate parasite, S scabiei spends its entire life cycle within the host. Impregnated female mites burrow into the epidermis after mating and lay eggs daily for 1 to 2 months. Eggs hatch 2 or 3 days later. Larvae then migrate to the skin surface; burrow into the stratum corneum, where they mature into adults; and then mate on the skin surface.^1,4

Clinical Presentation and Sequelae—Typically, scabies presents 2 to 6 weeks after initial exposure with generalized and intense itching and inflammatory pruritic papules on the finger webs, wrists, elbows, axillae, buttocks, umbilicus, genitalia, and areolae.¹ Burrows are specific for scabies but may not always be present. Often, there are nonspecific secondary lesions, including excoriations, dermatitis, and impetiginization.

Complications of scabies can be severe, with initial colonization and infection of the skin resulting in impetigo and cellulitis. Systematic sequelae from local skin infection include post-streptococcal glomerulonephritis, rheumatic fever, and sepsis. Mortality from sepsis in scabies can be high.^3,5

Classic Crusted Scabies and Other Variants—Crusted scabies presents with psoriasiform hyperkeratotic plaques involving the hands and feet with potential nail involvement that can become more generalized.¹ Alterations in CD4⁺ T-cell function have been implicated in the development of crusted scabies, in which an excessive helper T cell (T_H2) response is elicited against the ectoparasite, which may help explain the intense pruritus of scabies.⁶ Occasionally, iatrogenic immunosuppression contributes to development of crusted scabies,¹ as was the case with our patient. However, it is rare for crusted scabies to present with erythroderma.⁷

Other atypical presentations of scabies include a seborrheic dermatitis–like presentation in infants, nodular lesions in the groin and axillae in more chronic scabies, and vesicles or bullous lesions.¹

Diagnosis—Identification of mites, eggs, or feces is necessary for definitive diagnosis of scabies.⁸ These materials can be obtained through skin scrapings with mineral oil and observed under light microscopy or direct dermoscopy. Multiple scrapings on many lesions should be performed because failure to identify mites can be common and does not rule out scabies. Dermoscopic examination of active lesions under low power also can be helpful, given that identification of dark brown triangular structures can correspond to visualization of the pigmented anterior section of the mite.^9-11 A skin biopsy can help identify mites, but histopathology often shows a nonspecific hypersensitivity reaction.¹² Therefore, empiric treatment often is necessary.

Differential Diagnosis—The differential diagnosis of erythroderma is broad and includes a drug eruption; Sézary syndrome; and pre-existing skin diseases, including psoriasis, atopic dermatitis, pityriasis rubra pilaris, pemphigus foliaceus, and bullous pemphigoid. Histopathology is critical to differentiate these diagnoses. Bullous pemphigoid and pemphigus foliaceus are immunobullous diseases that typically are positive for immunoglobulin deposition on DIF. In rare cases, scabies also can present with bullae and positive DIF test results.¹³

Treatment—First-line treatment of crusted scabies in the United States is permethrin cream 5%, followed by oral ivermectin 200 μg/kg.^4,5,14,15 Other scabicides include topicals such as benzyl benzoate 10% to 25%; precipitated sulfur 2% to 10%; crotamiton 10%; malathion 0.5%; and lindane 1%.⁵ The association of neurotoxicity with lindane has considerably reduced the drug’s use.¹

During treatment of scabies, it is important to isolate patients to mitigate the possibility of spread.⁴ Pruritus can persist for a few weeks after completion of therapy.⁵ Patients should be closely monitored to ensure that this symptom is secondary to skin inflammation and not incomplete treatment.

Treatment of crusted scabies may require repeated treatments to decrease the notable mite burden as well as the associated crusting and scale. Adding a keratolytic such as 5% to 10% salicylic acid in petrolatum to the treatment regimen may be useful for breaking up thick scale.⁵

Immunosuppression—With numerous immunomodulatory drugs for treating autoimmunity comes an increased risk for iatrogenic immunosuppression that may contribute to the development of crusted scabies.¹⁶ In a number of autoimmune diseases such as rheumatoid arthritis,^17-19 psoriasis,^20,21 pemphigus vulgaris,²² systemic lupus erythematosus,²³ systemic sclerosis,^22,24 bullous pemphigoid,^25,26 and dermatomyositis,²⁷ patients have developed crusted scabies secondary to treatment-related immunosuppression. These immunosuppressive therapies include systemic steroids,^22-24,26-31 methotrexate,²³ infliximab,¹⁸ adalimumab,²¹ toclizumab,¹⁹ and etanercept.²⁰ In a case of drug-induced Stevens-Johnson syndrome, the patient developed crusted scabies during long-term use of oral steroids.²²

Patients with a malignancy who are being treated with chemotherapy also can develop crusted scabies.²⁸ Crusted scabies has even been associated with long-term topical steroid^32-34 and topical calcineurin inhibitor use.¹⁶

Iatrogenic immunosuppression in our patient resulted from treatment of GPA with azathioprine, an immunosuppressive drug that acts as an antagonist of the breakdown of purines, leading to inhibition of DNA, RNA, and protein synthesis.³⁵ On occasion, azathioprine can induce immunosuppression in the form of myelosuppression and resulting pancytopenia, as was the case with our patient.

Conclusion

Although scabies is designated as a neglected tropical disease by the World Health Organization, it still causes a notable burden worldwide, regardless of the economics. Our case highlights an unusual presentation of scabies as erythroderma in the setting of iatrogenic immunosuppression from azathioprine use. Dermatologists should consider crusted scabies in the differential diagnosis of erythroderma, especially in immunocompromised patients, to avoid delays in diagnosis and treatment. Immunosuppressive therapy is an important mainstay in the treatment of many conditions, but it is important to consider that these medications can place patients at an increased risk for rare opportunistic infections. Therefore, patients receiving such treatment should be closely monitored.

Scabies is caused by cutaneous ectoparasitic infection by the mite Sarcoptes scabiei var hominis. The infection is highly contagious via direct skin-to-skin contact or indirectly through infested bedding, clothing or fomites.^1,2 Scabies occurs at all ages, in all ethnic groups, and at all socioeconomic levels.¹ Analysis by the Global Burden of Disease estimates that 200 million individuals have been infected with scabies worldwide. The World Health Organization has declared scabies a neglected tropical disease.³

Crusted scabies is a severe and rare form of scabies, with hyperinfestation of thousands to millions of mites, and more commonly is associated with immunosuppressed states, including HIV and hematologic malignancies.^1,2,4 Crusted scabies has a high mortality rate due to sepsis when left untreated.^3,5

Occasionally, iatrogenic immunosuppression contributes to the development of crusted scabies.^1,2 Iatrogenic immunosuppression leading to crusted scabies most commonly occurs secondary to immunosuppression after bone marrow or solid organ transplantation.⁶ Less often, crusted scabies is caused by iatrogenic immunosuppression from other clinical scenarios.^1,2

We describe a patient with iatrogenic immunosuppression due to azathioprine-induced myelosuppression for the treatment of granulomatosis with polyangiitis (GPA) who developed crusted scabies that clinically presented as erythroderma. Crusted scabies should be included in the differential diagnosis of erythroderma, especially in the setting of iatrogenic immunosuppression, for timely and appropriate management.

Case Report

An 84-year-old man presented with worsening pruritus, erythema, and thick yellow scale that progressed to erythroderma over the last 2 weeks. He was diagnosed with GPA 6 months prior to presentation and was treated with azathioprine 150 mg/d, prednisone 10 mg/d, and sulfamethoxazole 800 mg plus trimethoprim 160 mg twice weekly for prophylaxis against Pneumocystis jirovecii pneumonia.

Three weeks prior to presentation, the patient was hospitalized for pancytopenia attributed to azathioprine-induced myelosuppression (hemoglobin, 6.1 g/dL [reference range, 13.5–18.0 g/dL]; hematocrit, 17.5% [reference range, 42%–52%]; white blood cell count, 1.66×10³/μL [reference range, 4.0–10.5×10³/μL]; platelet count, 146×10³/μL [reference range, 150–450×10³/μL]; absolute neutrophil count, 1.29×10³/μL [reference range, 1.4–6.5×10³/μL]). He was transferred to a skilled nursing facility after discharge and referred to dermatology for evaluation of the worsening pruritic rash.

At the current presentation, the patient denied close contact with anyone who had a similar rash at home or at the skilled nursing facility. Physical examination revealed diffuse erythroderma with yellow scale on the scalp, trunk, arms, and legs (Figure 1). The palms showed scattered 2- to 3-mm pustules. The mucosal surfaces did not have lesions. A punch biopsy of a pustule from the right arm revealed focal spongiosis, parakeratosis, and acanthosis, as well as a perivascular and interstitial mixed inflammatory infiltrate with lymphocytes and eosinophils. Organisms morphologically compatible with scabies were found in the stratum corneum (Figure 2). Another punch biopsy of a pustule from the right arm was performed for direct immunofluorescence (DIF) and was negative for immunoglobulin deposition. Mineral oil preparation from pustules on the palm was positive for mites.

The patient was treated with permethrin cream 5% and oral ivermectin 200 μg/kg on day 1 and day 10. The prednisone dosage was increased from 10 mg/d to 50 mg/d and tapered over 2 weeks to treat the symptomatic rash and GPA. He remains on maintenance rituximab for GPA, without recurrence of scabies.

Comment

Pathogenesis—As an obligate parasite, S scabiei spends its entire life cycle within the host. Impregnated female mites burrow into the epidermis after mating and lay eggs daily for 1 to 2 months. Eggs hatch 2 or 3 days later. Larvae then migrate to the skin surface; burrow into the stratum corneum, where they mature into adults; and then mate on the skin surface.^1,4

Clinical Presentation and Sequelae—Typically, scabies presents 2 to 6 weeks after initial exposure with generalized and intense itching and inflammatory pruritic papules on the finger webs, wrists, elbows, axillae, buttocks, umbilicus, genitalia, and areolae.¹ Burrows are specific for scabies but may not always be present. Often, there are nonspecific secondary lesions, including excoriations, dermatitis, and impetiginization.

Complications of scabies can be severe, with initial colonization and infection of the skin resulting in impetigo and cellulitis. Systematic sequelae from local skin infection include post-streptococcal glomerulonephritis, rheumatic fever, and sepsis. Mortality from sepsis in scabies can be high.^3,5

Classic Crusted Scabies and Other Variants—Crusted scabies presents with psoriasiform hyperkeratotic plaques involving the hands and feet with potential nail involvement that can become more generalized.¹ Alterations in CD4⁺ T-cell function have been implicated in the development of crusted scabies, in which an excessive helper T cell (T_H2) response is elicited against the ectoparasite, which may help explain the intense pruritus of scabies.⁶ Occasionally, iatrogenic immunosuppression contributes to development of crusted scabies,¹ as was the case with our patient. However, it is rare for crusted scabies to present with erythroderma.⁷

Other atypical presentations of scabies include a seborrheic dermatitis–like presentation in infants, nodular lesions in the groin and axillae in more chronic scabies, and vesicles or bullous lesions.¹

Diagnosis—Identification of mites, eggs, or feces is necessary for definitive diagnosis of scabies.⁸ These materials can be obtained through skin scrapings with mineral oil and observed under light microscopy or direct dermoscopy. Multiple scrapings on many lesions should be performed because failure to identify mites can be common and does not rule out scabies. Dermoscopic examination of active lesions under low power also can be helpful, given that identification of dark brown triangular structures can correspond to visualization of the pigmented anterior section of the mite.^9-11 A skin biopsy can help identify mites, but histopathology often shows a nonspecific hypersensitivity reaction.¹² Therefore, empiric treatment often is necessary.

Differential Diagnosis—The differential diagnosis of erythroderma is broad and includes a drug eruption; Sézary syndrome; and pre-existing skin diseases, including psoriasis, atopic dermatitis, pityriasis rubra pilaris, pemphigus foliaceus, and bullous pemphigoid. Histopathology is critical to differentiate these diagnoses. Bullous pemphigoid and pemphigus foliaceus are immunobullous diseases that typically are positive for immunoglobulin deposition on DIF. In rare cases, scabies also can present with bullae and positive DIF test results.¹³

Treatment—First-line treatment of crusted scabies in the United States is permethrin cream 5%, followed by oral ivermectin 200 μg/kg.^4,5,14,15 Other scabicides include topicals such as benzyl benzoate 10% to 25%; precipitated sulfur 2% to 10%; crotamiton 10%; malathion 0.5%; and lindane 1%.⁵ The association of neurotoxicity with lindane has considerably reduced the drug’s use.¹

During treatment of scabies, it is important to isolate patients to mitigate the possibility of spread.⁴ Pruritus can persist for a few weeks after completion of therapy.⁵ Patients should be closely monitored to ensure that this symptom is secondary to skin inflammation and not incomplete treatment.

Treatment of crusted scabies may require repeated treatments to decrease the notable mite burden as well as the associated crusting and scale. Adding a keratolytic such as 5% to 10% salicylic acid in petrolatum to the treatment regimen may be useful for breaking up thick scale.⁵

Immunosuppression—With numerous immunomodulatory drugs for treating autoimmunity comes an increased risk for iatrogenic immunosuppression that may contribute to the development of crusted scabies.¹⁶ In a number of autoimmune diseases such as rheumatoid arthritis,^17-19 psoriasis,^20,21 pemphigus vulgaris,²² systemic lupus erythematosus,²³ systemic sclerosis,^22,24 bullous pemphigoid,^25,26 and dermatomyositis,²⁷ patients have developed crusted scabies secondary to treatment-related immunosuppression. These immunosuppressive therapies include systemic steroids,^22-24,26-31 methotrexate,²³ infliximab,¹⁸ adalimumab,²¹ toclizumab,¹⁹ and etanercept.²⁰ In a case of drug-induced Stevens-Johnson syndrome, the patient developed crusted scabies during long-term use of oral steroids.²²

Patients with a malignancy who are being treated with chemotherapy also can develop crusted scabies.²⁸ Crusted scabies has even been associated with long-term topical steroid^32-34 and topical calcineurin inhibitor use.¹⁶

Iatrogenic immunosuppression in our patient resulted from treatment of GPA with azathioprine, an immunosuppressive drug that acts as an antagonist of the breakdown of purines, leading to inhibition of DNA, RNA, and protein synthesis.³⁵ On occasion, azathioprine can induce immunosuppression in the form of myelosuppression and resulting pancytopenia, as was the case with our patient.

Conclusion

Although scabies is designated as a neglected tropical disease by the World Health Organization, it still causes a notable burden worldwide, regardless of the economics. Our case highlights an unusual presentation of scabies as erythroderma in the setting of iatrogenic immunosuppression from azathioprine use. Dermatologists should consider crusted scabies in the differential diagnosis of erythroderma, especially in immunocompromised patients, to avoid delays in diagnosis and treatment. Immunosuppressive therapy is an important mainstay in the treatment of many conditions, but it is important to consider that these medications can place patients at an increased risk for rare opportunistic infections. Therefore, patients receiving such treatment should be closely monitored.

Scabies is caused by cutaneous ectoparasitic infection by the mite Sarcoptes scabiei var hominis. The infection is highly contagious via direct skin-to-skin contact or indirectly through infested bedding, clothing or fomites.^1,2 Scabies occurs at all ages, in all ethnic groups, and at all socioeconomic levels.¹ Analysis by the Global Burden of Disease estimates that 200 million individuals have been infected with scabies worldwide. The World Health Organization has declared scabies a neglected tropical disease.³

Crusted scabies is a severe and rare form of scabies, with hyperinfestation of thousands to millions of mites, and more commonly is associated with immunosuppressed states, including HIV and hematologic malignancies.^1,2,4 Crusted scabies has a high mortality rate due to sepsis when left untreated.^3,5

Occasionally, iatrogenic immunosuppression contributes to the development of crusted scabies.^1,2 Iatrogenic immunosuppression leading to crusted scabies most commonly occurs secondary to immunosuppression after bone marrow or solid organ transplantation.⁶ Less often, crusted scabies is caused by iatrogenic immunosuppression from other clinical scenarios.^1,2

We describe a patient with iatrogenic immunosuppression due to azathioprine-induced myelosuppression for the treatment of granulomatosis with polyangiitis (GPA) who developed crusted scabies that clinically presented as erythroderma. Crusted scabies should be included in the differential diagnosis of erythroderma, especially in the setting of iatrogenic immunosuppression, for timely and appropriate management.

Case Report

An 84-year-old man presented with worsening pruritus, erythema, and thick yellow scale that progressed to erythroderma over the last 2 weeks. He was diagnosed with GPA 6 months prior to presentation and was treated with azathioprine 150 mg/d, prednisone 10 mg/d, and sulfamethoxazole 800 mg plus trimethoprim 160 mg twice weekly for prophylaxis against Pneumocystis jirovecii pneumonia.

Three weeks prior to presentation, the patient was hospitalized for pancytopenia attributed to azathioprine-induced myelosuppression (hemoglobin, 6.1 g/dL [reference range, 13.5–18.0 g/dL]; hematocrit, 17.5% [reference range, 42%–52%]; white blood cell count, 1.66×10³/μL [reference range, 4.0–10.5×10³/μL]; platelet count, 146×10³/μL [reference range, 150–450×10³/μL]; absolute neutrophil count, 1.29×10³/μL [reference range, 1.4–6.5×10³/μL]). He was transferred to a skilled nursing facility after discharge and referred to dermatology for evaluation of the worsening pruritic rash.

At the current presentation, the patient denied close contact with anyone who had a similar rash at home or at the skilled nursing facility. Physical examination revealed diffuse erythroderma with yellow scale on the scalp, trunk, arms, and legs (Figure 1). The palms showed scattered 2- to 3-mm pustules. The mucosal surfaces did not have lesions. A punch biopsy of a pustule from the right arm revealed focal spongiosis, parakeratosis, and acanthosis, as well as a perivascular and interstitial mixed inflammatory infiltrate with lymphocytes and eosinophils. Organisms morphologically compatible with scabies were found in the stratum corneum (Figure 2). Another punch biopsy of a pustule from the right arm was performed for direct immunofluorescence (DIF) and was negative for immunoglobulin deposition. Mineral oil preparation from pustules on the palm was positive for mites.

The patient was treated with permethrin cream 5% and oral ivermectin 200 μg/kg on day 1 and day 10. The prednisone dosage was increased from 10 mg/d to 50 mg/d and tapered over 2 weeks to treat the symptomatic rash and GPA. He remains on maintenance rituximab for GPA, without recurrence of scabies.

Comment

Pathogenesis—As an obligate parasite, S scabiei spends its entire life cycle within the host. Impregnated female mites burrow into the epidermis after mating and lay eggs daily for 1 to 2 months. Eggs hatch 2 or 3 days later. Larvae then migrate to the skin surface; burrow into the stratum corneum, where they mature into adults; and then mate on the skin surface.^1,4

Clinical Presentation and Sequelae—Typically, scabies presents 2 to 6 weeks after initial exposure with generalized and intense itching and inflammatory pruritic papules on the finger webs, wrists, elbows, axillae, buttocks, umbilicus, genitalia, and areolae.¹ Burrows are specific for scabies but may not always be present. Often, there are nonspecific secondary lesions, including excoriations, dermatitis, and impetiginization.

Complications of scabies can be severe, with initial colonization and infection of the skin resulting in impetigo and cellulitis. Systematic sequelae from local skin infection include post-streptococcal glomerulonephritis, rheumatic fever, and sepsis. Mortality from sepsis in scabies can be high.^3,5

Classic Crusted Scabies and Other Variants—Crusted scabies presents with psoriasiform hyperkeratotic plaques involving the hands and feet with potential nail involvement that can become more generalized.¹ Alterations in CD4⁺ T-cell function have been implicated in the development of crusted scabies, in which an excessive helper T cell (T_H2) response is elicited against the ectoparasite, which may help explain the intense pruritus of scabies.⁶ Occasionally, iatrogenic immunosuppression contributes to development of crusted scabies,¹ as was the case with our patient. However, it is rare for crusted scabies to present with erythroderma.⁷

Other atypical presentations of scabies include a seborrheic dermatitis–like presentation in infants, nodular lesions in the groin and axillae in more chronic scabies, and vesicles or bullous lesions.¹

Diagnosis—Identification of mites, eggs, or feces is necessary for definitive diagnosis of scabies.⁸ These materials can be obtained through skin scrapings with mineral oil and observed under light microscopy or direct dermoscopy. Multiple scrapings on many lesions should be performed because failure to identify mites can be common and does not rule out scabies. Dermoscopic examination of active lesions under low power also can be helpful, given that identification of dark brown triangular structures can correspond to visualization of the pigmented anterior section of the mite.^9-11 A skin biopsy can help identify mites, but histopathology often shows a nonspecific hypersensitivity reaction.¹² Therefore, empiric treatment often is necessary.

Differential Diagnosis—The differential diagnosis of erythroderma is broad and includes a drug eruption; Sézary syndrome; and pre-existing skin diseases, including psoriasis, atopic dermatitis, pityriasis rubra pilaris, pemphigus foliaceus, and bullous pemphigoid. Histopathology is critical to differentiate these diagnoses. Bullous pemphigoid and pemphigus foliaceus are immunobullous diseases that typically are positive for immunoglobulin deposition on DIF. In rare cases, scabies also can present with bullae and positive DIF test results.¹³

Treatment—First-line treatment of crusted scabies in the United States is permethrin cream 5%, followed by oral ivermectin 200 μg/kg.^4,5,14,15 Other scabicides include topicals such as benzyl benzoate 10% to 25%; precipitated sulfur 2% to 10%; crotamiton 10%; malathion 0.5%; and lindane 1%.⁵ The association of neurotoxicity with lindane has considerably reduced the drug’s use.¹

During treatment of scabies, it is important to isolate patients to mitigate the possibility of spread.⁴ Pruritus can persist for a few weeks after completion of therapy.⁵ Patients should be closely monitored to ensure that this symptom is secondary to skin inflammation and not incomplete treatment.

Treatment of crusted scabies may require repeated treatments to decrease the notable mite burden as well as the associated crusting and scale. Adding a keratolytic such as 5% to 10% salicylic acid in petrolatum to the treatment regimen may be useful for breaking up thick scale.⁵

Immunosuppression—With numerous immunomodulatory drugs for treating autoimmunity comes an increased risk for iatrogenic immunosuppression that may contribute to the development of crusted scabies.¹⁶ In a number of autoimmune diseases such as rheumatoid arthritis,^17-19 psoriasis,^20,21 pemphigus vulgaris,²² systemic lupus erythematosus,²³ systemic sclerosis,^22,24 bullous pemphigoid,^25,26 and dermatomyositis,²⁷ patients have developed crusted scabies secondary to treatment-related immunosuppression. These immunosuppressive therapies include systemic steroids,^22-24,26-31 methotrexate,²³ infliximab,¹⁸ adalimumab,²¹ toclizumab,¹⁹ and etanercept.²⁰ In a case of drug-induced Stevens-Johnson syndrome, the patient developed crusted scabies during long-term use of oral steroids.²²

Patients with a malignancy who are being treated with chemotherapy also can develop crusted scabies.²⁸ Crusted scabies has even been associated with long-term topical steroid^32-34 and topical calcineurin inhibitor use.¹⁶

Iatrogenic immunosuppression in our patient resulted from treatment of GPA with azathioprine, an immunosuppressive drug that acts as an antagonist of the breakdown of purines, leading to inhibition of DNA, RNA, and protein synthesis.³⁵ On occasion, azathioprine can induce immunosuppression in the form of myelosuppression and resulting pancytopenia, as was the case with our patient.

Conclusion

Although scabies is designated as a neglected tropical disease by the World Health Organization, it still causes a notable burden worldwide, regardless of the economics. Our case highlights an unusual presentation of scabies as erythroderma in the setting of iatrogenic immunosuppression from azathioprine use. Dermatologists should consider crusted scabies in the differential diagnosis of erythroderma, especially in immunocompromised patients, to avoid delays in diagnosis and treatment. Immunosuppressive therapy is an important mainstay in the treatment of many conditions, but it is important to consider that these medications can place patients at an increased risk for rare opportunistic infections. Therefore, patients receiving such treatment should be closely monitored.

To the Editor:

A 47-year-old man presented to the dermatology service with an asymptomatic plaque on the right thigh of 2 months’ duration. He had a medical history of HIV and Kaposi sarcoma as well as a recently relapsed primary effusion lymphoma (PEL) subsequent to an allogeneic bone marrow transplant. He initially was diagnosed with PEL 3 years prior to the current presentation during a workup for fever and weight loss. Imaging at the time demonstrated a bladder mass, which was biopsied and demonstrated PEL. Further imaging demonstrated both sinus and bone marrow involvement. Prior to dermatologic consultation, he had been treated with 6 cycles of etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (EPOCH); 6 cycles of brentuximab; 4 cycles of rituximab with gemcitabine and oxaliplatin; and 2 cycles of ifosfamide, carboplatin, and etoposide. Despite these therapies, he had 3 relapses, and oncology determined the need for a matched unrelated donor allogeneic stem cell transplant for his PEL.

At the time of dermatology consultation, the patient was being managed on daratumumab and bortezomib. Physical examination revealed an infiltrative plaque on the right inferomedial thigh measuring approximately 6.0 cm (largest dimension) with a small amount of peripheral scale (Figure 1). An ultrasound revealed notable subcutaneous tissue edema and increased vascularity without a discrete mass or fluid collection. A 4-mm punch biopsy demonstrated a dense infiltrate comprised of collections of histiocytes admixed with scattered plasma cells and mature lymphoid aggregates. Additionally, rare enlarged plasmablastic cells with scant basophilic cytoplasm and slightly irregular nuclear contours were visualized (Figure 2A). Immunohistochemistry was positive for CD3 with a normal CD4:CD8 ratio, CD68-highlighted histiocytes within the lymphoid aggregates, and human herpesvirus 8 (HHV-8)(or Kaposi sarcoma–associated herpesvirus) demonstrated stippled nuclear staining within the scattered large cells (Figure 2B). Epstein-Barr virus–encoded RNA staining was negative, though the area of interest was lost on deeper sectioning of the tissue block. The histopathologic findings were consistent with cutaneous extracavitary PEL. Shortly after this diagnosis, he died from disease complications.

Primary effusion lymphoma is an aggressive non-Hodgkin B-cell lymphoma that was first described by Knowles et al¹ in 1989. Primary effusion lymphoma occurs exclusively in the setting of HHV-8 infection and typically is associated with chronic immunosuppression related to HIV/AIDS. Cases that are negative for HIV-1 are rare but have been reported in organ transplant recipients and elderly men from areas with a high prevalence of HHV-8 infections. Most HIV-associated cases show concurrent Epstein-Barr virus infection, though the pathogenic meaning of this co-infection remains unclear.^2,3

Primary effusion lymphoma classically presents as an isolated effusion of malignant lymphoid cells within body cavities in the absence of solid tumor masses. The pleural, peritoneal, and pericardial spaces most commonly are involved. Extracavitary PEL, a rare variant, may present as a solid mass without effusion. In general, extracavitary tumors may occur in the setting of de novo malignancy or recurrent PEL.⁴ Cutaneous manifestations associated with extracavitary PEL are rare; 4 cases have been described in which skin lesions were the heralding sign of the disease.³ Interestingly, despite obligatory underlying HHV-8 infection, a review by Pielasinski et al³ noted only 2 patients with cutaneous PEL who had prior or concurrent Kaposi sarcoma. This heterogeneity in HHV-8–related phenotypes may be related to differences in microRNA expression, but further study is needed.⁵

The diagnosis of PEL relies on histologic, immunophenotypic, and molecular analysis of the affected tissue. The malignant cells typically are large with round to irregular nuclei. These cells may demonstrate a variety of appearances, including anaplastic, plasmablastic, and immunoblastic morphologies.^6,7 The immunophenotype displays CD45 positivity and markers of lymphocyte activation (CD30, CD38, CD71), while typical B-cell (CD19, CD20, CD79a) and T-cell (CD3, CD4, CD8) markers often are absent.^6-8 Human herpesvirus 8 detection by polymerase chain reaction testing of the peripheral blood or by immunohistochemistry staining of the affected tissue is required for diagnosis.^6,7 Epstein-Barr virus infection may be detected via in situ hybridization, though it is not required for diagnosis.

The overall prognosis for PEL is poor; Brimo et al⁶ reported a median survival of less than 6 months, and Guillet et al⁹ reported 5-year overall survival (OS) for PEL vs extracavitary PEL to be 43% vs 39%. Another review noted variation in survival contingent on the number of body cavities involved; patients with a single body cavity involved experienced a median OS of 18 months, whereas patients with multiple involved cavities experienced a median OS of 4 months,⁷ possibly due to the limited study of treatment regimens or disease aggressiveness. Even in cases of successful initial treatment, relapse within 6 to 8 months is common. Extracavitary PEL may have improved disease-free survival relative to classic PEL, though the data were less clear for OS.⁹ Limitations of the Guillet et al⁹ study included a small sample size, the impossibility to randomize to disease type, and loss of power on the log-rank test for OS in the setting of possible nonproportional hazards (crossing survival curves). Overall, prognostic differences between the groups may be challenging to ascertain until further data are obtained.

As with many HIV-associated neoplasms, antiretroviral treatment (ART) for HIV-positive patients affords a better prognosis when used in addition to therapy directed at malignancy.⁷ The general approach is for concurrent ART with systemic therapies such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for the rare CD20⁺ cases, and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or dose-adjusted EPOCH therapy in the more common CD20⁻ PEL cases. Narkhede et al⁷ suggested avoidance of methotrexate in patients with effusions because of increased toxicity, but it is unclear if this recommendation is applicable in extracavitary PEL patients without an effusion. Additionally, second-line treatment modalities include radiation for solid PEL masses, HHV-8–targeted antivirals, and stem cell transplantation, though evidence is limited. Of note, there is a phase I-II trial (ClinicalTrials.gov identifier NCT02911142) ongoing for treatment-naïve PEL patients involving the experimental treatment DA-EPOCH-R plus lenalidomide, but the trial is ongoing.¹⁰

We report a case of cutaneous PEL in a patient with a history of Kaposi sarcoma. The patient’s deterioration and ultimate death despite initial treatment with EPOCH and bone marrow transplantation followed by final management with daratumumab and bortezomib confirm other reports that PEL has a poor prognosis and that optimal treatments are not well delineated for these patients. In general, the current approach is to utilize ART for HIV-positive patients and to then implement chemotherapy such as CHOP. Without continued research and careful planning of treatments, data will remain limited on how best to serve patients with PEL.

To the Editor:

A 47-year-old man presented to the dermatology service with an asymptomatic plaque on the right thigh of 2 months’ duration. He had a medical history of HIV and Kaposi sarcoma as well as a recently relapsed primary effusion lymphoma (PEL) subsequent to an allogeneic bone marrow transplant. He initially was diagnosed with PEL 3 years prior to the current presentation during a workup for fever and weight loss. Imaging at the time demonstrated a bladder mass, which was biopsied and demonstrated PEL. Further imaging demonstrated both sinus and bone marrow involvement. Prior to dermatologic consultation, he had been treated with 6 cycles of etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (EPOCH); 6 cycles of brentuximab; 4 cycles of rituximab with gemcitabine and oxaliplatin; and 2 cycles of ifosfamide, carboplatin, and etoposide. Despite these therapies, he had 3 relapses, and oncology determined the need for a matched unrelated donor allogeneic stem cell transplant for his PEL.

At the time of dermatology consultation, the patient was being managed on daratumumab and bortezomib. Physical examination revealed an infiltrative plaque on the right inferomedial thigh measuring approximately 6.0 cm (largest dimension) with a small amount of peripheral scale (Figure 1). An ultrasound revealed notable subcutaneous tissue edema and increased vascularity without a discrete mass or fluid collection. A 4-mm punch biopsy demonstrated a dense infiltrate comprised of collections of histiocytes admixed with scattered plasma cells and mature lymphoid aggregates. Additionally, rare enlarged plasmablastic cells with scant basophilic cytoplasm and slightly irregular nuclear contours were visualized (Figure 2A). Immunohistochemistry was positive for CD3 with a normal CD4:CD8 ratio, CD68-highlighted histiocytes within the lymphoid aggregates, and human herpesvirus 8 (HHV-8)(or Kaposi sarcoma–associated herpesvirus) demonstrated stippled nuclear staining within the scattered large cells (Figure 2B). Epstein-Barr virus–encoded RNA staining was negative, though the area of interest was lost on deeper sectioning of the tissue block. The histopathologic findings were consistent with cutaneous extracavitary PEL. Shortly after this diagnosis, he died from disease complications.

Primary effusion lymphoma is an aggressive non-Hodgkin B-cell lymphoma that was first described by Knowles et al¹ in 1989. Primary effusion lymphoma occurs exclusively in the setting of HHV-8 infection and typically is associated with chronic immunosuppression related to HIV/AIDS. Cases that are negative for HIV-1 are rare but have been reported in organ transplant recipients and elderly men from areas with a high prevalence of HHV-8 infections. Most HIV-associated cases show concurrent Epstein-Barr virus infection, though the pathogenic meaning of this co-infection remains unclear.^2,3

Primary effusion lymphoma classically presents as an isolated effusion of malignant lymphoid cells within body cavities in the absence of solid tumor masses. The pleural, peritoneal, and pericardial spaces most commonly are involved. Extracavitary PEL, a rare variant, may present as a solid mass without effusion. In general, extracavitary tumors may occur in the setting of de novo malignancy or recurrent PEL.⁴ Cutaneous manifestations associated with extracavitary PEL are rare; 4 cases have been described in which skin lesions were the heralding sign of the disease.³ Interestingly, despite obligatory underlying HHV-8 infection, a review by Pielasinski et al³ noted only 2 patients with cutaneous PEL who had prior or concurrent Kaposi sarcoma. This heterogeneity in HHV-8–related phenotypes may be related to differences in microRNA expression, but further study is needed.⁵

The diagnosis of PEL relies on histologic, immunophenotypic, and molecular analysis of the affected tissue. The malignant cells typically are large with round to irregular nuclei. These cells may demonstrate a variety of appearances, including anaplastic, plasmablastic, and immunoblastic morphologies.^6,7 The immunophenotype displays CD45 positivity and markers of lymphocyte activation (CD30, CD38, CD71), while typical B-cell (CD19, CD20, CD79a) and T-cell (CD3, CD4, CD8) markers often are absent.^6-8 Human herpesvirus 8 detection by polymerase chain reaction testing of the peripheral blood or by immunohistochemistry staining of the affected tissue is required for diagnosis.^6,7 Epstein-Barr virus infection may be detected via in situ hybridization, though it is not required for diagnosis.

The overall prognosis for PEL is poor; Brimo et al⁶ reported a median survival of less than 6 months, and Guillet et al⁹ reported 5-year overall survival (OS) for PEL vs extracavitary PEL to be 43% vs 39%. Another review noted variation in survival contingent on the number of body cavities involved; patients with a single body cavity involved experienced a median OS of 18 months, whereas patients with multiple involved cavities experienced a median OS of 4 months,⁷ possibly due to the limited study of treatment regimens or disease aggressiveness. Even in cases of successful initial treatment, relapse within 6 to 8 months is common. Extracavitary PEL may have improved disease-free survival relative to classic PEL, though the data were less clear for OS.⁹ Limitations of the Guillet et al⁹ study included a small sample size, the impossibility to randomize to disease type, and loss of power on the log-rank test for OS in the setting of possible nonproportional hazards (crossing survival curves). Overall, prognostic differences between the groups may be challenging to ascertain until further data are obtained.

As with many HIV-associated neoplasms, antiretroviral treatment (ART) for HIV-positive patients affords a better prognosis when used in addition to therapy directed at malignancy.⁷ The general approach is for concurrent ART with systemic therapies such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for the rare CD20⁺ cases, and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or dose-adjusted EPOCH therapy in the more common CD20⁻ PEL cases. Narkhede et al⁷ suggested avoidance of methotrexate in patients with effusions because of increased toxicity, but it is unclear if this recommendation is applicable in extracavitary PEL patients without an effusion. Additionally, second-line treatment modalities include radiation for solid PEL masses, HHV-8–targeted antivirals, and stem cell transplantation, though evidence is limited. Of note, there is a phase I-II trial (ClinicalTrials.gov identifier NCT02911142) ongoing for treatment-naïve PEL patients involving the experimental treatment DA-EPOCH-R plus lenalidomide, but the trial is ongoing.¹⁰

We report a case of cutaneous PEL in a patient with a history of Kaposi sarcoma. The patient’s deterioration and ultimate death despite initial treatment with EPOCH and bone marrow transplantation followed by final management with daratumumab and bortezomib confirm other reports that PEL has a poor prognosis and that optimal treatments are not well delineated for these patients. In general, the current approach is to utilize ART for HIV-positive patients and to then implement chemotherapy such as CHOP. Without continued research and careful planning of treatments, data will remain limited on how best to serve patients with PEL.

To the Editor:

A 47-year-old man presented to the dermatology service with an asymptomatic plaque on the right thigh of 2 months’ duration. He had a medical history of HIV and Kaposi sarcoma as well as a recently relapsed primary effusion lymphoma (PEL) subsequent to an allogeneic bone marrow transplant. He initially was diagnosed with PEL 3 years prior to the current presentation during a workup for fever and weight loss. Imaging at the time demonstrated a bladder mass, which was biopsied and demonstrated PEL. Further imaging demonstrated both sinus and bone marrow involvement. Prior to dermatologic consultation, he had been treated with 6 cycles of etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (EPOCH); 6 cycles of brentuximab; 4 cycles of rituximab with gemcitabine and oxaliplatin; and 2 cycles of ifosfamide, carboplatin, and etoposide. Despite these therapies, he had 3 relapses, and oncology determined the need for a matched unrelated donor allogeneic stem cell transplant for his PEL.

At the time of dermatology consultation, the patient was being managed on daratumumab and bortezomib. Physical examination revealed an infiltrative plaque on the right inferomedial thigh measuring approximately 6.0 cm (largest dimension) with a small amount of peripheral scale (Figure 1). An ultrasound revealed notable subcutaneous tissue edema and increased vascularity without a discrete mass or fluid collection. A 4-mm punch biopsy demonstrated a dense infiltrate comprised of collections of histiocytes admixed with scattered plasma cells and mature lymphoid aggregates. Additionally, rare enlarged plasmablastic cells with scant basophilic cytoplasm and slightly irregular nuclear contours were visualized (Figure 2A). Immunohistochemistry was positive for CD3 with a normal CD4:CD8 ratio, CD68-highlighted histiocytes within the lymphoid aggregates, and human herpesvirus 8 (HHV-8)(or Kaposi sarcoma–associated herpesvirus) demonstrated stippled nuclear staining within the scattered large cells (Figure 2B). Epstein-Barr virus–encoded RNA staining was negative, though the area of interest was lost on deeper sectioning of the tissue block. The histopathologic findings were consistent with cutaneous extracavitary PEL. Shortly after this diagnosis, he died from disease complications.

Primary effusion lymphoma is an aggressive non-Hodgkin B-cell lymphoma that was first described by Knowles et al¹ in 1989. Primary effusion lymphoma occurs exclusively in the setting of HHV-8 infection and typically is associated with chronic immunosuppression related to HIV/AIDS. Cases that are negative for HIV-1 are rare but have been reported in organ transplant recipients and elderly men from areas with a high prevalence of HHV-8 infections. Most HIV-associated cases show concurrent Epstein-Barr virus infection, though the pathogenic meaning of this co-infection remains unclear.^2,3

Primary effusion lymphoma classically presents as an isolated effusion of malignant lymphoid cells within body cavities in the absence of solid tumor masses. The pleural, peritoneal, and pericardial spaces most commonly are involved. Extracavitary PEL, a rare variant, may present as a solid mass without effusion. In general, extracavitary tumors may occur in the setting of de novo malignancy or recurrent PEL.⁴ Cutaneous manifestations associated with extracavitary PEL are rare; 4 cases have been described in which skin lesions were the heralding sign of the disease.³ Interestingly, despite obligatory underlying HHV-8 infection, a review by Pielasinski et al³ noted only 2 patients with cutaneous PEL who had prior or concurrent Kaposi sarcoma. This heterogeneity in HHV-8–related phenotypes may be related to differences in microRNA expression, but further study is needed.⁵

The diagnosis of PEL relies on histologic, immunophenotypic, and molecular analysis of the affected tissue. The malignant cells typically are large with round to irregular nuclei. These cells may demonstrate a variety of appearances, including anaplastic, plasmablastic, and immunoblastic morphologies.^6,7 The immunophenotype displays CD45 positivity and markers of lymphocyte activation (CD30, CD38, CD71), while typical B-cell (CD19, CD20, CD79a) and T-cell (CD3, CD4, CD8) markers often are absent.^6-8 Human herpesvirus 8 detection by polymerase chain reaction testing of the peripheral blood or by immunohistochemistry staining of the affected tissue is required for diagnosis.^6,7 Epstein-Barr virus infection may be detected via in situ hybridization, though it is not required for diagnosis.

The overall prognosis for PEL is poor; Brimo et al⁶ reported a median survival of less than 6 months, and Guillet et al⁹ reported 5-year overall survival (OS) for PEL vs extracavitary PEL to be 43% vs 39%. Another review noted variation in survival contingent on the number of body cavities involved; patients with a single body cavity involved experienced a median OS of 18 months, whereas patients with multiple involved cavities experienced a median OS of 4 months,⁷ possibly due to the limited study of treatment regimens or disease aggressiveness. Even in cases of successful initial treatment, relapse within 6 to 8 months is common. Extracavitary PEL may have improved disease-free survival relative to classic PEL, though the data were less clear for OS.⁹ Limitations of the Guillet et al⁹ study included a small sample size, the impossibility to randomize to disease type, and loss of power on the log-rank test for OS in the setting of possible nonproportional hazards (crossing survival curves). Overall, prognostic differences between the groups may be challenging to ascertain until further data are obtained.

As with many HIV-associated neoplasms, antiretroviral treatment (ART) for HIV-positive patients affords a better prognosis when used in addition to therapy directed at malignancy.⁷ The general approach is for concurrent ART with systemic therapies such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for the rare CD20⁺ cases, and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or dose-adjusted EPOCH therapy in the more common CD20⁻ PEL cases. Narkhede et al⁷ suggested avoidance of methotrexate in patients with effusions because of increased toxicity, but it is unclear if this recommendation is applicable in extracavitary PEL patients without an effusion. Additionally, second-line treatment modalities include radiation for solid PEL masses, HHV-8–targeted antivirals, and stem cell transplantation, though evidence is limited. Of note, there is a phase I-II trial (ClinicalTrials.gov identifier NCT02911142) ongoing for treatment-naïve PEL patients involving the experimental treatment DA-EPOCH-R plus lenalidomide, but the trial is ongoing.¹⁰

We report a case of cutaneous PEL in a patient with a history of Kaposi sarcoma. The patient’s deterioration and ultimate death despite initial treatment with EPOCH and bone marrow transplantation followed by final management with daratumumab and bortezomib confirm other reports that PEL has a poor prognosis and that optimal treatments are not well delineated for these patients. In general, the current approach is to utilize ART for HIV-positive patients and to then implement chemotherapy such as CHOP. Without continued research and careful planning of treatments, data will remain limited on how best to serve patients with PEL.

To the Editor:

Squamous cell carcinoma (SCC) is the second most common cancer of the scalp.¹ Mohs micrographic surgery is used to treat SCC, and it commonly generates a 2.5×2.5-cm open wound with exposed bone.² Although Mohs micrographic surgery effectively treats cutaneous lesions, it carries a high risk for complications such as infection, wound dehiscence, and partial or full-thickness skin graft necrosis.³ Recommended therapies to decrease these complications include linear closures, flaps, and peripheral autograft tissue.⁴ However, these procedures do not come without risks and carry their own complications. Therefore, we suggest a safe, less-invasive initial approach using a synthetic extracellular matrix (ECM)–based collagen dressing for secondary wound closure.

A 76-year-old woman presented to the infectious disease clinic at Monument Health Rapid City Clinic (Rapid City, South Dakota) for evaluation of a dehisced scalp wound 3 months following Mohs micrographic surgery for scalp SCC. The wound underwent primary closure following surgery and dehisced shortly after (Figure 1A). Various oral antimicrobials were used by the dermatologist to assist with wound closure but without success. The patient was referred to the wound clinic for management. At the first appointment, all necrotic tissue was debrided and the cranium was exposed in the wound base (Figure 1B). The wound measured 2.3×2.3×0.2 cm. An ECM-containing collagen dressing (Endoform Natural Restorative Bioscaffold [Aroa Biosurgery Inc]) was used to provide a scaffold for wound closure (Figure 2A). It was dressed with the petroleum-based gauze Xeroform (Cardinal Health) and covered with dry gauze to prevent evaporation and provide moist wound healing. The wound developed some budding tissue islands 3 weeks after weekly ECM-based collagen dressing applications (Figure 3A). The wound continued to decrease in size and formed an isthmus by the second month of therapy (Figure 3B). The wound fully closed within 3 months and showed minimal scarring after 3 years (Figure 2B).

Chronic wounds usually get trapped in the inflammatory stage of wound healing due to destruction of growth factors and ECM by metalloproteases (MMPs), which creates a vicious cycle and wound stalling. Wound debridement converts a chronic wound back into an acute wound, which is the first step of healing. Following wound debridement, collagen-based dressings can assist with healing by binding the destructive MMPs, and ECM matrix promotes the building of new tissue. The 3 most commonly used ECM-based collagen dressings are Endoform, PuraPly AM (Organogenesis Inc), and Puracol Ultra ECM (Medline Industries, Inc).

Endoform is ovine-based collagen and provides a natural porous bioscaffold for rapid cell infiltration.⁵ It contains more than 150 ECM proteins along with residual vascular channels that help re-establish new vasculature. Ovine-based collagen contains collagen types I, III, and IV arranged as native fibers that retain the 3-dimensional architecture present in tissue ECM.⁵ Although MMPs are essential in normal healing, the elevated presence of MMPs has been linked to stalled wound healing. Clinical observation and assessment may not be sufficient to identify a wound with elevated protease activity that can break down ECM, affect wound fibroblasts, and impair growth factor response. Although collagen ECM itself does not contain any growth factors, it preserves the destruction of native ECM and growth factors by MMPs by functioning as a sacrificial substrate. The addition of 0.3% ionic silver to the ECM has been shown to decrease bacterial growth and prevent biofilm formation.⁶

PuraPly AM is a native, type I porcine collagen matrix embedded with the polyhexamethylene biguanide for the management of chronic wounds.⁷ The addition of polyhexamethylene biguanide to the ECM matrix provides bactericidal activity against biofilm formation.⁸ PuraPly AM reduced the counts of biofilm-producing pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida species, and Aspergillus niger in nonclinical studies. Use of polyhexamethylene biguanide has been seen within ECM grafts (PuraPly AM).

Puracol Ultra ECM is made of porcine mesothelium and is comprised of types I, III, and IV collagens; elastin; fibronectin; laminin; and proteoglycans. It also contains fibroblast growth factors, contributing to angiogenesis in the wound.⁹

Application of ECM-based collagen dressings on debrided wounds requires moisture for absorption. Because cranium wounds lack sufficient exudate production, dermal templates need to be hydrated with sterile normal saline before application and covered with a moisture-retaining dressing. Extracellular matrix–based dressings are biodegradable and can be reapplied every 5 to 7 days. For chronic wounds, application of collagen dressings, such as Endoform, is essential and could be considered as the first step prior to switching to more advanced wound care modalities.^6,10 Additional studies investigating ECM-containing may determine their comparative efficacy.

To the Editor:

Squamous cell carcinoma (SCC) is the second most common cancer of the scalp.¹ Mohs micrographic surgery is used to treat SCC, and it commonly generates a 2.5×2.5-cm open wound with exposed bone.² Although Mohs micrographic surgery effectively treats cutaneous lesions, it carries a high risk for complications such as infection, wound dehiscence, and partial or full-thickness skin graft necrosis.³ Recommended therapies to decrease these complications include linear closures, flaps, and peripheral autograft tissue.⁴ However, these procedures do not come without risks and carry their own complications. Therefore, we suggest a safe, less-invasive initial approach using a synthetic extracellular matrix (ECM)–based collagen dressing for secondary wound closure.

A 76-year-old woman presented to the infectious disease clinic at Monument Health Rapid City Clinic (Rapid City, South Dakota) for evaluation of a dehisced scalp wound 3 months following Mohs micrographic surgery for scalp SCC. The wound underwent primary closure following surgery and dehisced shortly after (Figure 1A). Various oral antimicrobials were used by the dermatologist to assist with wound closure but without success. The patient was referred to the wound clinic for management. At the first appointment, all necrotic tissue was debrided and the cranium was exposed in the wound base (Figure 1B). The wound measured 2.3×2.3×0.2 cm. An ECM-containing collagen dressing (Endoform Natural Restorative Bioscaffold [Aroa Biosurgery Inc]) was used to provide a scaffold for wound closure (Figure 2A). It was dressed with the petroleum-based gauze Xeroform (Cardinal Health) and covered with dry gauze to prevent evaporation and provide moist wound healing. The wound developed some budding tissue islands 3 weeks after weekly ECM-based collagen dressing applications (Figure 3A). The wound continued to decrease in size and formed an isthmus by the second month of therapy (Figure 3B). The wound fully closed within 3 months and showed minimal scarring after 3 years (Figure 2B).

Chronic wounds usually get trapped in the inflammatory stage of wound healing due to destruction of growth factors and ECM by metalloproteases (MMPs), which creates a vicious cycle and wound stalling. Wound debridement converts a chronic wound back into an acute wound, which is the first step of healing. Following wound debridement, collagen-based dressings can assist with healing by binding the destructive MMPs, and ECM matrix promotes the building of new tissue. The 3 most commonly used ECM-based collagen dressings are Endoform, PuraPly AM (Organogenesis Inc), and Puracol Ultra ECM (Medline Industries, Inc).

Endoform is ovine-based collagen and provides a natural porous bioscaffold for rapid cell infiltration.⁵ It contains more than 150 ECM proteins along with residual vascular channels that help re-establish new vasculature. Ovine-based collagen contains collagen types I, III, and IV arranged as native fibers that retain the 3-dimensional architecture present in tissue ECM.⁵ Although MMPs are essential in normal healing, the elevated presence of MMPs has been linked to stalled wound healing. Clinical observation and assessment may not be sufficient to identify a wound with elevated protease activity that can break down ECM, affect wound fibroblasts, and impair growth factor response. Although collagen ECM itself does not contain any growth factors, it preserves the destruction of native ECM and growth factors by MMPs by functioning as a sacrificial substrate. The addition of 0.3% ionic silver to the ECM has been shown to decrease bacterial growth and prevent biofilm formation.⁶

PuraPly AM is a native, type I porcine collagen matrix embedded with the polyhexamethylene biguanide for the management of chronic wounds.⁷ The addition of polyhexamethylene biguanide to the ECM matrix provides bactericidal activity against biofilm formation.⁸ PuraPly AM reduced the counts of biofilm-producing pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida species, and Aspergillus niger in nonclinical studies. Use of polyhexamethylene biguanide has been seen within ECM grafts (PuraPly AM).

Puracol Ultra ECM is made of porcine mesothelium and is comprised of types I, III, and IV collagens; elastin; fibronectin; laminin; and proteoglycans. It also contains fibroblast growth factors, contributing to angiogenesis in the wound.⁹

Application of ECM-based collagen dressings on debrided wounds requires moisture for absorption. Because cranium wounds lack sufficient exudate production, dermal templates need to be hydrated with sterile normal saline before application and covered with a moisture-retaining dressing. Extracellular matrix–based dressings are biodegradable and can be reapplied every 5 to 7 days. For chronic wounds, application of collagen dressings, such as Endoform, is essential and could be considered as the first step prior to switching to more advanced wound care modalities.^6,10 Additional studies investigating ECM-containing may determine their comparative efficacy.

To the Editor:

Squamous cell carcinoma (SCC) is the second most common cancer of the scalp.¹ Mohs micrographic surgery is used to treat SCC, and it commonly generates a 2.5×2.5-cm open wound with exposed bone.² Although Mohs micrographic surgery effectively treats cutaneous lesions, it carries a high risk for complications such as infection, wound dehiscence, and partial or full-thickness skin graft necrosis.³ Recommended therapies to decrease these complications include linear closures, flaps, and peripheral autograft tissue.⁴ However, these procedures do not come without risks and carry their own complications. Therefore, we suggest a safe, less-invasive initial approach using a synthetic extracellular matrix (ECM)–based collagen dressing for secondary wound closure.

A 76-year-old woman presented to the infectious disease clinic at Monument Health Rapid City Clinic (Rapid City, South Dakota) for evaluation of a dehisced scalp wound 3 months following Mohs micrographic surgery for scalp SCC. The wound underwent primary closure following surgery and dehisced shortly after (Figure 1A). Various oral antimicrobials were used by the dermatologist to assist with wound closure but without success. The patient was referred to the wound clinic for management. At the first appointment, all necrotic tissue was debrided and the cranium was exposed in the wound base (Figure 1B). The wound measured 2.3×2.3×0.2 cm. An ECM-containing collagen dressing (Endoform Natural Restorative Bioscaffold [Aroa Biosurgery Inc]) was used to provide a scaffold for wound closure (Figure 2A). It was dressed with the petroleum-based gauze Xeroform (Cardinal Health) and covered with dry gauze to prevent evaporation and provide moist wound healing. The wound developed some budding tissue islands 3 weeks after weekly ECM-based collagen dressing applications (Figure 3A). The wound continued to decrease in size and formed an isthmus by the second month of therapy (Figure 3B). The wound fully closed within 3 months and showed minimal scarring after 3 years (Figure 2B).

Chronic wounds usually get trapped in the inflammatory stage of wound healing due to destruction of growth factors and ECM by metalloproteases (MMPs), which creates a vicious cycle and wound stalling. Wound debridement converts a chronic wound back into an acute wound, which is the first step of healing. Following wound debridement, collagen-based dressings can assist with healing by binding the destructive MMPs, and ECM matrix promotes the building of new tissue. The 3 most commonly used ECM-based collagen dressings are Endoform, PuraPly AM (Organogenesis Inc), and Puracol Ultra ECM (Medline Industries, Inc).

Endoform is ovine-based collagen and provides a natural porous bioscaffold for rapid cell infiltration.⁵ It contains more than 150 ECM proteins along with residual vascular channels that help re-establish new vasculature. Ovine-based collagen contains collagen types I, III, and IV arranged as native fibers that retain the 3-dimensional architecture present in tissue ECM.⁵ Although MMPs are essential in normal healing, the elevated presence of MMPs has been linked to stalled wound healing. Clinical observation and assessment may not be sufficient to identify a wound with elevated protease activity that can break down ECM, affect wound fibroblasts, and impair growth factor response. Although collagen ECM itself does not contain any growth factors, it preserves the destruction of native ECM and growth factors by MMPs by functioning as a sacrificial substrate. The addition of 0.3% ionic silver to the ECM has been shown to decrease bacterial growth and prevent biofilm formation.⁶

PuraPly AM is a native, type I porcine collagen matrix embedded with the polyhexamethylene biguanide for the management of chronic wounds.⁷ The addition of polyhexamethylene biguanide to the ECM matrix provides bactericidal activity against biofilm formation.⁸ PuraPly AM reduced the counts of biofilm-producing pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida species, and Aspergillus niger in nonclinical studies. Use of polyhexamethylene biguanide has been seen within ECM grafts (PuraPly AM).

Puracol Ultra ECM is made of porcine mesothelium and is comprised of types I, III, and IV collagens; elastin; fibronectin; laminin; and proteoglycans. It also contains fibroblast growth factors, contributing to angiogenesis in the wound.⁹

Application of ECM-based collagen dressings on debrided wounds requires moisture for absorption. Because cranium wounds lack sufficient exudate production, dermal templates need to be hydrated with sterile normal saline before application and covered with a moisture-retaining dressing. Extracellular matrix–based dressings are biodegradable and can be reapplied every 5 to 7 days. For chronic wounds, application of collagen dressings, such as Endoform, is essential and could be considered as the first step prior to switching to more advanced wound care modalities.^6,10 Additional studies investigating ECM-containing may determine their comparative efficacy.

To the Editor:

A 12-year-old girl presented to the dermatology clinic for evaluation of a congenital scalp lesion. The patient was diagnosed with alopecia areata by a dermatologist at 4 years of age, and she was treated with topical corticosteroids and minoxidil, which failed to resolve her condition. Physical examination revealed an 8×10-cm, well-demarcated, yellowish-pink plaque located over the vertex and right parietal scalp (Figure 1A), extending down to the right preauricular cheek (Figure 1B) in a linear configuration with blaschkoid features. The scalp plaque appeared bald and completely lacking in terminal hairs but contained numerous fine vellus hairs (Figure 1A). A 6-mm, oval-appearing, pigmented papule was present in the plaque, and a few smaller, scattered, pigmented papules were noted in the vertex region (Figure 1A).

The cutaneous examination was otherwise unremarkable. A review of systems was negative, except for a history of attention-deficit/hyperactivity disorder. There was no history of seizures or other neurocognitive developmental abnormalities.

A 4-mm punch biopsy of the vertex scalp included the pigmented lesion but excluded an adnexal neoplasm. Epidermal acanthosis and mild papillomatosis were reported on microscopic examination. Multiple prominent sebaceous glands without associated hair follicles, which emptied directly onto the epidermal surface, were noted in the dermis (Figure 2). Several apocrine glands were observed (Figure 3). Epidermal and dermal melanocytic nests were highlighted with SOX-10 and Melan-A immunohistochemical stains, confirming the presence of a benign compound nevus. The punch biopsy analysis confirmed the diagnosis of a nevus sebaceus (NS) of Jadassohn (organoid nevus) with incidental compound nevus. Additional 4-mm punch biopsies were obtained for genetic testing, performed by the Genomics and Pathology Services at Washington University (St. Louis, Missouri). A missense HRAS p.G12V variant was observed in the tissue. A negative blood test result ruled out a germline mutation. The patient was managed with active observation of the lesion to evaluate for potential formation of neoplasms, as well as continuity of care with the dermatology clinic, considering the extent of the lesions, to monitor the development of any new medical conditions that would be concerning for syndromes associated with NS.

Nevus sebaceus is a benign skin hamartoma caused by a congenital defect in the pilosebaceous follicular unit and consists of epidermal, sebaceous, and apocrine elements.^1,2 In dermatology patients, the prevalence of NS ranges from 0.05% to 1%.¹ In 90% of cases, NS presents at birth as a 1- to 10-cm, round or linear, yellowish-orange, hairless plaque located on the scalp. It also may appear on the face, neck, trunk, oral mucosa, or labia minora.^1,3 Although NS is a benign condition, secondary tumors may form within the lesion.³

The physical and histologic characteristics of NS evolve as the patient ages. In childhood, NS typically appears as a yellow-pink macule or patch with mild to moderate epidermal hyperplasia. Patients exhibit underdeveloped sebaceous glands, immature hair follicles, hyperkeratosis, and acanthosis.^1,3,4 The development of early lesions can be quite subtle and can lead to diagnostic uncertainty, as described in our patient. During puberty, lesions thicken due to papillomatous hyperplasia in the epidermis, and the number and size of sebaceous and apocrine glands increase.⁴ In adults, the risk for secondary tumor formation increases. These physical and histologic transformations, including secondary tumor formation, are thought to be stimulated by the action of postpubertal androgens.¹

Nevus sebaceus is associated with both benign and malignant secondary tumor formation; however, fewer than 1% of tumors are malignant.¹ In a retrospective analysis, Idriss and Elston⁵ (N=707) reported that 21.4% of patients with NS had secondary neoplasms; 18.9% of the secondary neoplasms were benign, and 2.5% were malignant. Additionally, this study showed that secondary tumor formation can occur in children, though it typically occurs in adults. Benign neoplasms were reported in 5 children in the subset aged 0 to 10 years and 10 children in the subset aged 11 to 17 years; 1 child developed a malignant neoplasm in the latter subset.⁵ The most common NS-associated benign neoplasms include trichoblastoma and syringocystadenoma papilliferum. Others include trichilemmoma, apocrine/eccrine adenoma, and sebaceoma.¹ Nevus sebaceus–associated malignant neoplasms include basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, carcinosarcoma, and sebaceous carcinoma.³

Our patient was incorrectly diagnosed and treated for alopecia areata before an eventual diagnosis of NS was confirmed by biopsy. Additional genetic studies revealed a novel mutation in the HRAS gene, the most commonly affected gene in NS. The most common mutation location seen in more than 90% of NS lesions is HRAS c.37G>C (p.G13R), while KRAS mutations account for almost all the remaining cases.³ In our patient, a pathogenic missense HRAS p.G12V variant of somatic origin was detected with DNA extraction and sequencing from a fresh tissue sample acquired from two 4-mm punch biopsies performed on the lesion. The following genes were sequenced and found to be uninvolved: BRAF, FGFR1, FGFR2, FGFR3, GNA11, GNAQ, KRAS, MAP3K3, NRAS, PIK3CA, and TEK. The Sanger sequencing method for comparative analysis performed on peripheral blood was negative.

Nevus sebaceus typically is caused by a sporadic mutation, though familial cases have been reported.¹ Additionally, germline HRAS mutations can lead to Costello syndrome, an autosomal-dominant disorder characterized by short stature; intellectual disabilities; coarse facial features; facial and perianal papillomata; cardiac defects; loose skin; joint hyperflexibility; and an increased risk for malignant tumors including rhabdomyosarcoma, neuroblastoma, and transitional cell carcinoma of the bladder.⁶

The diagnosis of NS often can be made clinically but can be difficult to confirm in underdeveloped lesions in young children. The differential diagnosis can include alopecia areata, aplasia cutis congenita, juvenile xanthogranuloma, epidermal nevus, de novo syringocystadenoma papilliferum, and solitary mastocytoma.¹ Nevus sebaceus can be associated with 4 additional syndromes: Schimmelpenning syndrome; phacomatosis pigmentokeratotica; didymosis aplasticosebacea; and SCALP (sebaceus nevus, central nervous system malformations, aplasia cutis congenital, limbal dermoid, pigmented nevus) syndrome.¹ Approximately 7% of NS cases may be associated with Schimmelpenning-Feuerstein-Mims (SFM) syndrome, a more severe condition that leads to systemic involvement and abnormalities in the neurological, ophthalmological, cardiovascular, genitourological, and skeletal systems.^1,3 Phacomatosis pigmentokeratotica has speckled lentiginous nevi, as well as abnormalities in the neurological, ophthalmological, cardiovascular, genitourological, and skeletal systems.¹ Didymosis aplasticosebacea is the concurrence of NS and aplasia cutis congenita.

The definitive treatment of NS is surgical excision. Alternative therapies include photodynamic therapy, fractional laser resurfacing, and dermabrasion; these are not definitive treatments, and patients must be monitored for the development of secondary neoplasms. Multiple variables must be considered when determining treatment, including patient age, risk potential for malignancy, and surgery-associated risks.¹ In our patient, given the extent of the lesions, active observation and follow-up was agreed upon for management.

This case demonstrates the importance of considering NS as an alternative diagnosis when alopecia areata has been diagnosed in a child who is unresponsive to treatments. After the diagnosis of NS is confirmed, more serious associated syndromes should be ruled out, and treatment should be tailored to each case.

To the Editor:

A 12-year-old girl presented to the dermatology clinic for evaluation of a congenital scalp lesion. The patient was diagnosed with alopecia areata by a dermatologist at 4 years of age, and she was treated with topical corticosteroids and minoxidil, which failed to resolve her condition. Physical examination revealed an 8×10-cm, well-demarcated, yellowish-pink plaque located over the vertex and right parietal scalp (Figure 1A), extending down to the right preauricular cheek (Figure 1B) in a linear configuration with blaschkoid features. The scalp plaque appeared bald and completely lacking in terminal hairs but contained numerous fine vellus hairs (Figure 1A). A 6-mm, oval-appearing, pigmented papule was present in the plaque, and a few smaller, scattered, pigmented papules were noted in the vertex region (Figure 1A).

The cutaneous examination was otherwise unremarkable. A review of systems was negative, except for a history of attention-deficit/hyperactivity disorder. There was no history of seizures or other neurocognitive developmental abnormalities.

A 4-mm punch biopsy of the vertex scalp included the pigmented lesion but excluded an adnexal neoplasm. Epidermal acanthosis and mild papillomatosis were reported on microscopic examination. Multiple prominent sebaceous glands without associated hair follicles, which emptied directly onto the epidermal surface, were noted in the dermis (Figure 2). Several apocrine glands were observed (Figure 3). Epidermal and dermal melanocytic nests were highlighted with SOX-10 and Melan-A immunohistochemical stains, confirming the presence of a benign compound nevus. The punch biopsy analysis confirmed the diagnosis of a nevus sebaceus (NS) of Jadassohn (organoid nevus) with incidental compound nevus. Additional 4-mm punch biopsies were obtained for genetic testing, performed by the Genomics and Pathology Services at Washington University (St. Louis, Missouri). A missense HRAS p.G12V variant was observed in the tissue. A negative blood test result ruled out a germline mutation. The patient was managed with active observation of the lesion to evaluate for potential formation of neoplasms, as well as continuity of care with the dermatology clinic, considering the extent of the lesions, to monitor the development of any new medical conditions that would be concerning for syndromes associated with NS.

Nevus sebaceus is a benign skin hamartoma caused by a congenital defect in the pilosebaceous follicular unit and consists of epidermal, sebaceous, and apocrine elements.^1,2 In dermatology patients, the prevalence of NS ranges from 0.05% to 1%.¹ In 90% of cases, NS presents at birth as a 1- to 10-cm, round or linear, yellowish-orange, hairless plaque located on the scalp. It also may appear on the face, neck, trunk, oral mucosa, or labia minora.^1,3 Although NS is a benign condition, secondary tumors may form within the lesion.³

The physical and histologic characteristics of NS evolve as the patient ages. In childhood, NS typically appears as a yellow-pink macule or patch with mild to moderate epidermal hyperplasia. Patients exhibit underdeveloped sebaceous glands, immature hair follicles, hyperkeratosis, and acanthosis.^1,3,4 The development of early lesions can be quite subtle and can lead to diagnostic uncertainty, as described in our patient. During puberty, lesions thicken due to papillomatous hyperplasia in the epidermis, and the number and size of sebaceous and apocrine glands increase.⁴ In adults, the risk for secondary tumor formation increases. These physical and histologic transformations, including secondary tumor formation, are thought to be stimulated by the action of postpubertal androgens.¹

Nevus sebaceus is associated with both benign and malignant secondary tumor formation; however, fewer than 1% of tumors are malignant.¹ In a retrospective analysis, Idriss and Elston⁵ (N=707) reported that 21.4% of patients with NS had secondary neoplasms; 18.9% of the secondary neoplasms were benign, and 2.5% were malignant. Additionally, this study showed that secondary tumor formation can occur in children, though it typically occurs in adults. Benign neoplasms were reported in 5 children in the subset aged 0 to 10 years and 10 children in the subset aged 11 to 17 years; 1 child developed a malignant neoplasm in the latter subset.⁵ The most common NS-associated benign neoplasms include trichoblastoma and syringocystadenoma papilliferum. Others include trichilemmoma, apocrine/eccrine adenoma, and sebaceoma.¹ Nevus sebaceus–associated malignant neoplasms include basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, carcinosarcoma, and sebaceous carcinoma.³

Our patient was incorrectly diagnosed and treated for alopecia areata before an eventual diagnosis of NS was confirmed by biopsy. Additional genetic studies revealed a novel mutation in the HRAS gene, the most commonly affected gene in NS. The most common mutation location seen in more than 90% of NS lesions is HRAS c.37G>C (p.G13R), while KRAS mutations account for almost all the remaining cases.³ In our patient, a pathogenic missense HRAS p.G12V variant of somatic origin was detected with DNA extraction and sequencing from a fresh tissue sample acquired from two 4-mm punch biopsies performed on the lesion. The following genes were sequenced and found to be uninvolved: BRAF, FGFR1, FGFR2, FGFR3, GNA11, GNAQ, KRAS, MAP3K3, NRAS, PIK3CA, and TEK. The Sanger sequencing method for comparative analysis performed on peripheral blood was negative.

Nevus sebaceus typically is caused by a sporadic mutation, though familial cases have been reported.¹ Additionally, germline HRAS mutations can lead to Costello syndrome, an autosomal-dominant disorder characterized by short stature; intellectual disabilities; coarse facial features; facial and perianal papillomata; cardiac defects; loose skin; joint hyperflexibility; and an increased risk for malignant tumors including rhabdomyosarcoma, neuroblastoma, and transitional cell carcinoma of the bladder.⁶

The diagnosis of NS often can be made clinically but can be difficult to confirm in underdeveloped lesions in young children. The differential diagnosis can include alopecia areata, aplasia cutis congenita, juvenile xanthogranuloma, epidermal nevus, de novo syringocystadenoma papilliferum, and solitary mastocytoma.¹ Nevus sebaceus can be associated with 4 additional syndromes: Schimmelpenning syndrome; phacomatosis pigmentokeratotica; didymosis aplasticosebacea; and SCALP (sebaceus nevus, central nervous system malformations, aplasia cutis congenital, limbal dermoid, pigmented nevus) syndrome.¹ Approximately 7% of NS cases may be associated with Schimmelpenning-Feuerstein-Mims (SFM) syndrome, a more severe condition that leads to systemic involvement and abnormalities in the neurological, ophthalmological, cardiovascular, genitourological, and skeletal systems.^1,3 Phacomatosis pigmentokeratotica has speckled lentiginous nevi, as well as abnormalities in the neurological, ophthalmological, cardiovascular, genitourological, and skeletal systems.¹ Didymosis aplasticosebacea is the concurrence of NS and aplasia cutis congenita.

The definitive treatment of NS is surgical excision. Alternative therapies include photodynamic therapy, fractional laser resurfacing, and dermabrasion; these are not definitive treatments, and patients must be monitored for the development of secondary neoplasms. Multiple variables must be considered when determining treatment, including patient age, risk potential for malignancy, and surgery-associated risks.¹ In our patient, given the extent of the lesions, active observation and follow-up was agreed upon for management.

This case demonstrates the importance of considering NS as an alternative diagnosis when alopecia areata has been diagnosed in a child who is unresponsive to treatments. After the diagnosis of NS is confirmed, more serious associated syndromes should be ruled out, and treatment should be tailored to each case.

To the Editor:

A 12-year-old girl presented to the dermatology clinic for evaluation of a congenital scalp lesion. The patient was diagnosed with alopecia areata by a dermatologist at 4 years of age, and she was treated with topical corticosteroids and minoxidil, which failed to resolve her condition. Physical examination revealed an 8×10-cm, well-demarcated, yellowish-pink plaque located over the vertex and right parietal scalp (Figure 1A), extending down to the right preauricular cheek (Figure 1B) in a linear configuration with blaschkoid features. The scalp plaque appeared bald and completely lacking in terminal hairs but contained numerous fine vellus hairs (Figure 1A). A 6-mm, oval-appearing, pigmented papule was present in the plaque, and a few smaller, scattered, pigmented papules were noted in the vertex region (Figure 1A).

The cutaneous examination was otherwise unremarkable. A review of systems was negative, except for a history of attention-deficit/hyperactivity disorder. There was no history of seizures or other neurocognitive developmental abnormalities.

A 4-mm punch biopsy of the vertex scalp included the pigmented lesion but excluded an adnexal neoplasm. Epidermal acanthosis and mild papillomatosis were reported on microscopic examination. Multiple prominent sebaceous glands without associated hair follicles, which emptied directly onto the epidermal surface, were noted in the dermis (Figure 2). Several apocrine glands were observed (Figure 3). Epidermal and dermal melanocytic nests were highlighted with SOX-10 and Melan-A immunohistochemical stains, confirming the presence of a benign compound nevus. The punch biopsy analysis confirmed the diagnosis of a nevus sebaceus (NS) of Jadassohn (organoid nevus) with incidental compound nevus. Additional 4-mm punch biopsies were obtained for genetic testing, performed by the Genomics and Pathology Services at Washington University (St. Louis, Missouri). A missense HRAS p.G12V variant was observed in the tissue. A negative blood test result ruled out a germline mutation. The patient was managed with active observation of the lesion to evaluate for potential formation of neoplasms, as well as continuity of care with the dermatology clinic, considering the extent of the lesions, to monitor the development of any new medical conditions that would be concerning for syndromes associated with NS.

Nevus sebaceus is a benign skin hamartoma caused by a congenital defect in the pilosebaceous follicular unit and consists of epidermal, sebaceous, and apocrine elements.^1,2 In dermatology patients, the prevalence of NS ranges from 0.05% to 1%.¹ In 90% of cases, NS presents at birth as a 1- to 10-cm, round or linear, yellowish-orange, hairless plaque located on the scalp. It also may appear on the face, neck, trunk, oral mucosa, or labia minora.^1,3 Although NS is a benign condition, secondary tumors may form within the lesion.³

The physical and histologic characteristics of NS evolve as the patient ages. In childhood, NS typically appears as a yellow-pink macule or patch with mild to moderate epidermal hyperplasia. Patients exhibit underdeveloped sebaceous glands, immature hair follicles, hyperkeratosis, and acanthosis.^1,3,4 The development of early lesions can be quite subtle and can lead to diagnostic uncertainty, as described in our patient. During puberty, lesions thicken due to papillomatous hyperplasia in the epidermis, and the number and size of sebaceous and apocrine glands increase.⁴ In adults, the risk for secondary tumor formation increases. These physical and histologic transformations, including secondary tumor formation, are thought to be stimulated by the action of postpubertal androgens.¹

Nevus sebaceus is associated with both benign and malignant secondary tumor formation; however, fewer than 1% of tumors are malignant.¹ In a retrospective analysis, Idriss and Elston⁵ (N=707) reported that 21.4% of patients with NS had secondary neoplasms; 18.9% of the secondary neoplasms were benign, and 2.5% were malignant. Additionally, this study showed that secondary tumor formation can occur in children, though it typically occurs in adults. Benign neoplasms were reported in 5 children in the subset aged 0 to 10 years and 10 children in the subset aged 11 to 17 years; 1 child developed a malignant neoplasm in the latter subset.⁵ The most common NS-associated benign neoplasms include trichoblastoma and syringocystadenoma papilliferum. Others include trichilemmoma, apocrine/eccrine adenoma, and sebaceoma.¹ Nevus sebaceus–associated malignant neoplasms include basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, carcinosarcoma, and sebaceous carcinoma.³

Our patient was incorrectly diagnosed and treated for alopecia areata before an eventual diagnosis of NS was confirmed by biopsy. Additional genetic studies revealed a novel mutation in the HRAS gene, the most commonly affected gene in NS. The most common mutation location seen in more than 90% of NS lesions is HRAS c.37G>C (p.G13R), while KRAS mutations account for almost all the remaining cases.³ In our patient, a pathogenic missense HRAS p.G12V variant of somatic origin was detected with DNA extraction and sequencing from a fresh tissue sample acquired from two 4-mm punch biopsies performed on the lesion. The following genes were sequenced and found to be uninvolved: BRAF, FGFR1, FGFR2, FGFR3, GNA11, GNAQ, KRAS, MAP3K3, NRAS, PIK3CA, and TEK. The Sanger sequencing method for comparative analysis performed on peripheral blood was negative.

Nevus sebaceus typically is caused by a sporadic mutation, though familial cases have been reported.¹ Additionally, germline HRAS mutations can lead to Costello syndrome, an autosomal-dominant disorder characterized by short stature; intellectual disabilities; coarse facial features; facial and perianal papillomata; cardiac defects; loose skin; joint hyperflexibility; and an increased risk for malignant tumors including rhabdomyosarcoma, neuroblastoma, and transitional cell carcinoma of the bladder.⁶

The diagnosis of NS often can be made clinically but can be difficult to confirm in underdeveloped lesions in young children. The differential diagnosis can include alopecia areata, aplasia cutis congenita, juvenile xanthogranuloma, epidermal nevus, de novo syringocystadenoma papilliferum, and solitary mastocytoma.¹ Nevus sebaceus can be associated with 4 additional syndromes: Schimmelpenning syndrome; phacomatosis pigmentokeratotica; didymosis aplasticosebacea; and SCALP (sebaceus nevus, central nervous system malformations, aplasia cutis congenital, limbal dermoid, pigmented nevus) syndrome.¹ Approximately 7% of NS cases may be associated with Schimmelpenning-Feuerstein-Mims (SFM) syndrome, a more severe condition that leads to systemic involvement and abnormalities in the neurological, ophthalmological, cardiovascular, genitourological, and skeletal systems.^1,3 Phacomatosis pigmentokeratotica has speckled lentiginous nevi, as well as abnormalities in the neurological, ophthalmological, cardiovascular, genitourological, and skeletal systems.¹ Didymosis aplasticosebacea is the concurrence of NS and aplasia cutis congenita.

The definitive treatment of NS is surgical excision. Alternative therapies include photodynamic therapy, fractional laser resurfacing, and dermabrasion; these are not definitive treatments, and patients must be monitored for the development of secondary neoplasms. Multiple variables must be considered when determining treatment, including patient age, risk potential for malignancy, and surgery-associated risks.¹ In our patient, given the extent of the lesions, active observation and follow-up was agreed upon for management.

This case demonstrates the importance of considering NS as an alternative diagnosis when alopecia areata has been diagnosed in a child who is unresponsive to treatments. After the diagnosis of NS is confirmed, more serious associated syndromes should be ruled out, and treatment should be tailored to each case.

To the Editor:

Chondrodermatitis nodularis helicis (CNH) is a benign inflammatory condition of the cartilage of the helix or antihelix as well as the overlying skin. Inflammation produces a firm painful nodule that often forms a central crust and enlarges rapidly, mimicking cutaneous malignancy. Chondrodermatitis nodularis helicis is believed to be caused by chronic pressure on the pinna, usually from sleeping, which causes compromised blood supply. However, there is a wide range of additional risk factors,¹ including trauma (eg, pressure), environmental insult (eg, sun or cold exposure), and autoimmune processes (eg, systemic lupus erythematosus, scleroderma). Chondrodermatitis nodularis helicis after Mohs micrographic surgery (MMS) is rare. We report a novel case of CNH as a postoperative complication of MMS following adjuvant radiation therapy.

A 61-year-old man presented to the MMS clinic for treatment of a primary squamous cell carcinoma of the right posterior helix. Stage I MMS demonstrated tumor invasion in the deep dermis directly overlying the auricular cartilage, as well as large-nerve (ie, >0.1 mm) perineural invasion. Two additional stages were taken; negative margins were obtained on Stage III. The defect was repaired by primary closure (Figure 1). Considering the presence of perineural invasion around a large nerve, the patient elected to receive adjuvant radiation therapy consisting of 50 Gy in 20 fractions administered to the right ear over 1 month.

Two months after completion of adjuvant radiation therapy, the patient returned to the clinic with a tender pink papule on the right crus within the radiation portal but nonadjacent to the surgical scar (Figure 2). Histopathology from a tangential biopsy revealed acanthosis, dermal sclerosis, and degenerated cartilage, consistent with CNH. Stellate fibroblasts also were seen, suggesting changes related to prior radiation therapy (Figure 3).

Although CNH is a benign condition, it can be concerning in the context of patient follow-up after MMS given its clinical appearance, which is similar to nonmelanoma skin cancer. The differential diagnosis of CNH includes hypertrophic actinic keratosis, basal cell carcinoma, and squamous cell carcinoma. The diagnosis is based on clinical history and confirmed by histopathologic examination.

Chondrodermatitis nodularis helicis in close proximity to a prior MMS site should lower the threshold for biopsy because the area is already known to be affected by actinic damage and cutaneous carcinogenesis. The histopathology of CNH often is characterized by epidermal acanthosis with ulceration, perichondral fibrosis, and a variable degree of cartilage degeneration associated with granulation tissue.²

The scarce subcutaneous tissue and limited blood supply of the pinna offer minimal cushioning and poor circulation to underlying cartilage. These anatomic features predispose the pinna to inflammation and ischemia.¹ Mohs micrographic surgery may inadvertently cause damage to surrounding tissue because of excision of cartilage, mechanical manipulation, severance of the extant blood supply, electrocautery, fenestration in preparation for skin grafting, compression from a wound dressing, and other factors related to surgery. In addition, following MMS, scar tissue and swelling with compression of adjacent structures can further inhibit circulation and lead to CNH.

In our case, multiple factors may have contributed to CNH after MMS, including postoperative swelling and compression, prior actinic damage, and other environmental factors. Given that CNH occurred within the radiation portal, we postulated that adjuvant radiation may have played a role in the pathogenesis of the patient’s CNH. Pandya et al³ reported CNH after radiation therapy for a brain tumor.

One prior study showed that CNH treated by surgical excision recurred in 34% of patients.⁴ In all of these patients, the CNH was completely excised; however, trauma from the surgical procedure itself likely resulted in recurrence of CNH. Darragh et al⁵ reported a case of CNH after MMS on the right nasal vestibule following wound reconstruction that utilized a cartilage graft from the right ear.

Our patient demonstrated an unusual but concerning complication associated with MMS. The location of CNH also was not in a traditional location but rather near the superior helical crus. Although CNH is benign by nature, it can mimic recurrence of a tumor when it presents close to the site of prior MMS. Diagnostic biopsy of CNH should be considered to rule out recurrence of skin cancer.

To the Editor:

Chondrodermatitis nodularis helicis (CNH) is a benign inflammatory condition of the cartilage of the helix or antihelix as well as the overlying skin. Inflammation produces a firm painful nodule that often forms a central crust and enlarges rapidly, mimicking cutaneous malignancy. Chondrodermatitis nodularis helicis is believed to be caused by chronic pressure on the pinna, usually from sleeping, which causes compromised blood supply. However, there is a wide range of additional risk factors,¹ including trauma (eg, pressure), environmental insult (eg, sun or cold exposure), and autoimmune processes (eg, systemic lupus erythematosus, scleroderma). Chondrodermatitis nodularis helicis after Mohs micrographic surgery (MMS) is rare. We report a novel case of CNH as a postoperative complication of MMS following adjuvant radiation therapy.

A 61-year-old man presented to the MMS clinic for treatment of a primary squamous cell carcinoma of the right posterior helix. Stage I MMS demonstrated tumor invasion in the deep dermis directly overlying the auricular cartilage, as well as large-nerve (ie, >0.1 mm) perineural invasion. Two additional stages were taken; negative margins were obtained on Stage III. The defect was repaired by primary closure (Figure 1). Considering the presence of perineural invasion around a large nerve, the patient elected to receive adjuvant radiation therapy consisting of 50 Gy in 20 fractions administered to the right ear over 1 month.

Two months after completion of adjuvant radiation therapy, the patient returned to the clinic with a tender pink papule on the right crus within the radiation portal but nonadjacent to the surgical scar (Figure 2). Histopathology from a tangential biopsy revealed acanthosis, dermal sclerosis, and degenerated cartilage, consistent with CNH. Stellate fibroblasts also were seen, suggesting changes related to prior radiation therapy (Figure 3).

Although CNH is a benign condition, it can be concerning in the context of patient follow-up after MMS given its clinical appearance, which is similar to nonmelanoma skin cancer. The differential diagnosis of CNH includes hypertrophic actinic keratosis, basal cell carcinoma, and squamous cell carcinoma. The diagnosis is based on clinical history and confirmed by histopathologic examination.

Chondrodermatitis nodularis helicis in close proximity to a prior MMS site should lower the threshold for biopsy because the area is already known to be affected by actinic damage and cutaneous carcinogenesis. The histopathology of CNH often is characterized by epidermal acanthosis with ulceration, perichondral fibrosis, and a variable degree of cartilage degeneration associated with granulation tissue.²

The scarce subcutaneous tissue and limited blood supply of the pinna offer minimal cushioning and poor circulation to underlying cartilage. These anatomic features predispose the pinna to inflammation and ischemia.¹ Mohs micrographic surgery may inadvertently cause damage to surrounding tissue because of excision of cartilage, mechanical manipulation, severance of the extant blood supply, electrocautery, fenestration in preparation for skin grafting, compression from a wound dressing, and other factors related to surgery. In addition, following MMS, scar tissue and swelling with compression of adjacent structures can further inhibit circulation and lead to CNH.

In our case, multiple factors may have contributed to CNH after MMS, including postoperative swelling and compression, prior actinic damage, and other environmental factors. Given that CNH occurred within the radiation portal, we postulated that adjuvant radiation may have played a role in the pathogenesis of the patient’s CNH. Pandya et al³ reported CNH after radiation therapy for a brain tumor.

One prior study showed that CNH treated by surgical excision recurred in 34% of patients.⁴ In all of these patients, the CNH was completely excised; however, trauma from the surgical procedure itself likely resulted in recurrence of CNH. Darragh et al⁵ reported a case of CNH after MMS on the right nasal vestibule following wound reconstruction that utilized a cartilage graft from the right ear.

Our patient demonstrated an unusual but concerning complication associated with MMS. The location of CNH also was not in a traditional location but rather near the superior helical crus. Although CNH is benign by nature, it can mimic recurrence of a tumor when it presents close to the site of prior MMS. Diagnostic biopsy of CNH should be considered to rule out recurrence of skin cancer.

To the Editor:

Chondrodermatitis nodularis helicis (CNH) is a benign inflammatory condition of the cartilage of the helix or antihelix as well as the overlying skin. Inflammation produces a firm painful nodule that often forms a central crust and enlarges rapidly, mimicking cutaneous malignancy. Chondrodermatitis nodularis helicis is believed to be caused by chronic pressure on the pinna, usually from sleeping, which causes compromised blood supply. However, there is a wide range of additional risk factors,¹ including trauma (eg, pressure), environmental insult (eg, sun or cold exposure), and autoimmune processes (eg, systemic lupus erythematosus, scleroderma). Chondrodermatitis nodularis helicis after Mohs micrographic surgery (MMS) is rare. We report a novel case of CNH as a postoperative complication of MMS following adjuvant radiation therapy.

A 61-year-old man presented to the MMS clinic for treatment of a primary squamous cell carcinoma of the right posterior helix. Stage I MMS demonstrated tumor invasion in the deep dermis directly overlying the auricular cartilage, as well as large-nerve (ie, >0.1 mm) perineural invasion. Two additional stages were taken; negative margins were obtained on Stage III. The defect was repaired by primary closure (Figure 1). Considering the presence of perineural invasion around a large nerve, the patient elected to receive adjuvant radiation therapy consisting of 50 Gy in 20 fractions administered to the right ear over 1 month.

Two months after completion of adjuvant radiation therapy, the patient returned to the clinic with a tender pink papule on the right crus within the radiation portal but nonadjacent to the surgical scar (Figure 2). Histopathology from a tangential biopsy revealed acanthosis, dermal sclerosis, and degenerated cartilage, consistent with CNH. Stellate fibroblasts also were seen, suggesting changes related to prior radiation therapy (Figure 3).

Although CNH is a benign condition, it can be concerning in the context of patient follow-up after MMS given its clinical appearance, which is similar to nonmelanoma skin cancer. The differential diagnosis of CNH includes hypertrophic actinic keratosis, basal cell carcinoma, and squamous cell carcinoma. The diagnosis is based on clinical history and confirmed by histopathologic examination.

Chondrodermatitis nodularis helicis in close proximity to a prior MMS site should lower the threshold for biopsy because the area is already known to be affected by actinic damage and cutaneous carcinogenesis. The histopathology of CNH often is characterized by epidermal acanthosis with ulceration, perichondral fibrosis, and a variable degree of cartilage degeneration associated with granulation tissue.²

The scarce subcutaneous tissue and limited blood supply of the pinna offer minimal cushioning and poor circulation to underlying cartilage. These anatomic features predispose the pinna to inflammation and ischemia.¹ Mohs micrographic surgery may inadvertently cause damage to surrounding tissue because of excision of cartilage, mechanical manipulation, severance of the extant blood supply, electrocautery, fenestration in preparation for skin grafting, compression from a wound dressing, and other factors related to surgery. In addition, following MMS, scar tissue and swelling with compression of adjacent structures can further inhibit circulation and lead to CNH.

In our case, multiple factors may have contributed to CNH after MMS, including postoperative swelling and compression, prior actinic damage, and other environmental factors. Given that CNH occurred within the radiation portal, we postulated that adjuvant radiation may have played a role in the pathogenesis of the patient’s CNH. Pandya et al³ reported CNH after radiation therapy for a brain tumor.

One prior study showed that CNH treated by surgical excision recurred in 34% of patients.⁴ In all of these patients, the CNH was completely excised; however, trauma from the surgical procedure itself likely resulted in recurrence of CNH. Darragh et al⁵ reported a case of CNH after MMS on the right nasal vestibule following wound reconstruction that utilized a cartilage graft from the right ear.

Our patient demonstrated an unusual but concerning complication associated with MMS. The location of CNH also was not in a traditional location but rather near the superior helical crus. Although CNH is benign by nature, it can mimic recurrence of a tumor when it presents close to the site of prior MMS. Diagnostic biopsy of CNH should be considered to rule out recurrence of skin cancer.

To the Editor:

A 67-year-old woman presented to the hospital with painful hands and feet. Two weeks prior, the patient experienced a few days of intermittent purple discoloration of the fingers, followed by black discoloration of the fingers, toes, and nose with notable pain. She reported no illness preceding the presenting symptoms, and there was no progression of symptoms in the days preceding presentation.

The patient had a history of smoking. She had a medical history of chronic obstructive pulmonary disease as well as recurrent non–small cell lung cancer that was treated most recently with a 1-year course of the programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor durvalumab (last treatment was 4 months prior to the current presentation).

Physical examination revealed necrosis of the tips of the second, third, and fourth fingers of the left hand, as well as the tips of the third and fourth fingers of the right hand, progressing to purpura proximally on all involved fingers (Figure, A); scattered purpura and necrotic papules on the toe pads (Figure, B); and a 2- to 3-cm black plaque on the nasal tip. The patient was afebrile.

An embolic and vascular workup was performed. Transthoracic echocardiography was negative for thrombi, ankle brachial indices were within reference range, and computed tomography angiography revealed a few nonocclusive coronary plaques. Conventional angiography was not performed.

Laboratory testing revealed a mildly elevated level of cryofibrinogens (cryocrit, 2.5%); cold agglutinins (1:32); mild monoclonal κ IgG gammopathy (0.1 g/dL); and elevated inflammatory markers (C-reactive protein, 76 mg/L [reference range, 0–10 mg/L]; erythrocyte sedimentation rate, 38 mm/h [reference range, 0–20 mm/h]; fibrinogen, 571 mg/dL [reference range, 150–450 mg/dL]; and ferritin, 394 ng/mL [reference range, 10–180 ng/mL]). Additional laboratory studies were negative or within reference range, including tests of anti-RNA polymerase antibody, rheumatoid factor, antinuclear antibody, anticardiolipin antibody, anti-β₂ glycoprotein antibody, antineutrophil cytoplasmic antibodies (myeloperoxidase and proteinase-3), cryoglobulins, and complement; human immunodeficiency virus and hepatitis B and C virus serologic studies; prothrombin time, partial thromboplastin time, and lupus anticoagulant; and a heparin-induced thrombocytopenia panel.

A skin biopsy adjacent to an area of necrosis on the finger showed thickened walls of dermal vessels, sparse leukocytoclastic debris, and evidence of recanalizing medium-sized vessels. Direct immunofluorescence studies were negative.

Based on the clinical history and histologic findings showing an absence of vasculitis, a diagnosis of acral necrosis associated with the PD-L1 immune checkpoint inhibitor durvalumab—a delayed immune-related event (DIRE)—was favored. The calcium channel blocker amlodipine was started at a dosage of 2.5 mg/d orally. Necrosis of the toes resolved over the course of 1 week; however, necrosis of the fingers remained unchanged. After 1 week of hospitalization, the patient was discharged at her request.

Acral necrosis following immune checkpoint inhibitor therapy has been reported as a rare and recalcitrant immune-related adverse event (AE).^1-4 However, our patient’s symptoms occurred months after treatment was discontinued, which is consistent with a DIRE.⁵ The course of acral necrosis begins with acrocyanosis (a Raynaud disease–like phenomenon) of the fingers that progresses to necrosis. A history of Raynaud disease or other autoimmune disorder generally is absent.¹ Our patient’s history indicated actively smoking at the time of presentation, similar to a case described by Khaddour et al.¹ Similarly, in a case presented by Comont et al,³ the patient also had a history of smoking. In a recent study of acute vascular events associated with immune checkpoint inhibitors, 16 of 31 patients had a history of smoking.⁶

No definitive diagnostic laboratory or pathologic findings are associated with acral necrosis following immune checkpoint inhibitor therapy. Histopathologic analysis does not demonstrate vasculitis or other overt vascular pathology.^2,3

The optimal treatment of immune checkpoint inhibitor–associated digital necrosis is unclear. Corticosteroids and discontinuation of the immune checkpoint inhibitor generally are employed,^1-4 though treatment response has been variable. Other therapies such as calcium channel blockers (as in our case), sympathectomy,¹ epoprostenol, botulinum injection, rituximab,² and alprostadil⁴ have been attempted without clear effect.

We considered a diagnosis of paraneoplastic acral vascular syndrome in our patient, which was ruled out because the syndrome typically occurs in the setting of a worsening underlying malignancy⁷; our patient’s cancer was stable to improved. Thromboangiitis obliterans was ruled out by the absence of a characteristic thrombus on biopsy, the patient’s older age, and involvement of the nose.

We report an unusual case of acral necrosis occurring as a DIRE in response to administration of an immune checkpoint inhibitor. Further description is needed to clarify the diagnostic criteria for and treatment of this rare autoimmune phenomenon.

To the Editor:

A 67-year-old woman presented to the hospital with painful hands and feet. Two weeks prior, the patient experienced a few days of intermittent purple discoloration of the fingers, followed by black discoloration of the fingers, toes, and nose with notable pain. She reported no illness preceding the presenting symptoms, and there was no progression of symptoms in the days preceding presentation.

The patient had a history of smoking. She had a medical history of chronic obstructive pulmonary disease as well as recurrent non–small cell lung cancer that was treated most recently with a 1-year course of the programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor durvalumab (last treatment was 4 months prior to the current presentation).

Physical examination revealed necrosis of the tips of the second, third, and fourth fingers of the left hand, as well as the tips of the third and fourth fingers of the right hand, progressing to purpura proximally on all involved fingers (Figure, A); scattered purpura and necrotic papules on the toe pads (Figure, B); and a 2- to 3-cm black plaque on the nasal tip. The patient was afebrile.

An embolic and vascular workup was performed. Transthoracic echocardiography was negative for thrombi, ankle brachial indices were within reference range, and computed tomography angiography revealed a few nonocclusive coronary plaques. Conventional angiography was not performed.

Laboratory testing revealed a mildly elevated level of cryofibrinogens (cryocrit, 2.5%); cold agglutinins (1:32); mild monoclonal κ IgG gammopathy (0.1 g/dL); and elevated inflammatory markers (C-reactive protein, 76 mg/L [reference range, 0–10 mg/L]; erythrocyte sedimentation rate, 38 mm/h [reference range, 0–20 mm/h]; fibrinogen, 571 mg/dL [reference range, 150–450 mg/dL]; and ferritin, 394 ng/mL [reference range, 10–180 ng/mL]). Additional laboratory studies were negative or within reference range, including tests of anti-RNA polymerase antibody, rheumatoid factor, antinuclear antibody, anticardiolipin antibody, anti-β₂ glycoprotein antibody, antineutrophil cytoplasmic antibodies (myeloperoxidase and proteinase-3), cryoglobulins, and complement; human immunodeficiency virus and hepatitis B and C virus serologic studies; prothrombin time, partial thromboplastin time, and lupus anticoagulant; and a heparin-induced thrombocytopenia panel.

A skin biopsy adjacent to an area of necrosis on the finger showed thickened walls of dermal vessels, sparse leukocytoclastic debris, and evidence of recanalizing medium-sized vessels. Direct immunofluorescence studies were negative.

Based on the clinical history and histologic findings showing an absence of vasculitis, a diagnosis of acral necrosis associated with the PD-L1 immune checkpoint inhibitor durvalumab—a delayed immune-related event (DIRE)—was favored. The calcium channel blocker amlodipine was started at a dosage of 2.5 mg/d orally. Necrosis of the toes resolved over the course of 1 week; however, necrosis of the fingers remained unchanged. After 1 week of hospitalization, the patient was discharged at her request.

Acral necrosis following immune checkpoint inhibitor therapy has been reported as a rare and recalcitrant immune-related adverse event (AE).^1-4 However, our patient’s symptoms occurred months after treatment was discontinued, which is consistent with a DIRE.⁵ The course of acral necrosis begins with acrocyanosis (a Raynaud disease–like phenomenon) of the fingers that progresses to necrosis. A history of Raynaud disease or other autoimmune disorder generally is absent.¹ Our patient’s history indicated actively smoking at the time of presentation, similar to a case described by Khaddour et al.¹ Similarly, in a case presented by Comont et al,³ the patient also had a history of smoking. In a recent study of acute vascular events associated with immune checkpoint inhibitors, 16 of 31 patients had a history of smoking.⁶

No definitive diagnostic laboratory or pathologic findings are associated with acral necrosis following immune checkpoint inhibitor therapy. Histopathologic analysis does not demonstrate vasculitis or other overt vascular pathology.^2,3

The optimal treatment of immune checkpoint inhibitor–associated digital necrosis is unclear. Corticosteroids and discontinuation of the immune checkpoint inhibitor generally are employed,^1-4 though treatment response has been variable. Other therapies such as calcium channel blockers (as in our case), sympathectomy,¹ epoprostenol, botulinum injection, rituximab,² and alprostadil⁴ have been attempted without clear effect.

We considered a diagnosis of paraneoplastic acral vascular syndrome in our patient, which was ruled out because the syndrome typically occurs in the setting of a worsening underlying malignancy⁷; our patient’s cancer was stable to improved. Thromboangiitis obliterans was ruled out by the absence of a characteristic thrombus on biopsy, the patient’s older age, and involvement of the nose.

We report an unusual case of acral necrosis occurring as a DIRE in response to administration of an immune checkpoint inhibitor. Further description is needed to clarify the diagnostic criteria for and treatment of this rare autoimmune phenomenon.

To the Editor:

A 67-year-old woman presented to the hospital with painful hands and feet. Two weeks prior, the patient experienced a few days of intermittent purple discoloration of the fingers, followed by black discoloration of the fingers, toes, and nose with notable pain. She reported no illness preceding the presenting symptoms, and there was no progression of symptoms in the days preceding presentation.

The patient had a history of smoking. She had a medical history of chronic obstructive pulmonary disease as well as recurrent non–small cell lung cancer that was treated most recently with a 1-year course of the programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor durvalumab (last treatment was 4 months prior to the current presentation).

Physical examination revealed necrosis of the tips of the second, third, and fourth fingers of the left hand, as well as the tips of the third and fourth fingers of the right hand, progressing to purpura proximally on all involved fingers (Figure, A); scattered purpura and necrotic papules on the toe pads (Figure, B); and a 2- to 3-cm black plaque on the nasal tip. The patient was afebrile.

An embolic and vascular workup was performed. Transthoracic echocardiography was negative for thrombi, ankle brachial indices were within reference range, and computed tomography angiography revealed a few nonocclusive coronary plaques. Conventional angiography was not performed.

Laboratory testing revealed a mildly elevated level of cryofibrinogens (cryocrit, 2.5%); cold agglutinins (1:32); mild monoclonal κ IgG gammopathy (0.1 g/dL); and elevated inflammatory markers (C-reactive protein, 76 mg/L [reference range, 0–10 mg/L]; erythrocyte sedimentation rate, 38 mm/h [reference range, 0–20 mm/h]; fibrinogen, 571 mg/dL [reference range, 150–450 mg/dL]; and ferritin, 394 ng/mL [reference range, 10–180 ng/mL]). Additional laboratory studies were negative or within reference range, including tests of anti-RNA polymerase antibody, rheumatoid factor, antinuclear antibody, anticardiolipin antibody, anti-β₂ glycoprotein antibody, antineutrophil cytoplasmic antibodies (myeloperoxidase and proteinase-3), cryoglobulins, and complement; human immunodeficiency virus and hepatitis B and C virus serologic studies; prothrombin time, partial thromboplastin time, and lupus anticoagulant; and a heparin-induced thrombocytopenia panel.

A skin biopsy adjacent to an area of necrosis on the finger showed thickened walls of dermal vessels, sparse leukocytoclastic debris, and evidence of recanalizing medium-sized vessels. Direct immunofluorescence studies were negative.

Based on the clinical history and histologic findings showing an absence of vasculitis, a diagnosis of acral necrosis associated with the PD-L1 immune checkpoint inhibitor durvalumab—a delayed immune-related event (DIRE)—was favored. The calcium channel blocker amlodipine was started at a dosage of 2.5 mg/d orally. Necrosis of the toes resolved over the course of 1 week; however, necrosis of the fingers remained unchanged. After 1 week of hospitalization, the patient was discharged at her request.

Acral necrosis following immune checkpoint inhibitor therapy has been reported as a rare and recalcitrant immune-related adverse event (AE).^1-4 However, our patient’s symptoms occurred months after treatment was discontinued, which is consistent with a DIRE.⁵ The course of acral necrosis begins with acrocyanosis (a Raynaud disease–like phenomenon) of the fingers that progresses to necrosis. A history of Raynaud disease or other autoimmune disorder generally is absent.¹ Our patient’s history indicated actively smoking at the time of presentation, similar to a case described by Khaddour et al.¹ Similarly, in a case presented by Comont et al,³ the patient also had a history of smoking. In a recent study of acute vascular events associated with immune checkpoint inhibitors, 16 of 31 patients had a history of smoking.⁶

No definitive diagnostic laboratory or pathologic findings are associated with acral necrosis following immune checkpoint inhibitor therapy. Histopathologic analysis does not demonstrate vasculitis or other overt vascular pathology.^2,3

The optimal treatment of immune checkpoint inhibitor–associated digital necrosis is unclear. Corticosteroids and discontinuation of the immune checkpoint inhibitor generally are employed,^1-4 though treatment response has been variable. Other therapies such as calcium channel blockers (as in our case), sympathectomy,¹ epoprostenol, botulinum injection, rituximab,² and alprostadil⁴ have been attempted without clear effect.

We considered a diagnosis of paraneoplastic acral vascular syndrome in our patient, which was ruled out because the syndrome typically occurs in the setting of a worsening underlying malignancy⁷; our patient’s cancer was stable to improved. Thromboangiitis obliterans was ruled out by the absence of a characteristic thrombus on biopsy, the patient’s older age, and involvement of the nose.

We report an unusual case of acral necrosis occurring as a DIRE in response to administration of an immune checkpoint inhibitor. Further description is needed to clarify the diagnostic criteria for and treatment of this rare autoimmune phenomenon.

To the Editor:

Programmed cell death protein 1 (PD-1) inhibitors have been widely used in the treatment of various cancers. Programmed cell death-ligand 1 (PD-L1) and programmed cell death-ligand 2 located on cancer cells will bind to PD-1 receptors on T cells and suppress them, which will prevent cancer cell destruction. Programmed cell death protein 1 inhibitors block the binding of PD-L1 to cancer cells, which then prevents T-cell immunosuppression.¹ However, cutaneous adverse effects have been associated with PD-1 inhibitors. Dermatitis associated with PD-1 inhibitor therapy occurs more frequently in patients with cutaneous tumors such as melanoma compared to those with head and neck cancers.² Curry et al¹ reported that treatment with an immune checkpoint blockade can lead to immune-related adverse effects, most commonly affecting the gastrointestinal tract, liver, and skin. The same report cited dermatologic toxicity as an adverse effect in approximately 39% of patients treated with anti–PD-1 and approximately 17% of anti–PD-L1.¹ The 4 main categories of dermatologic toxicities to immunotherapies in general include inflammatory disorders, immunobullous disorders, alterations of keratinocytes, and alteration of melanocytes. The most common adverse effects from the use of the PD-1 inhibitor nivolumab were skin rashes, not otherwise specified (14%–20%), pruritus (13%–18%), and vitiligo (~8%).¹ Of the cutaneous dermatitic reactions to PD-1 and PD-L1 inhibitors that were biopsied, the 2 most common were lichenoid dermatitis and spongiotic dermatitis.² Seldomly, there have been reports of keratoacanthomas (KAs) in association with anti–PD-1 therapy.³

A KA is a common skin tumor that appears most frequently as a solitary lesion and is thought to arise from the hair follicle.⁴ It resembles squamous cell carcinoma and commonly regresses within months without intervention. Exposure to UV light is a known risk factor for the development of KAs.

Eruptive KAs have been found in association with 10 cases of various cancers treated with the PD-1 inhibitors pembrolizumab and nivolumab.³ Multiple lesions on photodistributed areas of the body were reported in all 10 cases. Various treatments were used in these 10 cases—doxycycline and niacinamide, electrodesiccation and curettage, clobetasol ointment and/or intralesional triamcinolone, cryotherapy, imiquimod, or no treatment—as well as the cessation of PD-1 inhibitor therapy, with 4 cases continuing therapy and 6 cases discontinuing therapy. Nine cases regressed by 6 months; electrodesiccation and curettage of the lesions was used in the tenth case.³ We report a case of eruptive KA after 1 cycle of nivolumab therapy for metastatic melanoma.

A 79-year-old woman with stage III melanoma presented to her dermatologist after developing generalized pruritic lichenoid eruptions involving the torso, arms, and legs, as well as erosions on the lips, buccal mucosa, and palate 1 month after starting nivolumab therapy. The patient initially presented to dermatology with an irregularly shaped lesion on the left upper back 3 months prior. Biopsy results at that time revealed a diagnosis of malignant melanoma, lentigo maligna type. The lesion was 1.5-mm thick and classified as Clark level IV with a mitotic count of 6 per mm². Molecular genetic studies showed expression of PD-L1 and no expression of c-KIT. The patient underwent wide local excision, and a sentinel lymph node biopsy was positive. Positron emission tomography did not show any hypermetabolic lesions, and magnetic resonance imaging did not indicate brain metastasis. The patient underwent an axillary dissection, which did not show any residual melanoma. She was started on adjuvant immunotherapy with intravenous nivolumab 480 mg monthly and developed pruritic crusted lesions on the arms, legs, and torso 1 month later, which prompted follow-up to dermatology.

At the current presentation 4 months after the onset of lesions, physical examination revealed lichenoid patches with serous crusting that were concentrated on the torso but also affected the arms and legs. She developed erosions on the upper and lower lips, buccal mucosa, and hard and soft palates, as well as painful, erythematous, dome-shaped papules and nodules on the legs (Figure 1). Her oncologist previously had initiated treatment at the onset of the lesions with clobetasol cream and valacyclovir for the lesions, but the patient showed no improvement.

Four months after the onset of the lesions, the patient was re-referred to her dermatologist, and a biopsy was performed on the left lower leg that showed squamous cell carcinoma, KA type. Additionally, flat erythematous patches were seen on the legs that were consistent with a lichenoid drug eruption. Two weeks later, she was started on halobetasol propionate ointment 0.05% for treatment of the KAs. At 2-week follow-up, 5 months after the onset of the lesions, the patient showed no signs of improvement. An oral prednisone taper of 60 mg for 3 days, 40 mg for 3 days, and then 20 mg daily for a total of 4 weeks was started to treat the lichenoid dermatitis and eruptive KAs. At the next follow-up 6.5 months following the first eruptive KAs, she was no longer using topical or oral steroids, she did not have any new eruptive KAs, and old lesions showed regression (Figure 2). The patient still experienced postinflammatory erythema and hyperpigmentation at the location of the KAs but showed improvement of the lichenoid drug eruption.

We describe a case of eruptive KAs after use of a PD-1 inhibitor for treatment of melanoma. Our patient developed eruptive KAs after only 1 nivolumab treatment. Another report described onset of eruptive KAs after 1 month of nivolumab infusions.³ The KAs experienced by our patient took 6.5 months to regress, which is unusual compared to other case reports in which the KAs self-resolved within a few months, though one other case described lesions that persisted for 6 months.³

Our patient was treated with topical steroids and an oral steroid taper for the concomitant lichenoid drug eruption. It is unknown if the steroids affected the course of the KAs or if they spontaneously regressed on their own. Freites-Martinez et al⁵ described that regression of KAs may be related to an immune response, but corticosteroids are inherently immunosuppressive. They hypothesized that corticosteroids help to temper the heightened immune response of eruptive KAs.⁵

Our patient had oral ulcers, which may have been indicative of an oral lichenoid drug eruption, as well as skin lesions representative of a cutaneous lichenoid drug eruption. This is a favorable reaction, as lichenoid dermatitis is thought to represent successful PD-1 inhibition and therefore a better response to oncologic therapies.² Comorbid lichenoid drug eruption lesions and eruptive KAs may be suggestive of increased T-cell activity,^2,6,7 though some prior case studies have reported eruptive KAs in isolation.³

Discontinuation of immunotherapy due to development of eruptive KAs presents a challenge in the treatment of underlying malignancies such as melanoma. Immunotherapy was discontinued in 7 of 11 cases due to these cutaneous reactions.³ Similarly, our patient underwent only 1 cycle of immunotherapy before developing eruptive KAs and discontinuing PD-1 inhibitor therapy. If we are better able to treat eruptive KAs, then patients can remain on immunotherapy to treat underlying malignancies. Crow et al⁸ showed improvement in lesions when 3 patients with eruptive KAs were treated with hydroxychloroquine; the Goeckerman regimen consisting of steroids, UVB phototherapy, and crude coal tar; and Unna boots with zinc oxide and compression stockings. The above may be added to a list of possible treatments to consider for hastening the regression of eruptive KAs.

Our patient’s clinical course was similar to reports on the regressive nature of eruptive KAs within 6 months after initial eruption. Although it is likely that KAs will regress on their own, treatment modalities that speed up recovery are a future source for research.

To the Editor:

Programmed cell death protein 1 (PD-1) inhibitors have been widely used in the treatment of various cancers. Programmed cell death-ligand 1 (PD-L1) and programmed cell death-ligand 2 located on cancer cells will bind to PD-1 receptors on T cells and suppress them, which will prevent cancer cell destruction. Programmed cell death protein 1 inhibitors block the binding of PD-L1 to cancer cells, which then prevents T-cell immunosuppression.¹ However, cutaneous adverse effects have been associated with PD-1 inhibitors. Dermatitis associated with PD-1 inhibitor therapy occurs more frequently in patients with cutaneous tumors such as melanoma compared to those with head and neck cancers.² Curry et al¹ reported that treatment with an immune checkpoint blockade can lead to immune-related adverse effects, most commonly affecting the gastrointestinal tract, liver, and skin. The same report cited dermatologic toxicity as an adverse effect in approximately 39% of patients treated with anti–PD-1 and approximately 17% of anti–PD-L1.¹ The 4 main categories of dermatologic toxicities to immunotherapies in general include inflammatory disorders, immunobullous disorders, alterations of keratinocytes, and alteration of melanocytes. The most common adverse effects from the use of the PD-1 inhibitor nivolumab were skin rashes, not otherwise specified (14%–20%), pruritus (13%–18%), and vitiligo (~8%).¹ Of the cutaneous dermatitic reactions to PD-1 and PD-L1 inhibitors that were biopsied, the 2 most common were lichenoid dermatitis and spongiotic dermatitis.² Seldomly, there have been reports of keratoacanthomas (KAs) in association with anti–PD-1 therapy.³

A KA is a common skin tumor that appears most frequently as a solitary lesion and is thought to arise from the hair follicle.⁴ It resembles squamous cell carcinoma and commonly regresses within months without intervention. Exposure to UV light is a known risk factor for the development of KAs.

Eruptive KAs have been found in association with 10 cases of various cancers treated with the PD-1 inhibitors pembrolizumab and nivolumab.³ Multiple lesions on photodistributed areas of the body were reported in all 10 cases. Various treatments were used in these 10 cases—doxycycline and niacinamide, electrodesiccation and curettage, clobetasol ointment and/or intralesional triamcinolone, cryotherapy, imiquimod, or no treatment—as well as the cessation of PD-1 inhibitor therapy, with 4 cases continuing therapy and 6 cases discontinuing therapy. Nine cases regressed by 6 months; electrodesiccation and curettage of the lesions was used in the tenth case.³ We report a case of eruptive KA after 1 cycle of nivolumab therapy for metastatic melanoma.

A 79-year-old woman with stage III melanoma presented to her dermatologist after developing generalized pruritic lichenoid eruptions involving the torso, arms, and legs, as well as erosions on the lips, buccal mucosa, and palate 1 month after starting nivolumab therapy. The patient initially presented to dermatology with an irregularly shaped lesion on the left upper back 3 months prior. Biopsy results at that time revealed a diagnosis of malignant melanoma, lentigo maligna type. The lesion was 1.5-mm thick and classified as Clark level IV with a mitotic count of 6 per mm². Molecular genetic studies showed expression of PD-L1 and no expression of c-KIT. The patient underwent wide local excision, and a sentinel lymph node biopsy was positive. Positron emission tomography did not show any hypermetabolic lesions, and magnetic resonance imaging did not indicate brain metastasis. The patient underwent an axillary dissection, which did not show any residual melanoma. She was started on adjuvant immunotherapy with intravenous nivolumab 480 mg monthly and developed pruritic crusted lesions on the arms, legs, and torso 1 month later, which prompted follow-up to dermatology.

At the current presentation 4 months after the onset of lesions, physical examination revealed lichenoid patches with serous crusting that were concentrated on the torso but also affected the arms and legs. She developed erosions on the upper and lower lips, buccal mucosa, and hard and soft palates, as well as painful, erythematous, dome-shaped papules and nodules on the legs (Figure 1). Her oncologist previously had initiated treatment at the onset of the lesions with clobetasol cream and valacyclovir for the lesions, but the patient showed no improvement.

Four months after the onset of the lesions, the patient was re-referred to her dermatologist, and a biopsy was performed on the left lower leg that showed squamous cell carcinoma, KA type. Additionally, flat erythematous patches were seen on the legs that were consistent with a lichenoid drug eruption. Two weeks later, she was started on halobetasol propionate ointment 0.05% for treatment of the KAs. At 2-week follow-up, 5 months after the onset of the lesions, the patient showed no signs of improvement. An oral prednisone taper of 60 mg for 3 days, 40 mg for 3 days, and then 20 mg daily for a total of 4 weeks was started to treat the lichenoid dermatitis and eruptive KAs. At the next follow-up 6.5 months following the first eruptive KAs, she was no longer using topical or oral steroids, she did not have any new eruptive KAs, and old lesions showed regression (Figure 2). The patient still experienced postinflammatory erythema and hyperpigmentation at the location of the KAs but showed improvement of the lichenoid drug eruption.

We describe a case of eruptive KAs after use of a PD-1 inhibitor for treatment of melanoma. Our patient developed eruptive KAs after only 1 nivolumab treatment. Another report described onset of eruptive KAs after 1 month of nivolumab infusions.³ The KAs experienced by our patient took 6.5 months to regress, which is unusual compared to other case reports in which the KAs self-resolved within a few months, though one other case described lesions that persisted for 6 months.³

Our patient was treated with topical steroids and an oral steroid taper for the concomitant lichenoid drug eruption. It is unknown if the steroids affected the course of the KAs or if they spontaneously regressed on their own. Freites-Martinez et al⁵ described that regression of KAs may be related to an immune response, but corticosteroids are inherently immunosuppressive. They hypothesized that corticosteroids help to temper the heightened immune response of eruptive KAs.⁵

Our patient had oral ulcers, which may have been indicative of an oral lichenoid drug eruption, as well as skin lesions representative of a cutaneous lichenoid drug eruption. This is a favorable reaction, as lichenoid dermatitis is thought to represent successful PD-1 inhibition and therefore a better response to oncologic therapies.² Comorbid lichenoid drug eruption lesions and eruptive KAs may be suggestive of increased T-cell activity,^2,6,7 though some prior case studies have reported eruptive KAs in isolation.³

Discontinuation of immunotherapy due to development of eruptive KAs presents a challenge in the treatment of underlying malignancies such as melanoma. Immunotherapy was discontinued in 7 of 11 cases due to these cutaneous reactions.³ Similarly, our patient underwent only 1 cycle of immunotherapy before developing eruptive KAs and discontinuing PD-1 inhibitor therapy. If we are better able to treat eruptive KAs, then patients can remain on immunotherapy to treat underlying malignancies. Crow et al⁸ showed improvement in lesions when 3 patients with eruptive KAs were treated with hydroxychloroquine; the Goeckerman regimen consisting of steroids, UVB phototherapy, and crude coal tar; and Unna boots with zinc oxide and compression stockings. The above may be added to a list of possible treatments to consider for hastening the regression of eruptive KAs.

Our patient’s clinical course was similar to reports on the regressive nature of eruptive KAs within 6 months after initial eruption. Although it is likely that KAs will regress on their own, treatment modalities that speed up recovery are a future source for research.

To the Editor:

Programmed cell death protein 1 (PD-1) inhibitors have been widely used in the treatment of various cancers. Programmed cell death-ligand 1 (PD-L1) and programmed cell death-ligand 2 located on cancer cells will bind to PD-1 receptors on T cells and suppress them, which will prevent cancer cell destruction. Programmed cell death protein 1 inhibitors block the binding of PD-L1 to cancer cells, which then prevents T-cell immunosuppression.¹ However, cutaneous adverse effects have been associated with PD-1 inhibitors. Dermatitis associated with PD-1 inhibitor therapy occurs more frequently in patients with cutaneous tumors such as melanoma compared to those with head and neck cancers.² Curry et al¹ reported that treatment with an immune checkpoint blockade can lead to immune-related adverse effects, most commonly affecting the gastrointestinal tract, liver, and skin. The same report cited dermatologic toxicity as an adverse effect in approximately 39% of patients treated with anti–PD-1 and approximately 17% of anti–PD-L1.¹ The 4 main categories of dermatologic toxicities to immunotherapies in general include inflammatory disorders, immunobullous disorders, alterations of keratinocytes, and alteration of melanocytes. The most common adverse effects from the use of the PD-1 inhibitor nivolumab were skin rashes, not otherwise specified (14%–20%), pruritus (13%–18%), and vitiligo (~8%).¹ Of the cutaneous dermatitic reactions to PD-1 and PD-L1 inhibitors that were biopsied, the 2 most common were lichenoid dermatitis and spongiotic dermatitis.² Seldomly, there have been reports of keratoacanthomas (KAs) in association with anti–PD-1 therapy.³

A KA is a common skin tumor that appears most frequently as a solitary lesion and is thought to arise from the hair follicle.⁴ It resembles squamous cell carcinoma and commonly regresses within months without intervention. Exposure to UV light is a known risk factor for the development of KAs.

Eruptive KAs have been found in association with 10 cases of various cancers treated with the PD-1 inhibitors pembrolizumab and nivolumab.³ Multiple lesions on photodistributed areas of the body were reported in all 10 cases. Various treatments were used in these 10 cases—doxycycline and niacinamide, electrodesiccation and curettage, clobetasol ointment and/or intralesional triamcinolone, cryotherapy, imiquimod, or no treatment—as well as the cessation of PD-1 inhibitor therapy, with 4 cases continuing therapy and 6 cases discontinuing therapy. Nine cases regressed by 6 months; electrodesiccation and curettage of the lesions was used in the tenth case.³ We report a case of eruptive KA after 1 cycle of nivolumab therapy for metastatic melanoma.

A 79-year-old woman with stage III melanoma presented to her dermatologist after developing generalized pruritic lichenoid eruptions involving the torso, arms, and legs, as well as erosions on the lips, buccal mucosa, and palate 1 month after starting nivolumab therapy. The patient initially presented to dermatology with an irregularly shaped lesion on the left upper back 3 months prior. Biopsy results at that time revealed a diagnosis of malignant melanoma, lentigo maligna type. The lesion was 1.5-mm thick and classified as Clark level IV with a mitotic count of 6 per mm². Molecular genetic studies showed expression of PD-L1 and no expression of c-KIT. The patient underwent wide local excision, and a sentinel lymph node biopsy was positive. Positron emission tomography did not show any hypermetabolic lesions, and magnetic resonance imaging did not indicate brain metastasis. The patient underwent an axillary dissection, which did not show any residual melanoma. She was started on adjuvant immunotherapy with intravenous nivolumab 480 mg monthly and developed pruritic crusted lesions on the arms, legs, and torso 1 month later, which prompted follow-up to dermatology.

At the current presentation 4 months after the onset of lesions, physical examination revealed lichenoid patches with serous crusting that were concentrated on the torso but also affected the arms and legs. She developed erosions on the upper and lower lips, buccal mucosa, and hard and soft palates, as well as painful, erythematous, dome-shaped papules and nodules on the legs (Figure 1). Her oncologist previously had initiated treatment at the onset of the lesions with clobetasol cream and valacyclovir for the lesions, but the patient showed no improvement.

Four months after the onset of the lesions, the patient was re-referred to her dermatologist, and a biopsy was performed on the left lower leg that showed squamous cell carcinoma, KA type. Additionally, flat erythematous patches were seen on the legs that were consistent with a lichenoid drug eruption. Two weeks later, she was started on halobetasol propionate ointment 0.05% for treatment of the KAs. At 2-week follow-up, 5 months after the onset of the lesions, the patient showed no signs of improvement. An oral prednisone taper of 60 mg for 3 days, 40 mg for 3 days, and then 20 mg daily for a total of 4 weeks was started to treat the lichenoid dermatitis and eruptive KAs. At the next follow-up 6.5 months following the first eruptive KAs, she was no longer using topical or oral steroids, she did not have any new eruptive KAs, and old lesions showed regression (Figure 2). The patient still experienced postinflammatory erythema and hyperpigmentation at the location of the KAs but showed improvement of the lichenoid drug eruption.

We describe a case of eruptive KAs after use of a PD-1 inhibitor for treatment of melanoma. Our patient developed eruptive KAs after only 1 nivolumab treatment. Another report described onset of eruptive KAs after 1 month of nivolumab infusions.³ The KAs experienced by our patient took 6.5 months to regress, which is unusual compared to other case reports in which the KAs self-resolved within a few months, though one other case described lesions that persisted for 6 months.³

Our patient was treated with topical steroids and an oral steroid taper for the concomitant lichenoid drug eruption. It is unknown if the steroids affected the course of the KAs or if they spontaneously regressed on their own. Freites-Martinez et al⁵ described that regression of KAs may be related to an immune response, but corticosteroids are inherently immunosuppressive. They hypothesized that corticosteroids help to temper the heightened immune response of eruptive KAs.⁵

Our patient had oral ulcers, which may have been indicative of an oral lichenoid drug eruption, as well as skin lesions representative of a cutaneous lichenoid drug eruption. This is a favorable reaction, as lichenoid dermatitis is thought to represent successful PD-1 inhibition and therefore a better response to oncologic therapies.² Comorbid lichenoid drug eruption lesions and eruptive KAs may be suggestive of increased T-cell activity,^2,6,7 though some prior case studies have reported eruptive KAs in isolation.³

Discontinuation of immunotherapy due to development of eruptive KAs presents a challenge in the treatment of underlying malignancies such as melanoma. Immunotherapy was discontinued in 7 of 11 cases due to these cutaneous reactions.³ Similarly, our patient underwent only 1 cycle of immunotherapy before developing eruptive KAs and discontinuing PD-1 inhibitor therapy. If we are better able to treat eruptive KAs, then patients can remain on immunotherapy to treat underlying malignancies. Crow et al⁸ showed improvement in lesions when 3 patients with eruptive KAs were treated with hydroxychloroquine; the Goeckerman regimen consisting of steroids, UVB phototherapy, and crude coal tar; and Unna boots with zinc oxide and compression stockings. The above may be added to a list of possible treatments to consider for hastening the regression of eruptive KAs.

Our patient’s clinical course was similar to reports on the regressive nature of eruptive KAs within 6 months after initial eruption. Although it is likely that KAs will regress on their own, treatment modalities that speed up recovery are a future source for research.

To the Editor:

Pemphigoid gestationis (PG), or gestational pemphigoid, is a rare autoimmune bullous disease (AIBD) occurring in 1 in 50,000 pregnancies. It is characterized by abrupt development of intensely pruritic papules and urticarial plaques, followed by an eruption of blisters.¹ We present a case of new-onset PG that erupted 10 days following SARs-CoV-2 messenger RNA (mRNA) vaccination with BNT162b2 (Pfizer-BioNTech).

A 36-year-old pregnant woman (gravida 1, para 0, aborta 0) at 37 weeks’ gestation presented to our AIBD clinic with a pruritic dermatitis of 6 weeks’ duration that developed 10 days after receiving the second dose of BNT162b2. Multiple intensely pruritic, red bumps presented first on the forearms and within days spread to the thighs, hands, and abdomen, followed by progression to the ankles, feet, and back 2 weeks later. An initial biopsy was consistent with subacute spongiotic dermatitis with rare eosinophils. She found minimal relief from diphenhydramine or topical steroids. She denied oral, nasal, ocular, or genital involvement or history of any other skin disease. The pregnancy had been otherwise uneventful.

Physical examination revealed annular edematous plaques on the trunk and buttocks; excoriated and erythematous papules on the neck, trunk, arms, and legs; and scattered vesicles along the fingers, arms, hands, abdomen, back, legs, and feet (Figure 1). The Bullous Pemphigoid Disease Area Index (BPDAI) total skin activity score was 25.3, corresponding to moderate disease activity (validated at 20–56).² The BPDAI total pruritus component score was 20. A repeat biopsy for direct immunofluorescence showed faint linear deposits of IgG and bright linear deposits of C3 along the basement membrane zone. Indirect immunofluorescence showed linear deposits of IgG localized to the blister roof of salt-split skin at a dilution of 1:40. An enzyme-linked immunosorbent assay for anti-BP180 was 62 U/mL (negative, <9 U/mL; positive, ≥9 U/mL), and anti-BP230 autoantibodies were less than 9 U/mL (negative <9 U/mL; positive, ≥9 U/mL). Given these clinical and histopathologic findings, PG was diagnosed. 

The patient was started on prednisone 20 mg and antihistamines while continuing topical steroids. Pruritus and blistering improved close to delivery. Fetal monitoring with regular biophysical profiles remained normal. The patient delivered a healthy neonate without skin lesions at 40 weeks’ gestation. The disease flared 2 days after delivery, and prednisone was increased to 40 mg and slowly tapered. Two months after delivery, the patient remained on prednisone 10 mg daily with ongoing but reduced blistering and pruritus (Figure 2). The BPDAI total skin activity and pruritus component scores remained elevated at 20.3 and 14, respectively, and anti-BP180 was 44 U/mL. After a discussion with the patient on safe systemic therapy while breastfeeding, intravenous immunoglobulin (IVIG) was initiated. The patient received 3 monthly infusions at 2 g/kg and was able to taper the prednisone to 5 mg every other day without new lesions. Four months after completion of IVIG therapy, she achieved complete remission off all therapy.

Management of PG begins with topical corticosteroids, but most patients require systemic steroid therapy.¹ Remission commonly occurs close to delivery, and 75% of patients flare post partum, though the disease typically resolves 6 months following delivery.^1,3,4 For persistent intrapartum cases requiring more than prednisone 20 mg daily, therapy can include dapsone, IVIG, azathioprine, rituximab, or plasmapheresis.^4,5 Dapsone and IVIG are compatible with breastfeeding postpartum, but if dapsone is selected, the infant must be monitored for hemolytic anemia.⁵ Pemphigoid gestationis increases the risk for a premature or small-for-gestational-age neonate, necessitating regular fetal monitoring until delivery.¹ Cutaneous lesions may affect the newborn, though this occurrence is rare and self-limiting.⁶Pemphigoid gestationis may recur in subsequent pregnancies at a rate of 33% to 55%, with earlier and more severe presentations.⁴

Clinically and histologically, PG closely resembles bullous pemphigoid (BP), but the exact pathogenesis is not fully understood. Recently, another case of what was termed pseudo-PG has been described 3 days following administration of the second dose of the Pfizer-BioNTech COVID-19 vaccine.⁷ Since the introduction of COVID-19 mRNA vaccines, cases of postvaccination BP, BP-like eruptions, and pemphigus vulgaris have been described.^8-11 Tomayko et al¹⁰ reported 12 cases of subepidermal eruptions, including BP, in which 7 patients developed blisters after the second dose of either the Pfizer-BioNTech or Moderna mRNA vaccine. Three patients who developed BP after the first dose of the vaccine and chose to receive the second dose tolerated it well, with a mild flare observed in 1 patient.¹⁰ Similarly, subsequent vaccine doses in reports of vaccine-associated AIBD resulted in increased disease activity in 21% of cases.¹² COVID-19 vaccine–associated BP, similar to drug-induced BP, seemingly displays a milder course of disease compared to the classic form of BP.^10,13 More follow-up is needed to better understand these reactions and inform appropriate discussions on the administration of booster doses. Currently, completion of the vaccination series against COVID-19 is advisable given the paucity of reports of postvaccination AIBD and the risk for COVID-19 infection, but careful discussions on a case-by-case basis are warranted related to the risk for disease exacerbation following subsequent vaccinations.

The clinical presentation and diagnostic evaluation of our patient’s rash were consistent with PG. The temporal relationship between vaccine administration and PG lesion onset suggests the mRNA vaccine triggered AIBD in our patient. Interestingly, AIBD associated with COVID-19 is not unique to only the vaccines and has been observed following infection with the virus itself.¹⁴ The high rate of vaccination against COVID-19 in contrast with the low number of reported cases of AIBD after vaccination supports the overall safety of COVID-19 vaccines but identifies a need for further understanding of the processes that lead to the development of autoimmune conditions in at-risk populations.

To the Editor:

Pemphigoid gestationis (PG), or gestational pemphigoid, is a rare autoimmune bullous disease (AIBD) occurring in 1 in 50,000 pregnancies. It is characterized by abrupt development of intensely pruritic papules and urticarial plaques, followed by an eruption of blisters.¹ We present a case of new-onset PG that erupted 10 days following SARs-CoV-2 messenger RNA (mRNA) vaccination with BNT162b2 (Pfizer-BioNTech).

A 36-year-old pregnant woman (gravida 1, para 0, aborta 0) at 37 weeks’ gestation presented to our AIBD clinic with a pruritic dermatitis of 6 weeks’ duration that developed 10 days after receiving the second dose of BNT162b2. Multiple intensely pruritic, red bumps presented first on the forearms and within days spread to the thighs, hands, and abdomen, followed by progression to the ankles, feet, and back 2 weeks later. An initial biopsy was consistent with subacute spongiotic dermatitis with rare eosinophils. She found minimal relief from diphenhydramine or topical steroids. She denied oral, nasal, ocular, or genital involvement or history of any other skin disease. The pregnancy had been otherwise uneventful.

Physical examination revealed annular edematous plaques on the trunk and buttocks; excoriated and erythematous papules on the neck, trunk, arms, and legs; and scattered vesicles along the fingers, arms, hands, abdomen, back, legs, and feet (Figure 1). The Bullous Pemphigoid Disease Area Index (BPDAI) total skin activity score was 25.3, corresponding to moderate disease activity (validated at 20–56).² The BPDAI total pruritus component score was 20. A repeat biopsy for direct immunofluorescence showed faint linear deposits of IgG and bright linear deposits of C3 along the basement membrane zone. Indirect immunofluorescence showed linear deposits of IgG localized to the blister roof of salt-split skin at a dilution of 1:40. An enzyme-linked immunosorbent assay for anti-BP180 was 62 U/mL (negative, <9 U/mL; positive, ≥9 U/mL), and anti-BP230 autoantibodies were less than 9 U/mL (negative <9 U/mL; positive, ≥9 U/mL). Given these clinical and histopathologic findings, PG was diagnosed. 

The patient was started on prednisone 20 mg and antihistamines while continuing topical steroids. Pruritus and blistering improved close to delivery. Fetal monitoring with regular biophysical profiles remained normal. The patient delivered a healthy neonate without skin lesions at 40 weeks’ gestation. The disease flared 2 days after delivery, and prednisone was increased to 40 mg and slowly tapered. Two months after delivery, the patient remained on prednisone 10 mg daily with ongoing but reduced blistering and pruritus (Figure 2). The BPDAI total skin activity and pruritus component scores remained elevated at 20.3 and 14, respectively, and anti-BP180 was 44 U/mL. After a discussion with the patient on safe systemic therapy while breastfeeding, intravenous immunoglobulin (IVIG) was initiated. The patient received 3 monthly infusions at 2 g/kg and was able to taper the prednisone to 5 mg every other day without new lesions. Four months after completion of IVIG therapy, she achieved complete remission off all therapy.

Management of PG begins with topical corticosteroids, but most patients require systemic steroid therapy.¹ Remission commonly occurs close to delivery, and 75% of patients flare post partum, though the disease typically resolves 6 months following delivery.^1,3,4 For persistent intrapartum cases requiring more than prednisone 20 mg daily, therapy can include dapsone, IVIG, azathioprine, rituximab, or plasmapheresis.^4,5 Dapsone and IVIG are compatible with breastfeeding postpartum, but if dapsone is selected, the infant must be monitored for hemolytic anemia.⁵ Pemphigoid gestationis increases the risk for a premature or small-for-gestational-age neonate, necessitating regular fetal monitoring until delivery.¹ Cutaneous lesions may affect the newborn, though this occurrence is rare and self-limiting.⁶Pemphigoid gestationis may recur in subsequent pregnancies at a rate of 33% to 55%, with earlier and more severe presentations.⁴

Clinically and histologically, PG closely resembles bullous pemphigoid (BP), but the exact pathogenesis is not fully understood. Recently, another case of what was termed pseudo-PG has been described 3 days following administration of the second dose of the Pfizer-BioNTech COVID-19 vaccine.⁷ Since the introduction of COVID-19 mRNA vaccines, cases of postvaccination BP, BP-like eruptions, and pemphigus vulgaris have been described.^8-11 Tomayko et al¹⁰ reported 12 cases of subepidermal eruptions, including BP, in which 7 patients developed blisters after the second dose of either the Pfizer-BioNTech or Moderna mRNA vaccine. Three patients who developed BP after the first dose of the vaccine and chose to receive the second dose tolerated it well, with a mild flare observed in 1 patient.¹⁰ Similarly, subsequent vaccine doses in reports of vaccine-associated AIBD resulted in increased disease activity in 21% of cases.¹² COVID-19 vaccine–associated BP, similar to drug-induced BP, seemingly displays a milder course of disease compared to the classic form of BP.^10,13 More follow-up is needed to better understand these reactions and inform appropriate discussions on the administration of booster doses. Currently, completion of the vaccination series against COVID-19 is advisable given the paucity of reports of postvaccination AIBD and the risk for COVID-19 infection, but careful discussions on a case-by-case basis are warranted related to the risk for disease exacerbation following subsequent vaccinations.

The clinical presentation and diagnostic evaluation of our patient’s rash were consistent with PG. The temporal relationship between vaccine administration and PG lesion onset suggests the mRNA vaccine triggered AIBD in our patient. Interestingly, AIBD associated with COVID-19 is not unique to only the vaccines and has been observed following infection with the virus itself.¹⁴ The high rate of vaccination against COVID-19 in contrast with the low number of reported cases of AIBD after vaccination supports the overall safety of COVID-19 vaccines but identifies a need for further understanding of the processes that lead to the development of autoimmune conditions in at-risk populations.

To the Editor:

Pemphigoid gestationis (PG), or gestational pemphigoid, is a rare autoimmune bullous disease (AIBD) occurring in 1 in 50,000 pregnancies. It is characterized by abrupt development of intensely pruritic papules and urticarial plaques, followed by an eruption of blisters.¹ We present a case of new-onset PG that erupted 10 days following SARs-CoV-2 messenger RNA (mRNA) vaccination with BNT162b2 (Pfizer-BioNTech).

A 36-year-old pregnant woman (gravida 1, para 0, aborta 0) at 37 weeks’ gestation presented to our AIBD clinic with a pruritic dermatitis of 6 weeks’ duration that developed 10 days after receiving the second dose of BNT162b2. Multiple intensely pruritic, red bumps presented first on the forearms and within days spread to the thighs, hands, and abdomen, followed by progression to the ankles, feet, and back 2 weeks later. An initial biopsy was consistent with subacute spongiotic dermatitis with rare eosinophils. She found minimal relief from diphenhydramine or topical steroids. She denied oral, nasal, ocular, or genital involvement or history of any other skin disease. The pregnancy had been otherwise uneventful.

Physical examination revealed annular edematous plaques on the trunk and buttocks; excoriated and erythematous papules on the neck, trunk, arms, and legs; and scattered vesicles along the fingers, arms, hands, abdomen, back, legs, and feet (Figure 1). The Bullous Pemphigoid Disease Area Index (BPDAI) total skin activity score was 25.3, corresponding to moderate disease activity (validated at 20–56).² The BPDAI total pruritus component score was 20. A repeat biopsy for direct immunofluorescence showed faint linear deposits of IgG and bright linear deposits of C3 along the basement membrane zone. Indirect immunofluorescence showed linear deposits of IgG localized to the blister roof of salt-split skin at a dilution of 1:40. An enzyme-linked immunosorbent assay for anti-BP180 was 62 U/mL (negative, <9 U/mL; positive, ≥9 U/mL), and anti-BP230 autoantibodies were less than 9 U/mL (negative <9 U/mL; positive, ≥9 U/mL). Given these clinical and histopathologic findings, PG was diagnosed. 

The patient was started on prednisone 20 mg and antihistamines while continuing topical steroids. Pruritus and blistering improved close to delivery. Fetal monitoring with regular biophysical profiles remained normal. The patient delivered a healthy neonate without skin lesions at 40 weeks’ gestation. The disease flared 2 days after delivery, and prednisone was increased to 40 mg and slowly tapered. Two months after delivery, the patient remained on prednisone 10 mg daily with ongoing but reduced blistering and pruritus (Figure 2). The BPDAI total skin activity and pruritus component scores remained elevated at 20.3 and 14, respectively, and anti-BP180 was 44 U/mL. After a discussion with the patient on safe systemic therapy while breastfeeding, intravenous immunoglobulin (IVIG) was initiated. The patient received 3 monthly infusions at 2 g/kg and was able to taper the prednisone to 5 mg every other day without new lesions. Four months after completion of IVIG therapy, she achieved complete remission off all therapy.

Management of PG begins with topical corticosteroids, but most patients require systemic steroid therapy.¹ Remission commonly occurs close to delivery, and 75% of patients flare post partum, though the disease typically resolves 6 months following delivery.^1,3,4 For persistent intrapartum cases requiring more than prednisone 20 mg daily, therapy can include dapsone, IVIG, azathioprine, rituximab, or plasmapheresis.^4,5 Dapsone and IVIG are compatible with breastfeeding postpartum, but if dapsone is selected, the infant must be monitored for hemolytic anemia.⁵ Pemphigoid gestationis increases the risk for a premature or small-for-gestational-age neonate, necessitating regular fetal monitoring until delivery.¹ Cutaneous lesions may affect the newborn, though this occurrence is rare and self-limiting.⁶Pemphigoid gestationis may recur in subsequent pregnancies at a rate of 33% to 55%, with earlier and more severe presentations.⁴

Clinically and histologically, PG closely resembles bullous pemphigoid (BP), but the exact pathogenesis is not fully understood. Recently, another case of what was termed pseudo-PG has been described 3 days following administration of the second dose of the Pfizer-BioNTech COVID-19 vaccine.⁷ Since the introduction of COVID-19 mRNA vaccines, cases of postvaccination BP, BP-like eruptions, and pemphigus vulgaris have been described.^8-11 Tomayko et al¹⁰ reported 12 cases of subepidermal eruptions, including BP, in which 7 patients developed blisters after the second dose of either the Pfizer-BioNTech or Moderna mRNA vaccine. Three patients who developed BP after the first dose of the vaccine and chose to receive the second dose tolerated it well, with a mild flare observed in 1 patient.¹⁰ Similarly, subsequent vaccine doses in reports of vaccine-associated AIBD resulted in increased disease activity in 21% of cases.¹² COVID-19 vaccine–associated BP, similar to drug-induced BP, seemingly displays a milder course of disease compared to the classic form of BP.^10,13 More follow-up is needed to better understand these reactions and inform appropriate discussions on the administration of booster doses. Currently, completion of the vaccination series against COVID-19 is advisable given the paucity of reports of postvaccination AIBD and the risk for COVID-19 infection, but careful discussions on a case-by-case basis are warranted related to the risk for disease exacerbation following subsequent vaccinations.

The clinical presentation and diagnostic evaluation of our patient’s rash were consistent with PG. The temporal relationship between vaccine administration and PG lesion onset suggests the mRNA vaccine triggered AIBD in our patient. Interestingly, AIBD associated with COVID-19 is not unique to only the vaccines and has been observed following infection with the virus itself.¹⁴ The high rate of vaccination against COVID-19 in contrast with the low number of reported cases of AIBD after vaccination supports the overall safety of COVID-19 vaccines but identifies a need for further understanding of the processes that lead to the development of autoimmune conditions in at-risk populations.

To the Editor:

Miliarial gout is a rare intradermal manifestation of tophaceous gout. It was first described in 2007 when a patient presented with multiple small papules with a red base containing a white- to cream-colored substance,¹ which has rarely been reported,^1-6 according to a PubMed search of articles indexed for MEDLINE from 2007 to 2023 using the term miliarial gout. We describe a case of miliarial gout in a patient with a history of gout, uric acid levels within reference range, and immunocompromised status due to a prior orthotopic heart transplant.

A 59-year-old man presented with innumerable subcutaneous, firm, popcornlike clustered papules on the posterior surfaces of the upper arms and thighs of 5 years’ duration (Figure 1). The involved areas were sometimes painful on manipulation, but the patient was otherwise asymptomatic. His medical history was notable for tophaceous gout of more than 10 years’ duration, calcinosis cutis, adrenal insufficiency, essential hypertension, and an orthotopic heart transplant 2 years prior to the current presentation. At the current presentation he was taking tacrolimus, colchicine, febuxostat, and low-dose prednisone. The patient denied any other skin changes such as ulceration or bullae. In addition to the innumerable subcutaneous papules, he had much larger firm deep nodules bilaterally on the elbow (Figure 2). A complete blood cell count with differential and comprehensive metabolic panel results were within reference range. A 4-mm punch biopsy of the right posterior arm revealed dermal deposits consistent with gout on hematoxylin and eosin staining (Figure 3) but no calcium deposits on von Kossa staining, consistent with miliarial gout.

He was treated with 0.6 mg of colchicine daily, 80 mg of febuxostat twice daily, and 2.5 mg of prednisone daily. Unfortunately, the patient had difficulty affording his medications and therefore experienced frequent flares.

Gout is caused by inflammation that occurs from deposition of monosodium urate crystals in tissues, most commonly occurring in the skin and joints. Gout affects8.3 million individuals and is one of the most common rheumatic diseases of adulthood. The classic presentation of the acute form is monoarticular with associated swelling, erythema, and pain. The chronic form (also known as tophaceous gout) affects soft tissue and presents with smooth or multilobulated nodules.² Miliarial gout is a rare variant of chronic tophaceous gout, and the diagnosis is based on atypical location, size, and distribution of tophi deposition.

In the updated American College of Rheumatology criteria for gout published in 2020, tophi are defined as draining or chalklike subcutaneous nodules that typically are located in joints, ears, olecranon bursae, finger pads, and tendons.³ The term miliarial gout, which is not universally defined, is used to describe the morphology and distribution of tophi deposition in areas outside of the typical locations defined by the American College of Rheumatology criteria. Miliarial refers to the small, multilobulated, and disseminated presentation of tophi. The involvement of atypical locations distinguishes miliarial gout from chronic tophaceous gout.

The cause of tophi deposition in atypical locations is unknown. It is thought that patients with a history of sustained hyperuricemia have a much greater burden of urate crystal deposition, which can lead to involvement of atypical locations. Our patient had innumerable, discrete, 1- to 5-mm, multilobulated tophi located on the posterior upper arms and thighs even though his uric acid levels were within reference range over the last 5 years.

Miliarial gout is a rare entity.¹ In 2007, Shukla et al¹ coined the term miliarial gout when reporting the first known presentation of a patient with multiple tiny papules containing a white or creamlike substance scattered on an erythematous base. Other cases of miliarial gout have commonly involved the metacarpophalangeal joints of the hands, knees, abdomen, extensor forearms, and thighs.⁵ Similarly, our patient had disease involvement of the posterior upper arms and thighs. Furthermore, miliarial gout has been associated with carpal tunnel syndrome; monosodium urate crystal deposition in this space can lead to a clinical diagnosis of this condition.⁶

With a history of orthotopic heart transplant, it is possible that our patient’s immunocompromised status could have increased his susceptibility for the miliarial form of chronic tophaceous gout. Gout reportedly is the most common inflammatory arthritis in transplant recipients, with the highest prevalence following renal and heart transplantation.⁷ Pretransplant hyperuricemia is correlated with higher probabilities of posttransplant gout.⁸ In patients with a heart transplant, hyperuricemia may be due to diuretic use. Additionally, the presence of a gout diagnosis before transplant nearly triples the likelihood of posttransplant gout, which often is more severe than de novo gout, as seen in our patient. Calcineurin inhibitors, including tacrolimus, also can predispose patients to hyperuricemia and more severe forms of gout in the posttransplant phase by limiting fractional urate excretion within the first 3 months of therapy.⁷ Treatment with oral steroids, as in our patient, also has been identified as a potential inciting factor for the development of cutaneous tophaceous gout.⁹

Treatment with allopurinol and colchicine has been effective in patients with miliarial gout. Obesity and long-term treatment with furosemide (which our patient was not taking) are considered risk factors for the deposition of dermal and hypodermal urates.⁹ Our patient had a body mass index of 35 (≥30 indicates obesity); therefore, he also should be counseled on lifestyle modifications for optimal disease control.

To the Editor:

Miliarial gout is a rare intradermal manifestation of tophaceous gout. It was first described in 2007 when a patient presented with multiple small papules with a red base containing a white- to cream-colored substance,¹ which has rarely been reported,^1-6 according to a PubMed search of articles indexed for MEDLINE from 2007 to 2023 using the term miliarial gout. We describe a case of miliarial gout in a patient with a history of gout, uric acid levels within reference range, and immunocompromised status due to a prior orthotopic heart transplant.

A 59-year-old man presented with innumerable subcutaneous, firm, popcornlike clustered papules on the posterior surfaces of the upper arms and thighs of 5 years’ duration (Figure 1). The involved areas were sometimes painful on manipulation, but the patient was otherwise asymptomatic. His medical history was notable for tophaceous gout of more than 10 years’ duration, calcinosis cutis, adrenal insufficiency, essential hypertension, and an orthotopic heart transplant 2 years prior to the current presentation. At the current presentation he was taking tacrolimus, colchicine, febuxostat, and low-dose prednisone. The patient denied any other skin changes such as ulceration or bullae. In addition to the innumerable subcutaneous papules, he had much larger firm deep nodules bilaterally on the elbow (Figure 2). A complete blood cell count with differential and comprehensive metabolic panel results were within reference range. A 4-mm punch biopsy of the right posterior arm revealed dermal deposits consistent with gout on hematoxylin and eosin staining (Figure 3) but no calcium deposits on von Kossa staining, consistent with miliarial gout.

He was treated with 0.6 mg of colchicine daily, 80 mg of febuxostat twice daily, and 2.5 mg of prednisone daily. Unfortunately, the patient had difficulty affording his medications and therefore experienced frequent flares.

Gout is caused by inflammation that occurs from deposition of monosodium urate crystals in tissues, most commonly occurring in the skin and joints. Gout affects8.3 million individuals and is one of the most common rheumatic diseases of adulthood. The classic presentation of the acute form is monoarticular with associated swelling, erythema, and pain. The chronic form (also known as tophaceous gout) affects soft tissue and presents with smooth or multilobulated nodules.² Miliarial gout is a rare variant of chronic tophaceous gout, and the diagnosis is based on atypical location, size, and distribution of tophi deposition.

In the updated American College of Rheumatology criteria for gout published in 2020, tophi are defined as draining or chalklike subcutaneous nodules that typically are located in joints, ears, olecranon bursae, finger pads, and tendons.³ The term miliarial gout, which is not universally defined, is used to describe the morphology and distribution of tophi deposition in areas outside of the typical locations defined by the American College of Rheumatology criteria. Miliarial refers to the small, multilobulated, and disseminated presentation of tophi. The involvement of atypical locations distinguishes miliarial gout from chronic tophaceous gout.

The cause of tophi deposition in atypical locations is unknown. It is thought that patients with a history of sustained hyperuricemia have a much greater burden of urate crystal deposition, which can lead to involvement of atypical locations. Our patient had innumerable, discrete, 1- to 5-mm, multilobulated tophi located on the posterior upper arms and thighs even though his uric acid levels were within reference range over the last 5 years.

Miliarial gout is a rare entity.¹ In 2007, Shukla et al¹ coined the term miliarial gout when reporting the first known presentation of a patient with multiple tiny papules containing a white or creamlike substance scattered on an erythematous base. Other cases of miliarial gout have commonly involved the metacarpophalangeal joints of the hands, knees, abdomen, extensor forearms, and thighs.⁵ Similarly, our patient had disease involvement of the posterior upper arms and thighs. Furthermore, miliarial gout has been associated with carpal tunnel syndrome; monosodium urate crystal deposition in this space can lead to a clinical diagnosis of this condition.⁶

With a history of orthotopic heart transplant, it is possible that our patient’s immunocompromised status could have increased his susceptibility for the miliarial form of chronic tophaceous gout. Gout reportedly is the most common inflammatory arthritis in transplant recipients, with the highest prevalence following renal and heart transplantation.⁷ Pretransplant hyperuricemia is correlated with higher probabilities of posttransplant gout.⁸ In patients with a heart transplant, hyperuricemia may be due to diuretic use. Additionally, the presence of a gout diagnosis before transplant nearly triples the likelihood of posttransplant gout, which often is more severe than de novo gout, as seen in our patient. Calcineurin inhibitors, including tacrolimus, also can predispose patients to hyperuricemia and more severe forms of gout in the posttransplant phase by limiting fractional urate excretion within the first 3 months of therapy.⁷ Treatment with oral steroids, as in our patient, also has been identified as a potential inciting factor for the development of cutaneous tophaceous gout.⁹

Treatment with allopurinol and colchicine has been effective in patients with miliarial gout. Obesity and long-term treatment with furosemide (which our patient was not taking) are considered risk factors for the deposition of dermal and hypodermal urates.⁹ Our patient had a body mass index of 35 (≥30 indicates obesity); therefore, he also should be counseled on lifestyle modifications for optimal disease control.

To the Editor:

Miliarial gout is a rare intradermal manifestation of tophaceous gout. It was first described in 2007 when a patient presented with multiple small papules with a red base containing a white- to cream-colored substance,¹ which has rarely been reported,^1-6 according to a PubMed search of articles indexed for MEDLINE from 2007 to 2023 using the term miliarial gout. We describe a case of miliarial gout in a patient with a history of gout, uric acid levels within reference range, and immunocompromised status due to a prior orthotopic heart transplant.

A 59-year-old man presented with innumerable subcutaneous, firm, popcornlike clustered papules on the posterior surfaces of the upper arms and thighs of 5 years’ duration (Figure 1). The involved areas were sometimes painful on manipulation, but the patient was otherwise asymptomatic. His medical history was notable for tophaceous gout of more than 10 years’ duration, calcinosis cutis, adrenal insufficiency, essential hypertension, and an orthotopic heart transplant 2 years prior to the current presentation. At the current presentation he was taking tacrolimus, colchicine, febuxostat, and low-dose prednisone. The patient denied any other skin changes such as ulceration or bullae. In addition to the innumerable subcutaneous papules, he had much larger firm deep nodules bilaterally on the elbow (Figure 2). A complete blood cell count with differential and comprehensive metabolic panel results were within reference range. A 4-mm punch biopsy of the right posterior arm revealed dermal deposits consistent with gout on hematoxylin and eosin staining (Figure 3) but no calcium deposits on von Kossa staining, consistent with miliarial gout.

He was treated with 0.6 mg of colchicine daily, 80 mg of febuxostat twice daily, and 2.5 mg of prednisone daily. Unfortunately, the patient had difficulty affording his medications and therefore experienced frequent flares.

Gout is caused by inflammation that occurs from deposition of monosodium urate crystals in tissues, most commonly occurring in the skin and joints. Gout affects8.3 million individuals and is one of the most common rheumatic diseases of adulthood. The classic presentation of the acute form is monoarticular with associated swelling, erythema, and pain. The chronic form (also known as tophaceous gout) affects soft tissue and presents with smooth or multilobulated nodules.² Miliarial gout is a rare variant of chronic tophaceous gout, and the diagnosis is based on atypical location, size, and distribution of tophi deposition.

In the updated American College of Rheumatology criteria for gout published in 2020, tophi are defined as draining or chalklike subcutaneous nodules that typically are located in joints, ears, olecranon bursae, finger pads, and tendons.³ The term miliarial gout, which is not universally defined, is used to describe the morphology and distribution of tophi deposition in areas outside of the typical locations defined by the American College of Rheumatology criteria. Miliarial refers to the small, multilobulated, and disseminated presentation of tophi. The involvement of atypical locations distinguishes miliarial gout from chronic tophaceous gout.

The cause of tophi deposition in atypical locations is unknown. It is thought that patients with a history of sustained hyperuricemia have a much greater burden of urate crystal deposition, which can lead to involvement of atypical locations. Our patient had innumerable, discrete, 1- to 5-mm, multilobulated tophi located on the posterior upper arms and thighs even though his uric acid levels were within reference range over the last 5 years.

Miliarial gout is a rare entity.¹ In 2007, Shukla et al¹ coined the term miliarial gout when reporting the first known presentation of a patient with multiple tiny papules containing a white or creamlike substance scattered on an erythematous base. Other cases of miliarial gout have commonly involved the metacarpophalangeal joints of the hands, knees, abdomen, extensor forearms, and thighs.⁵ Similarly, our patient had disease involvement of the posterior upper arms and thighs. Furthermore, miliarial gout has been associated with carpal tunnel syndrome; monosodium urate crystal deposition in this space can lead to a clinical diagnosis of this condition.⁶

With a history of orthotopic heart transplant, it is possible that our patient’s immunocompromised status could have increased his susceptibility for the miliarial form of chronic tophaceous gout. Gout reportedly is the most common inflammatory arthritis in transplant recipients, with the highest prevalence following renal and heart transplantation.⁷ Pretransplant hyperuricemia is correlated with higher probabilities of posttransplant gout.⁸ In patients with a heart transplant, hyperuricemia may be due to diuretic use. Additionally, the presence of a gout diagnosis before transplant nearly triples the likelihood of posttransplant gout, which often is more severe than de novo gout, as seen in our patient. Calcineurin inhibitors, including tacrolimus, also can predispose patients to hyperuricemia and more severe forms of gout in the posttransplant phase by limiting fractional urate excretion within the first 3 months of therapy.⁷ Treatment with oral steroids, as in our patient, also has been identified as a potential inciting factor for the development of cutaneous tophaceous gout.⁹

Treatment with allopurinol and colchicine has been effective in patients with miliarial gout. Obesity and long-term treatment with furosemide (which our patient was not taking) are considered risk factors for the deposition of dermal and hypodermal urates.⁹ Our patient had a body mass index of 35 (≥30 indicates obesity); therefore, he also should be counseled on lifestyle modifications for optimal disease control.