Cutis

The Diagnosis: Cutaneous Blastomycosis

A skin biopsy and fungal cultures confirmed the diagnosis of cutaneous blastomycosis. Grocott- Gomori methenamine-silver staining highlighted fungal organisms with refractile walls and broad-based budding consistent with cutaneous blastomycosis (Figure 1). The histopathologic specimen also demonstrated marked pseudoepitheliomatous hyperplasia (Figure 2A) with neutrophilic microabscesses (Figure 2B). Acid-fast bacillus and Fite staining were negative for bacterial organisms. A fungal culture was positive for Blastomyces dermatitidis. Urine and serum blastomycosis antigen were positive. Although Histoplasma serum antigen also was positive, this likely was from cross-reactivity. Chest radiography was negative for lung involvement, and the patient displayed no neurologic symptoms. He was started on oral itraconazole therapy for the treatment of cutaneous blastomycosis.

Blastomyces dermatitidis, the causative organism of blastomycosis, is endemic to the Ohio and Mississippi River valleys, Great Lakes region, and southeastern United States. It is a thermally dimorphic fungus found in soils that grows as a mold at 25 °C and yeast at 37 °C. Primary infection of the lungs—blastomycosis pneumonia—often is the only clinical manifestation¹; however, subsequent hematogenous dissemination to extrapulmonary sites such as the skin, bones, and genitourinary system can occur. Cutaneous blastomycosis, the most common extrapulmonary manifestation, typically follows pulmonary infection. In rare cases, it can occur from direct inoculation.^2,3 Skin lesions can occur anywhere but frequently are found on exposed surfaces of the head, neck, and extremities. Lesions classically present as verrucous crusting plaques with draining microabscesses. Violaceous nodules, ulcers, and pustules also may occur.¹

Diagnosis involves obtaining a thorough history of possible environmental exposures such as the patient’s geographic area of residence, occupation, and outdoor activities involving soil or decaying wood. Because blastomycosis can remain latent, remote exposures are relevant. Definitive diagnosis of cutaneous blastomycosis involves skin biopsy of the lesion with fungal culture, but the yeast’s distinctive thick wall and broad-based budding seen with periodic acid–Schiff or Grocott-Gomori methenamine-silver staining provides a rapid presumptive diagnosis.³ Pseudoepitheliomatous hyperplasia and microabscesses also are characteristic features.² Urine antigen testing for a component of the polysaccharide cell wall has a sensitivity of 93% but a lower specificity of 79% due to cross-reactivity with histoplasmosis.⁴ Treatment consists of itraconazole for mild to moderate blastomycosis or amphotericin B for those with severe disease or central nervous system involvement or those who are immunosuppressed.¹

The differential diagnosis for our patient’s lesion included infectious vs neoplastic etiologies. Histoplasma capsulatum, the dimorphic fungus that causes histoplasmosis, also is endemic to the Ohio and Mississippi River valleys. It is found in soil and droppings of some bats and birds such as chickens and pigeons. Similar to blastomycosis, the primary infection site most commonly is the lungs. It subsequently may disseminate to the skin or less commonly via direct inoculation of injured skin. It can present as papules, plaques, ulcers, purpura, or abscesses. Unlike blastomycosis, tissue biopsy of a cutaneous lesion reveals granuloma formation and distinctive oval, narrow-based budding yeast.⁵ Atypical mycobacteria are another source of infection to consider. For example, cutaneous Mycobacterium kansasii may present as papules and pustules forming verrucous or granulomatous plaques and ulceration. Histopathologic findings distinguishing mycobacterial infection from blastomycosis include granulomas and acid-fast bacilli in histiocytes.⁶

Noninfectious etiologies in the differential may include cutaneous squamous cell carcinoma or pemphigus vegetans. Squamous cell carcinoma may present with a broad range of clinical features—papules, plaques, or nodules with smooth, scaly, verrucous, or ulcerative secondary features all are possible presentations.⁷ Fairskinned individuals, such as our patient, would be at a higher risk in sun-damaged skin. Histologically, cutaneous squamous cell carcinoma is defined as an invasion of the dermis by neoplastic squamous epithelial cells in the form of cords, sheets, individual cells, nodules, or cystic structures.⁷ Pemphigus vegetans is the rarest variant of a group of autoimmune vesiculobullous diseases known as pemphigus. It can be differentiated from the most common variant—pemphigus vulgaris—by the presence of vegetative plaques in intertriginous areas. However, these verrucous vegetations can be misleading and make clinical diagnosis difficult. Histopathologic findings of hyperkeratosis, pseudoepitheliomatous hyperplasia, papillomatosis, and acantholysis with a suprabasal cleft would confirm the diagnosis.⁸

In summary, cutaneous blastomycosis classically presents as verrucous crusting plaques, as seen in our patient. It is important to conduct a thorough history for environmental exposures, but definitive diagnosis of cutaneous blastomycosis involves skin biopsy with fungal culture. Treatment depends on the severity of disease and organ involvement. Itraconazole would be appropriate for mild to moderate blastomycosis.

The Diagnosis: Cutaneous Blastomycosis

A skin biopsy and fungal cultures confirmed the diagnosis of cutaneous blastomycosis. Grocott- Gomori methenamine-silver staining highlighted fungal organisms with refractile walls and broad-based budding consistent with cutaneous blastomycosis (Figure 1). The histopathologic specimen also demonstrated marked pseudoepitheliomatous hyperplasia (Figure 2A) with neutrophilic microabscesses (Figure 2B). Acid-fast bacillus and Fite staining were negative for bacterial organisms. A fungal culture was positive for Blastomyces dermatitidis. Urine and serum blastomycosis antigen were positive. Although Histoplasma serum antigen also was positive, this likely was from cross-reactivity. Chest radiography was negative for lung involvement, and the patient displayed no neurologic symptoms. He was started on oral itraconazole therapy for the treatment of cutaneous blastomycosis.

Blastomyces dermatitidis, the causative organism of blastomycosis, is endemic to the Ohio and Mississippi River valleys, Great Lakes region, and southeastern United States. It is a thermally dimorphic fungus found in soils that grows as a mold at 25 °C and yeast at 37 °C. Primary infection of the lungs—blastomycosis pneumonia—often is the only clinical manifestation¹; however, subsequent hematogenous dissemination to extrapulmonary sites such as the skin, bones, and genitourinary system can occur. Cutaneous blastomycosis, the most common extrapulmonary manifestation, typically follows pulmonary infection. In rare cases, it can occur from direct inoculation.^2,3 Skin lesions can occur anywhere but frequently are found on exposed surfaces of the head, neck, and extremities. Lesions classically present as verrucous crusting plaques with draining microabscesses. Violaceous nodules, ulcers, and pustules also may occur.¹

Diagnosis involves obtaining a thorough history of possible environmental exposures such as the patient’s geographic area of residence, occupation, and outdoor activities involving soil or decaying wood. Because blastomycosis can remain latent, remote exposures are relevant. Definitive diagnosis of cutaneous blastomycosis involves skin biopsy of the lesion with fungal culture, but the yeast’s distinctive thick wall and broad-based budding seen with periodic acid–Schiff or Grocott-Gomori methenamine-silver staining provides a rapid presumptive diagnosis.³ Pseudoepitheliomatous hyperplasia and microabscesses also are characteristic features.² Urine antigen testing for a component of the polysaccharide cell wall has a sensitivity of 93% but a lower specificity of 79% due to cross-reactivity with histoplasmosis.⁴ Treatment consists of itraconazole for mild to moderate blastomycosis or amphotericin B for those with severe disease or central nervous system involvement or those who are immunosuppressed.¹

The differential diagnosis for our patient’s lesion included infectious vs neoplastic etiologies. Histoplasma capsulatum, the dimorphic fungus that causes histoplasmosis, also is endemic to the Ohio and Mississippi River valleys. It is found in soil and droppings of some bats and birds such as chickens and pigeons. Similar to blastomycosis, the primary infection site most commonly is the lungs. It subsequently may disseminate to the skin or less commonly via direct inoculation of injured skin. It can present as papules, plaques, ulcers, purpura, or abscesses. Unlike blastomycosis, tissue biopsy of a cutaneous lesion reveals granuloma formation and distinctive oval, narrow-based budding yeast.⁵ Atypical mycobacteria are another source of infection to consider. For example, cutaneous Mycobacterium kansasii may present as papules and pustules forming verrucous or granulomatous plaques and ulceration. Histopathologic findings distinguishing mycobacterial infection from blastomycosis include granulomas and acid-fast bacilli in histiocytes.⁶

Noninfectious etiologies in the differential may include cutaneous squamous cell carcinoma or pemphigus vegetans. Squamous cell carcinoma may present with a broad range of clinical features—papules, plaques, or nodules with smooth, scaly, verrucous, or ulcerative secondary features all are possible presentations.⁷ Fairskinned individuals, such as our patient, would be at a higher risk in sun-damaged skin. Histologically, cutaneous squamous cell carcinoma is defined as an invasion of the dermis by neoplastic squamous epithelial cells in the form of cords, sheets, individual cells, nodules, or cystic structures.⁷ Pemphigus vegetans is the rarest variant of a group of autoimmune vesiculobullous diseases known as pemphigus. It can be differentiated from the most common variant—pemphigus vulgaris—by the presence of vegetative plaques in intertriginous areas. However, these verrucous vegetations can be misleading and make clinical diagnosis difficult. Histopathologic findings of hyperkeratosis, pseudoepitheliomatous hyperplasia, papillomatosis, and acantholysis with a suprabasal cleft would confirm the diagnosis.⁸

In summary, cutaneous blastomycosis classically presents as verrucous crusting plaques, as seen in our patient. It is important to conduct a thorough history for environmental exposures, but definitive diagnosis of cutaneous blastomycosis involves skin biopsy with fungal culture. Treatment depends on the severity of disease and organ involvement. Itraconazole would be appropriate for mild to moderate blastomycosis.

The Diagnosis: Cutaneous Blastomycosis

A skin biopsy and fungal cultures confirmed the diagnosis of cutaneous blastomycosis. Grocott- Gomori methenamine-silver staining highlighted fungal organisms with refractile walls and broad-based budding consistent with cutaneous blastomycosis (Figure 1). The histopathologic specimen also demonstrated marked pseudoepitheliomatous hyperplasia (Figure 2A) with neutrophilic microabscesses (Figure 2B). Acid-fast bacillus and Fite staining were negative for bacterial organisms. A fungal culture was positive for Blastomyces dermatitidis. Urine and serum blastomycosis antigen were positive. Although Histoplasma serum antigen also was positive, this likely was from cross-reactivity. Chest radiography was negative for lung involvement, and the patient displayed no neurologic symptoms. He was started on oral itraconazole therapy for the treatment of cutaneous blastomycosis.

Blastomyces dermatitidis, the causative organism of blastomycosis, is endemic to the Ohio and Mississippi River valleys, Great Lakes region, and southeastern United States. It is a thermally dimorphic fungus found in soils that grows as a mold at 25 °C and yeast at 37 °C. Primary infection of the lungs—blastomycosis pneumonia—often is the only clinical manifestation¹; however, subsequent hematogenous dissemination to extrapulmonary sites such as the skin, bones, and genitourinary system can occur. Cutaneous blastomycosis, the most common extrapulmonary manifestation, typically follows pulmonary infection. In rare cases, it can occur from direct inoculation.^2,3 Skin lesions can occur anywhere but frequently are found on exposed surfaces of the head, neck, and extremities. Lesions classically present as verrucous crusting plaques with draining microabscesses. Violaceous nodules, ulcers, and pustules also may occur.¹

Diagnosis involves obtaining a thorough history of possible environmental exposures such as the patient’s geographic area of residence, occupation, and outdoor activities involving soil or decaying wood. Because blastomycosis can remain latent, remote exposures are relevant. Definitive diagnosis of cutaneous blastomycosis involves skin biopsy of the lesion with fungal culture, but the yeast’s distinctive thick wall and broad-based budding seen with periodic acid–Schiff or Grocott-Gomori methenamine-silver staining provides a rapid presumptive diagnosis.³ Pseudoepitheliomatous hyperplasia and microabscesses also are characteristic features.² Urine antigen testing for a component of the polysaccharide cell wall has a sensitivity of 93% but a lower specificity of 79% due to cross-reactivity with histoplasmosis.⁴ Treatment consists of itraconazole for mild to moderate blastomycosis or amphotericin B for those with severe disease or central nervous system involvement or those who are immunosuppressed.¹

The differential diagnosis for our patient’s lesion included infectious vs neoplastic etiologies. Histoplasma capsulatum, the dimorphic fungus that causes histoplasmosis, also is endemic to the Ohio and Mississippi River valleys. It is found in soil and droppings of some bats and birds such as chickens and pigeons. Similar to blastomycosis, the primary infection site most commonly is the lungs. It subsequently may disseminate to the skin or less commonly via direct inoculation of injured skin. It can present as papules, plaques, ulcers, purpura, or abscesses. Unlike blastomycosis, tissue biopsy of a cutaneous lesion reveals granuloma formation and distinctive oval, narrow-based budding yeast.⁵ Atypical mycobacteria are another source of infection to consider. For example, cutaneous Mycobacterium kansasii may present as papules and pustules forming verrucous or granulomatous plaques and ulceration. Histopathologic findings distinguishing mycobacterial infection from blastomycosis include granulomas and acid-fast bacilli in histiocytes.⁶

Noninfectious etiologies in the differential may include cutaneous squamous cell carcinoma or pemphigus vegetans. Squamous cell carcinoma may present with a broad range of clinical features—papules, plaques, or nodules with smooth, scaly, verrucous, or ulcerative secondary features all are possible presentations.⁷ Fairskinned individuals, such as our patient, would be at a higher risk in sun-damaged skin. Histologically, cutaneous squamous cell carcinoma is defined as an invasion of the dermis by neoplastic squamous epithelial cells in the form of cords, sheets, individual cells, nodules, or cystic structures.⁷ Pemphigus vegetans is the rarest variant of a group of autoimmune vesiculobullous diseases known as pemphigus. It can be differentiated from the most common variant—pemphigus vulgaris—by the presence of vegetative plaques in intertriginous areas. However, these verrucous vegetations can be misleading and make clinical diagnosis difficult. Histopathologic findings of hyperkeratosis, pseudoepitheliomatous hyperplasia, papillomatosis, and acantholysis with a suprabasal cleft would confirm the diagnosis.⁸

In summary, cutaneous blastomycosis classically presents as verrucous crusting plaques, as seen in our patient. It is important to conduct a thorough history for environmental exposures, but definitive diagnosis of cutaneous blastomycosis involves skin biopsy with fungal culture. Treatment depends on the severity of disease and organ involvement. Itraconazole would be appropriate for mild to moderate blastomycosis.

The Diagnosis: Borrelial Lymphocytoma (Lymphocytoma Cutis)

A punch biopsy revealed an atypical lobular lymphoid infiltrate within the dermis and subcutaneous tissue with a mixed composition of CD3⁺ T cells and CD20⁺ B cells (quiz image, bottom). Immunohistochemical studies revealed a normal CD4:CD8 ratio with preservation of CD5 and CD7. CD30 was largely negative. CD21 failed to detect follicular dendritic cell networks, and κ/λ light chain staining confirmed a preserved ratio of polytypic plasma cells. There was limited staining with B-cell lymphoma (Bcl-2 and Bcl-6). Polymerase chain reaction studies for both T- and B-cell receptors were negative (polyclonal).

Lyme disease is the most frequently reported vectorborne infectious disease in the United States, and borrelial lymphocytoma (BL) is a rare clinical sequela. Borrelial lymphocytoma is a variant of lymphocytoma cutis (also known as benign reactive lymphoid hyperplasia), which is an inflammatory lesion that can mimic malignant lymphoma clinically and histologically. Lymphocytoma cutis is considered the prototypical example of cutaneous B-cell pseudolymphoma.¹ Due to suspicion for lymphocytoma cutis based on the histologic findings and characteristic location of the lesions in our patient, Lyme serologies were ordered and were positive for IgM antibodies against p23, p39, and p41 antigens in high titers. Our patient was treated with doxycycline 100 mg twice daily for 3 weeks with complete resolution of the lesions at 3-month follow-up.

Clinically, BL appears as erythematous papules, plaques, or nodules commonly on the lobules of the ears (quiz image, top). Most cases of lymphocytoma cutis are idiopathic but may be triggered by identifiable associated etiologies including Borrelia burgdorferi, Leishmania donovani, molluscum contagiosum, herpes zoster virus, vaccinations, tattoos, insect bites, and drugs. The main differential diagnosis of lymphocytoma cutis is cutaneous B-cell lymphoma. Pseudolymphoma of the skin can mimic nearly all immunohistochemical staining patterns of true B-cell lymphomas.²

Primary cutaneous follicle center lymphoma frequently occurs on the head and neck. This true lymphoma of the skin can demonstrate prominent follicle centers with centrocytes and fragmented germinal centers (Figure 1) or show a diffuse pattern.³ Most cases show conspicuous Bcl-6 staining, and IgH gene rearrangements can detect a clonal B-cell population in more than 50% of cases.⁴

Diffuse large B-cell lymphoma can occur as a primary cutaneous malignancy or as a manifestation of systemic disease.4 When arising in the skin, lesions tend to affect the extremities, and the disease is classified as diffuse large B-cell lymphoma, leg type. Histologically, sheets of large atypical lymphocytes with numerous mitoses are seen (Figure 2). These cells stain positively with Bcl-2 and frequently demonstrate Bcl-6 and MUM-1, none of which were seen in our case.4 Lymphomatoid papulosis (LyP) tends to present with relapsing erythematous papules. Patients occasionally develop LyP in association with mycosis fungoides or other lymphomas. Both LyP and primary cutaneous anaplastic large cell lymphoma demonstrate conspicuous CD30+ large cells that can be multinucleated or resemble the Reed-Sternberg cells seen in Hodgkin lymphoma (Figure 3).4 Arthropod bite reactions are common but may be confused with lymphomas and pseudolymphomas. The perivascular lymphocytic infiltrate seen in arthropod bite reactions may be dense and usually is associated with numerous eosinophils (Figure 4). Occasional plasma cells also can be seen, and if the infiltrate closely adheres to vascular structures, a diagnosis of erythema chronicum migrans also can be considered. Patients with chronic lymphocytic leukemia/lymphoma may demonstrate exaggerated or persistent arthropod bite reactions, and atypical lymphocytes can be detected admixed with the otherwise reactive infiltrate.⁴

Borrelia burgdorferi is primarily endemic to North America and Europe. It is a spirochete bacterium spread by the Ixodes tick that was first recognized as the etiologic agent in 1975 in Old Lyme, Connecticut, where it received its name.⁵ Most reported cases of Lyme disease occur in the northeastern United States, which correlates with this case given our patient’s place of residence.⁶ Borrelial lymphocytoma cutis occurs in areas endemic for the Ixodes tick in Europe and North America.⁷ When describing the genotyping of Borrelia seen in BL, the strain B burgdorferi previously was grouped with Borrelia afzelii and Borrelia garinii.² In the contemporary literature, however, B burgdorferi is referred to as sensu stricto when specifically talking about the strain B burgdorferi, and the term sensu lato is used when referencing the combination of strains (B burgdorferi, B afzelii, B garinii).

A 2016 study by Maraspin et al⁸ comprising 144 patients diagnosed with BL showed that the lesions mainly were located on the breast (106 patients [73.6%]) and the earlobe (27 patients [18.8%]), with the remaining cases occurring elsewhere on the body (11 patients [7.6%]). The Borrelia strains isolated from the BL lesions included B afzelii, Borrelia bissettii, and B garinii, with B afzelii being the most commonly identified (84.6% [11/13]).⁸

Borrelial lymphocytoma usually is categorized as a form of early disseminated Lyme disease and is treated as such. The treatment of choice for early disseminated Lyme disease is doxycycline 100 mg twice daily for 14 to 21 days. Ceftriaxone and azithromycin are reasonable treatment options for patients who have tetracycline allergies or who are pregnant.⁹

In conclusion, the presentation of red papules or nodules on the ears should prompt clinical suspicion of Lyme disease, particularly in endemic areas. Differentiating pseudolymphomas from true lymphomas and other reactive conditions can be challenging.

The Diagnosis: Borrelial Lymphocytoma (Lymphocytoma Cutis)

A punch biopsy revealed an atypical lobular lymphoid infiltrate within the dermis and subcutaneous tissue with a mixed composition of CD3⁺ T cells and CD20⁺ B cells (quiz image, bottom). Immunohistochemical studies revealed a normal CD4:CD8 ratio with preservation of CD5 and CD7. CD30 was largely negative. CD21 failed to detect follicular dendritic cell networks, and κ/λ light chain staining confirmed a preserved ratio of polytypic plasma cells. There was limited staining with B-cell lymphoma (Bcl-2 and Bcl-6). Polymerase chain reaction studies for both T- and B-cell receptors were negative (polyclonal).

Lyme disease is the most frequently reported vectorborne infectious disease in the United States, and borrelial lymphocytoma (BL) is a rare clinical sequela. Borrelial lymphocytoma is a variant of lymphocytoma cutis (also known as benign reactive lymphoid hyperplasia), which is an inflammatory lesion that can mimic malignant lymphoma clinically and histologically. Lymphocytoma cutis is considered the prototypical example of cutaneous B-cell pseudolymphoma.¹ Due to suspicion for lymphocytoma cutis based on the histologic findings and characteristic location of the lesions in our patient, Lyme serologies were ordered and were positive for IgM antibodies against p23, p39, and p41 antigens in high titers. Our patient was treated with doxycycline 100 mg twice daily for 3 weeks with complete resolution of the lesions at 3-month follow-up.

Clinically, BL appears as erythematous papules, plaques, or nodules commonly on the lobules of the ears (quiz image, top). Most cases of lymphocytoma cutis are idiopathic but may be triggered by identifiable associated etiologies including Borrelia burgdorferi, Leishmania donovani, molluscum contagiosum, herpes zoster virus, vaccinations, tattoos, insect bites, and drugs. The main differential diagnosis of lymphocytoma cutis is cutaneous B-cell lymphoma. Pseudolymphoma of the skin can mimic nearly all immunohistochemical staining patterns of true B-cell lymphomas.²

Primary cutaneous follicle center lymphoma frequently occurs on the head and neck. This true lymphoma of the skin can demonstrate prominent follicle centers with centrocytes and fragmented germinal centers (Figure 1) or show a diffuse pattern.³ Most cases show conspicuous Bcl-6 staining, and IgH gene rearrangements can detect a clonal B-cell population in more than 50% of cases.⁴

Diffuse large B-cell lymphoma can occur as a primary cutaneous malignancy or as a manifestation of systemic disease.4 When arising in the skin, lesions tend to affect the extremities, and the disease is classified as diffuse large B-cell lymphoma, leg type. Histologically, sheets of large atypical lymphocytes with numerous mitoses are seen (Figure 2). These cells stain positively with Bcl-2 and frequently demonstrate Bcl-6 and MUM-1, none of which were seen in our case.4 Lymphomatoid papulosis (LyP) tends to present with relapsing erythematous papules. Patients occasionally develop LyP in association with mycosis fungoides or other lymphomas. Both LyP and primary cutaneous anaplastic large cell lymphoma demonstrate conspicuous CD30+ large cells that can be multinucleated or resemble the Reed-Sternberg cells seen in Hodgkin lymphoma (Figure 3).4 Arthropod bite reactions are common but may be confused with lymphomas and pseudolymphomas. The perivascular lymphocytic infiltrate seen in arthropod bite reactions may be dense and usually is associated with numerous eosinophils (Figure 4). Occasional plasma cells also can be seen, and if the infiltrate closely adheres to vascular structures, a diagnosis of erythema chronicum migrans also can be considered. Patients with chronic lymphocytic leukemia/lymphoma may demonstrate exaggerated or persistent arthropod bite reactions, and atypical lymphocytes can be detected admixed with the otherwise reactive infiltrate.⁴

Borrelia burgdorferi is primarily endemic to North America and Europe. It is a spirochete bacterium spread by the Ixodes tick that was first recognized as the etiologic agent in 1975 in Old Lyme, Connecticut, where it received its name.⁵ Most reported cases of Lyme disease occur in the northeastern United States, which correlates with this case given our patient’s place of residence.⁶ Borrelial lymphocytoma cutis occurs in areas endemic for the Ixodes tick in Europe and North America.⁷ When describing the genotyping of Borrelia seen in BL, the strain B burgdorferi previously was grouped with Borrelia afzelii and Borrelia garinii.² In the contemporary literature, however, B burgdorferi is referred to as sensu stricto when specifically talking about the strain B burgdorferi, and the term sensu lato is used when referencing the combination of strains (B burgdorferi, B afzelii, B garinii).

A 2016 study by Maraspin et al⁸ comprising 144 patients diagnosed with BL showed that the lesions mainly were located on the breast (106 patients [73.6%]) and the earlobe (27 patients [18.8%]), with the remaining cases occurring elsewhere on the body (11 patients [7.6%]). The Borrelia strains isolated from the BL lesions included B afzelii, Borrelia bissettii, and B garinii, with B afzelii being the most commonly identified (84.6% [11/13]).⁸

Borrelial lymphocytoma usually is categorized as a form of early disseminated Lyme disease and is treated as such. The treatment of choice for early disseminated Lyme disease is doxycycline 100 mg twice daily for 14 to 21 days. Ceftriaxone and azithromycin are reasonable treatment options for patients who have tetracycline allergies or who are pregnant.⁹

In conclusion, the presentation of red papules or nodules on the ears should prompt clinical suspicion of Lyme disease, particularly in endemic areas. Differentiating pseudolymphomas from true lymphomas and other reactive conditions can be challenging.

The Diagnosis: Borrelial Lymphocytoma (Lymphocytoma Cutis)

A punch biopsy revealed an atypical lobular lymphoid infiltrate within the dermis and subcutaneous tissue with a mixed composition of CD3⁺ T cells and CD20⁺ B cells (quiz image, bottom). Immunohistochemical studies revealed a normal CD4:CD8 ratio with preservation of CD5 and CD7. CD30 was largely negative. CD21 failed to detect follicular dendritic cell networks, and κ/λ light chain staining confirmed a preserved ratio of polytypic plasma cells. There was limited staining with B-cell lymphoma (Bcl-2 and Bcl-6). Polymerase chain reaction studies for both T- and B-cell receptors were negative (polyclonal).

Lyme disease is the most frequently reported vectorborne infectious disease in the United States, and borrelial lymphocytoma (BL) is a rare clinical sequela. Borrelial lymphocytoma is a variant of lymphocytoma cutis (also known as benign reactive lymphoid hyperplasia), which is an inflammatory lesion that can mimic malignant lymphoma clinically and histologically. Lymphocytoma cutis is considered the prototypical example of cutaneous B-cell pseudolymphoma.¹ Due to suspicion for lymphocytoma cutis based on the histologic findings and characteristic location of the lesions in our patient, Lyme serologies were ordered and were positive for IgM antibodies against p23, p39, and p41 antigens in high titers. Our patient was treated with doxycycline 100 mg twice daily for 3 weeks with complete resolution of the lesions at 3-month follow-up.

Clinically, BL appears as erythematous papules, plaques, or nodules commonly on the lobules of the ears (quiz image, top). Most cases of lymphocytoma cutis are idiopathic but may be triggered by identifiable associated etiologies including Borrelia burgdorferi, Leishmania donovani, molluscum contagiosum, herpes zoster virus, vaccinations, tattoos, insect bites, and drugs. The main differential diagnosis of lymphocytoma cutis is cutaneous B-cell lymphoma. Pseudolymphoma of the skin can mimic nearly all immunohistochemical staining patterns of true B-cell lymphomas.²

Primary cutaneous follicle center lymphoma frequently occurs on the head and neck. This true lymphoma of the skin can demonstrate prominent follicle centers with centrocytes and fragmented germinal centers (Figure 1) or show a diffuse pattern.³ Most cases show conspicuous Bcl-6 staining, and IgH gene rearrangements can detect a clonal B-cell population in more than 50% of cases.⁴

Diffuse large B-cell lymphoma can occur as a primary cutaneous malignancy or as a manifestation of systemic disease.4 When arising in the skin, lesions tend to affect the extremities, and the disease is classified as diffuse large B-cell lymphoma, leg type. Histologically, sheets of large atypical lymphocytes with numerous mitoses are seen (Figure 2). These cells stain positively with Bcl-2 and frequently demonstrate Bcl-6 and MUM-1, none of which were seen in our case.4 Lymphomatoid papulosis (LyP) tends to present with relapsing erythematous papules. Patients occasionally develop LyP in association with mycosis fungoides or other lymphomas. Both LyP and primary cutaneous anaplastic large cell lymphoma demonstrate conspicuous CD30+ large cells that can be multinucleated or resemble the Reed-Sternberg cells seen in Hodgkin lymphoma (Figure 3).4 Arthropod bite reactions are common but may be confused with lymphomas and pseudolymphomas. The perivascular lymphocytic infiltrate seen in arthropod bite reactions may be dense and usually is associated with numerous eosinophils (Figure 4). Occasional plasma cells also can be seen, and if the infiltrate closely adheres to vascular structures, a diagnosis of erythema chronicum migrans also can be considered. Patients with chronic lymphocytic leukemia/lymphoma may demonstrate exaggerated or persistent arthropod bite reactions, and atypical lymphocytes can be detected admixed with the otherwise reactive infiltrate.⁴

Borrelia burgdorferi is primarily endemic to North America and Europe. It is a spirochete bacterium spread by the Ixodes tick that was first recognized as the etiologic agent in 1975 in Old Lyme, Connecticut, where it received its name.⁵ Most reported cases of Lyme disease occur in the northeastern United States, which correlates with this case given our patient’s place of residence.⁶ Borrelial lymphocytoma cutis occurs in areas endemic for the Ixodes tick in Europe and North America.⁷ When describing the genotyping of Borrelia seen in BL, the strain B burgdorferi previously was grouped with Borrelia afzelii and Borrelia garinii.² In the contemporary literature, however, B burgdorferi is referred to as sensu stricto when specifically talking about the strain B burgdorferi, and the term sensu lato is used when referencing the combination of strains (B burgdorferi, B afzelii, B garinii).

A 2016 study by Maraspin et al⁸ comprising 144 patients diagnosed with BL showed that the lesions mainly were located on the breast (106 patients [73.6%]) and the earlobe (27 patients [18.8%]), with the remaining cases occurring elsewhere on the body (11 patients [7.6%]). The Borrelia strains isolated from the BL lesions included B afzelii, Borrelia bissettii, and B garinii, with B afzelii being the most commonly identified (84.6% [11/13]).⁸

Borrelial lymphocytoma usually is categorized as a form of early disseminated Lyme disease and is treated as such. The treatment of choice for early disseminated Lyme disease is doxycycline 100 mg twice daily for 14 to 21 days. Ceftriaxone and azithromycin are reasonable treatment options for patients who have tetracycline allergies or who are pregnant.⁹

In conclusion, the presentation of red papules or nodules on the ears should prompt clinical suspicion of Lyme disease, particularly in endemic areas. Differentiating pseudolymphomas from true lymphomas and other reactive conditions can be challenging.

An ancient tree of the Ginkgoaceae family, Ginkgo biloba is known as a living fossil because its genome has been identified in fossils older than 200 million years.¹ An individual tree can live longer than 1000 years. Originating in China, G biloba (here, “ginkgo”) is cultivated worldwide for its attractive foliage (Figure 1). Ginkgo extract has long been used in traditional Chinese medicine; however, contact with the plant proper can provoke allergic contact dermatitis.

Dermatitis-Inducing Components

The allergenic component of the ginkgo tree is ginkgolic acid, which is structurally similar to urushiol and anacardic acid.^2,3 This compound can cause a cross-reaction in a person previously sensitized by contact with other plants. Urushiol is found in poison ivy(Toxicodendron radicans); anacardic acid is found in the cashew tree (Anacardium occidentale). Both plants belong to the family Anacardiaceae, commonly known as the cashew family.

Members of Anacardiaceae are the most common causes of plant-induced allergic contact dermatitis and include the cashew tree, mango tree, poison ivy, poison oak, and poison sumac. These plants can cross-react to cause contact dermatitis (Table).³ Patch tests have revealed that some individuals who are sensitive to components of the ginkgo tree also demonstrate sensitivity to poison ivy and poison sumac^4,5; countering this finding, Lepoittevin and colleagues⁶ demonstrated in animal studies that there was no cross-reactivity between ginkgo and urushiol, suggesting that patients with a reported cross-reaction might truly have been previously sensitized to both plants. In general, patients who have a history of a reaction to any Anacardiaceae plant should take precautions when handling them.

Therapeutic Benefit of Ginkgo

Ginkgo extract is sold as the herbal supplement EGB761, which acts as an antioxidant.⁷ In France, Germany, and China, it is a commonly prescribed herbal medicine.⁸ It is purported to support memory and attention; studies have shown improvement in cognition and in involvement with activities of daily living for patients with dementia.^9,10 Ginkgo extract might lessen peripheral vascular disease and cerebral circulatory disease, having been shown in vitro and in animal models to prevent platelet aggregation induced by platelet-activating factor and to stimulate vasodilation by increasing production of nitric oxide.^11,12

Furthermore, purified ginkgo extract might have beneficial effects on skin. A study in rats showed that when intraperitoneal ginkgo extract was given prior to radiation therapy, 100% of rats receiving placebo developed radiation dermatitis vs 13% of those that received ginkgo extract (P<.0001). An excisional skin biopsy showed a decrease in markers of oxidative stress in rats that received ginkgo extract prior to radiation.⁷

A randomized, double-blind clinical trial showed a significant reduction in disease progression in vitiligo patients assigned to receive ginkgo extract orally compared to placebo (P=.006).¹³ Research for many possible uses of ginkgo extract is ongoing.

Cutaneous Manifestations

Contact with the fruit of the ginkgo tree can induce allergic contact dermatitis,¹⁴ most often as erythematous papules, vesicles, and in some cases edema.^5,15

Exposures While Picking Berries—In 1939, Bolus¹⁵ reported the case of a patient who presented with edema, erythema, and vesicular lesions involving the hands and face after picking berries from a ginkgo tree. Later, patch testing on this patient, using ginkgo fruit, resulted in burning and stinging that necessitated removal of the patch, suggesting an irritant reaction. This was followed by a vesicular reaction that then developed within 24 hours, which was more consistent with allergy. Similarly, in 1988, a case series of contact dermatitis was reported in 3 patients after gathering ginkgo fruit.⁵

Incidental Exposure While Walking—In 1965, dermatitis broke out in 35 high school students, mainly affecting exposed portions of the leg, after ginkgo fruit fell and its pulp was exposed on a path at their school.⁴ Subsequently, patch testing was performed on 29 volunteers—some who had been exposed to ginkgo on that path, others without prior exposure. It was established that testing with ginkgo pulp directly caused an irritant reaction in all students, regardless of prior ginkgo exposure, but all prior ginkgo-exposed students in this study reacted positively to an acetone extract of ginkgo pulp and either poison ivy extract or pentadecylcatechol.⁴

Systemic Contact After Eating Fruit—An illustrative case of dermatitis, stomatitis, and proctitis was reported in a man with history of poison oak contact dermatitis who had eaten fruit from a ginkgo tree, suggesting systemic contact dermatitis. Weeks after resolution of symptoms, he reacted positively to ginkgo fruit and poison ivy extracts on patch testing.¹⁶

Ginkgo dermatitis tends to resolve upon removal of the inciting agent and application of a topical steroid.^8,17 Although many reported cases involve the fruit, allergic contact dermatitis can result from exposure to any part of the plant. In a reported case, a woman developed airborne contact dermatitis from working with sarcotesta of the ginkgo plant.¹⁸ Despite wearing rubber gloves, she broke out 1 week after exposure with erythema on the face and arms and severe facial edema.

Ginkgo leaves also can cause allergic contact dermatitis.¹⁹ Precautions should be taken when handling any component of the ginkgo tree.

Oral ginkgo supplementation has been implicated in a variety of other cutaneous reactions—from benign to life-threatening. When the ginkgo allergen concentration is too high within the supplement, as has been noted in some formulations, patients have presented with a diffuse morbilliform eruption within 1 or 2 weeks after taking ginkgo.²⁰ One patient—who was not taking any other medication—experienced an episode of acute generalized exanthematous pustulosis 48 hours after taking ginkgo.²¹ Ingestion of ginkgo extract also has been associated with Stevens-Johnson syndrome.^22-24

Other Adverse Reactions

The adverse effects of ginkgo supplement vary widely. In addition to dermatitis, ginkgo supplement can cause headaches, palpitations, tachycardia, vasculitis, nausea, and other symptoms.¹⁴

Metabolic Disturbance—One patient taking ginkgo who died after a seizure was found to have subtherapeutic levels of valproate and phenytoin,²⁵ which could be due to ginkgo’s effect on cytochrome p450 enzyme CYP2C19.²⁶ Ginkgo interactions with many cytochrome enzymes have been studied for potential drug interactions. Any other direct effects remain variable and controversial.^27,28

Hemorrhage—Another serious effect associated with taking ginkgo supplements is hemorrhage, often in conjunction with warfarin¹⁴; however, a meta-analysis indicated that ginkgo generally does not increase the risk of bleeding.²⁹ Other studies have shown that taking ginkgo with warfarin showed no difference in clotting status, and ginkgo with aspirin resulted in no clinically significant difference in bruising, bleeding, or platelet function in an analysis over a period of 1 month.^30,31 These findings notwithstanding, pregnant women, surgical patients, and those taking a blood thinner are advised as a general precaution not to take ginkgo extract.

Carcinogenesis—Ginkgo extract has antioxidant properties, but there is evidence that it might act as a carcinogen. An animal study reported by the US National Toxicology Program found that ginkgo induced mutagenic activity in the liver, thyroid, and nose of mice and rats. Over time, rodent liver underwent changes consistent with hepatic enzyme induction.³² More research is needed to clarify the role of ginkgo in this process.

Toxicity by Ingestion—Ginkgo seeds can cause food poisoning due to the compound 4’-O-methylpyridoxine (also known as ginkgotoxin).³³ Because methylpyridoxine can cause depletion of pyridoxal phosphate (a form of vitamin B₆ necessary for the synthesis of γ-aminobutyric acid), overconsumption of ginkgo seeds, even when fully cooked, might result in convulsions and even death.³³

Nomenclature and Distribution of Plants

Gingko biloba belongs to the Ginkgoaceae family (class Ginkgophytes). The tree originated in China but might no longer exist in a truly wild form. It is grown worldwide for its beauty and longevity. The female ginkgo tree is a gymnosperm, producing fruit with seeds that are not coated by an ovary wall¹⁵; male (nonfruiting) trees are preferentially planted because the fruit is surrounded by a pulp that, when dropped, emits a sour smell described variously as rancid butter, vomit, or excrement.⁵

Identifying Features and Plant Facts

The deciduous ginkgo tree has unique fan-shaped leaves and is cultivated for its beauty and resistance to disease (Figure 2).^4,34 It is nicknamed the maidenhair tree because the leaves are similar to the pinnae of the maidenhair fern.³⁴ Because G biloba is resistant to pollution, it often is planted along city streets.¹⁷ The leaf—5- to 8-cm wide and a symbol of the city of Tokyo, Japan³⁴—grows in clusters (Figure 3)⁵ and is green but turns yellow before it falls in autumn.³⁴ Leaf veins branch out into the blade without anastomosing.³⁴

Male flowers grow in a catkinlike pattern; female flowers grow on long stems.⁵ The fruit is small, dark, and shriveled, with a hint of silver⁴; it typically is 2 to 2.5 cm in diameter and contains the ginkgo nut or seed. The kernel of the ginkgo nut is edible when roasted and is used in traditional Chinese and Japanese cuisine as a dish served on special occasions in autumn.³³

Final Thoughts

Given that G biloba is a beautiful, commonly planted ornamental tree, gardeners and landscapers should be aware of the risk for allergic contact dermatitis and use proper protection. Dermatologists should be aware of its cross-reactivity with other common plants such as poison ivy and poison oak to help patients identify the cause of their reactions and avoid the inciting agent. Because ginkgo extract also can cause a cutaneous reaction or interact with other medications, providers should remember to take a thorough medication history that includes herbal medicines and supplements.

An ancient tree of the Ginkgoaceae family, Ginkgo biloba is known as a living fossil because its genome has been identified in fossils older than 200 million years.¹ An individual tree can live longer than 1000 years. Originating in China, G biloba (here, “ginkgo”) is cultivated worldwide for its attractive foliage (Figure 1). Ginkgo extract has long been used in traditional Chinese medicine; however, contact with the plant proper can provoke allergic contact dermatitis.

Dermatitis-Inducing Components

The allergenic component of the ginkgo tree is ginkgolic acid, which is structurally similar to urushiol and anacardic acid.^2,3 This compound can cause a cross-reaction in a person previously sensitized by contact with other plants. Urushiol is found in poison ivy(Toxicodendron radicans); anacardic acid is found in the cashew tree (Anacardium occidentale). Both plants belong to the family Anacardiaceae, commonly known as the cashew family.

Members of Anacardiaceae are the most common causes of plant-induced allergic contact dermatitis and include the cashew tree, mango tree, poison ivy, poison oak, and poison sumac. These plants can cross-react to cause contact dermatitis (Table).³ Patch tests have revealed that some individuals who are sensitive to components of the ginkgo tree also demonstrate sensitivity to poison ivy and poison sumac^4,5; countering this finding, Lepoittevin and colleagues⁶ demonstrated in animal studies that there was no cross-reactivity between ginkgo and urushiol, suggesting that patients with a reported cross-reaction might truly have been previously sensitized to both plants. In general, patients who have a history of a reaction to any Anacardiaceae plant should take precautions when handling them.

Therapeutic Benefit of Ginkgo

Ginkgo extract is sold as the herbal supplement EGB761, which acts as an antioxidant.⁷ In France, Germany, and China, it is a commonly prescribed herbal medicine.⁸ It is purported to support memory and attention; studies have shown improvement in cognition and in involvement with activities of daily living for patients with dementia.^9,10 Ginkgo extract might lessen peripheral vascular disease and cerebral circulatory disease, having been shown in vitro and in animal models to prevent platelet aggregation induced by platelet-activating factor and to stimulate vasodilation by increasing production of nitric oxide.^11,12

Furthermore, purified ginkgo extract might have beneficial effects on skin. A study in rats showed that when intraperitoneal ginkgo extract was given prior to radiation therapy, 100% of rats receiving placebo developed radiation dermatitis vs 13% of those that received ginkgo extract (P<.0001). An excisional skin biopsy showed a decrease in markers of oxidative stress in rats that received ginkgo extract prior to radiation.⁷

A randomized, double-blind clinical trial showed a significant reduction in disease progression in vitiligo patients assigned to receive ginkgo extract orally compared to placebo (P=.006).¹³ Research for many possible uses of ginkgo extract is ongoing.

Cutaneous Manifestations

Contact with the fruit of the ginkgo tree can induce allergic contact dermatitis,¹⁴ most often as erythematous papules, vesicles, and in some cases edema.^5,15

Exposures While Picking Berries—In 1939, Bolus¹⁵ reported the case of a patient who presented with edema, erythema, and vesicular lesions involving the hands and face after picking berries from a ginkgo tree. Later, patch testing on this patient, using ginkgo fruit, resulted in burning and stinging that necessitated removal of the patch, suggesting an irritant reaction. This was followed by a vesicular reaction that then developed within 24 hours, which was more consistent with allergy. Similarly, in 1988, a case series of contact dermatitis was reported in 3 patients after gathering ginkgo fruit.⁵

Incidental Exposure While Walking—In 1965, dermatitis broke out in 35 high school students, mainly affecting exposed portions of the leg, after ginkgo fruit fell and its pulp was exposed on a path at their school.⁴ Subsequently, patch testing was performed on 29 volunteers—some who had been exposed to ginkgo on that path, others without prior exposure. It was established that testing with ginkgo pulp directly caused an irritant reaction in all students, regardless of prior ginkgo exposure, but all prior ginkgo-exposed students in this study reacted positively to an acetone extract of ginkgo pulp and either poison ivy extract or pentadecylcatechol.⁴

Systemic Contact After Eating Fruit—An illustrative case of dermatitis, stomatitis, and proctitis was reported in a man with history of poison oak contact dermatitis who had eaten fruit from a ginkgo tree, suggesting systemic contact dermatitis. Weeks after resolution of symptoms, he reacted positively to ginkgo fruit and poison ivy extracts on patch testing.¹⁶

Ginkgo dermatitis tends to resolve upon removal of the inciting agent and application of a topical steroid.^8,17 Although many reported cases involve the fruit, allergic contact dermatitis can result from exposure to any part of the plant. In a reported case, a woman developed airborne contact dermatitis from working with sarcotesta of the ginkgo plant.¹⁸ Despite wearing rubber gloves, she broke out 1 week after exposure with erythema on the face and arms and severe facial edema.

Ginkgo leaves also can cause allergic contact dermatitis.¹⁹ Precautions should be taken when handling any component of the ginkgo tree.

Oral ginkgo supplementation has been implicated in a variety of other cutaneous reactions—from benign to life-threatening. When the ginkgo allergen concentration is too high within the supplement, as has been noted in some formulations, patients have presented with a diffuse morbilliform eruption within 1 or 2 weeks after taking ginkgo.²⁰ One patient—who was not taking any other medication—experienced an episode of acute generalized exanthematous pustulosis 48 hours after taking ginkgo.²¹ Ingestion of ginkgo extract also has been associated with Stevens-Johnson syndrome.^22-24

Other Adverse Reactions

The adverse effects of ginkgo supplement vary widely. In addition to dermatitis, ginkgo supplement can cause headaches, palpitations, tachycardia, vasculitis, nausea, and other symptoms.¹⁴

Metabolic Disturbance—One patient taking ginkgo who died after a seizure was found to have subtherapeutic levels of valproate and phenytoin,²⁵ which could be due to ginkgo’s effect on cytochrome p450 enzyme CYP2C19.²⁶ Ginkgo interactions with many cytochrome enzymes have been studied for potential drug interactions. Any other direct effects remain variable and controversial.^27,28

Hemorrhage—Another serious effect associated with taking ginkgo supplements is hemorrhage, often in conjunction with warfarin¹⁴; however, a meta-analysis indicated that ginkgo generally does not increase the risk of bleeding.²⁹ Other studies have shown that taking ginkgo with warfarin showed no difference in clotting status, and ginkgo with aspirin resulted in no clinically significant difference in bruising, bleeding, or platelet function in an analysis over a period of 1 month.^30,31 These findings notwithstanding, pregnant women, surgical patients, and those taking a blood thinner are advised as a general precaution not to take ginkgo extract.

Carcinogenesis—Ginkgo extract has antioxidant properties, but there is evidence that it might act as a carcinogen. An animal study reported by the US National Toxicology Program found that ginkgo induced mutagenic activity in the liver, thyroid, and nose of mice and rats. Over time, rodent liver underwent changes consistent with hepatic enzyme induction.³² More research is needed to clarify the role of ginkgo in this process.

Toxicity by Ingestion—Ginkgo seeds can cause food poisoning due to the compound 4’-O-methylpyridoxine (also known as ginkgotoxin).³³ Because methylpyridoxine can cause depletion of pyridoxal phosphate (a form of vitamin B₆ necessary for the synthesis of γ-aminobutyric acid), overconsumption of ginkgo seeds, even when fully cooked, might result in convulsions and even death.³³

Nomenclature and Distribution of Plants

Gingko biloba belongs to the Ginkgoaceae family (class Ginkgophytes). The tree originated in China but might no longer exist in a truly wild form. It is grown worldwide for its beauty and longevity. The female ginkgo tree is a gymnosperm, producing fruit with seeds that are not coated by an ovary wall¹⁵; male (nonfruiting) trees are preferentially planted because the fruit is surrounded by a pulp that, when dropped, emits a sour smell described variously as rancid butter, vomit, or excrement.⁵

Identifying Features and Plant Facts

The deciduous ginkgo tree has unique fan-shaped leaves and is cultivated for its beauty and resistance to disease (Figure 2).^4,34 It is nicknamed the maidenhair tree because the leaves are similar to the pinnae of the maidenhair fern.³⁴ Because G biloba is resistant to pollution, it often is planted along city streets.¹⁷ The leaf—5- to 8-cm wide and a symbol of the city of Tokyo, Japan³⁴—grows in clusters (Figure 3)⁵ and is green but turns yellow before it falls in autumn.³⁴ Leaf veins branch out into the blade without anastomosing.³⁴

Male flowers grow in a catkinlike pattern; female flowers grow on long stems.⁵ The fruit is small, dark, and shriveled, with a hint of silver⁴; it typically is 2 to 2.5 cm in diameter and contains the ginkgo nut or seed. The kernel of the ginkgo nut is edible when roasted and is used in traditional Chinese and Japanese cuisine as a dish served on special occasions in autumn.³³

Final Thoughts

Given that G biloba is a beautiful, commonly planted ornamental tree, gardeners and landscapers should be aware of the risk for allergic contact dermatitis and use proper protection. Dermatologists should be aware of its cross-reactivity with other common plants such as poison ivy and poison oak to help patients identify the cause of their reactions and avoid the inciting agent. Because ginkgo extract also can cause a cutaneous reaction or interact with other medications, providers should remember to take a thorough medication history that includes herbal medicines and supplements.

An ancient tree of the Ginkgoaceae family, Ginkgo biloba is known as a living fossil because its genome has been identified in fossils older than 200 million years.¹ An individual tree can live longer than 1000 years. Originating in China, G biloba (here, “ginkgo”) is cultivated worldwide for its attractive foliage (Figure 1). Ginkgo extract has long been used in traditional Chinese medicine; however, contact with the plant proper can provoke allergic contact dermatitis.

Dermatitis-Inducing Components

The allergenic component of the ginkgo tree is ginkgolic acid, which is structurally similar to urushiol and anacardic acid.^2,3 This compound can cause a cross-reaction in a person previously sensitized by contact with other plants. Urushiol is found in poison ivy(Toxicodendron radicans); anacardic acid is found in the cashew tree (Anacardium occidentale). Both plants belong to the family Anacardiaceae, commonly known as the cashew family.

Members of Anacardiaceae are the most common causes of plant-induced allergic contact dermatitis and include the cashew tree, mango tree, poison ivy, poison oak, and poison sumac. These plants can cross-react to cause contact dermatitis (Table).³ Patch tests have revealed that some individuals who are sensitive to components of the ginkgo tree also demonstrate sensitivity to poison ivy and poison sumac^4,5; countering this finding, Lepoittevin and colleagues⁶ demonstrated in animal studies that there was no cross-reactivity between ginkgo and urushiol, suggesting that patients with a reported cross-reaction might truly have been previously sensitized to both plants. In general, patients who have a history of a reaction to any Anacardiaceae plant should take precautions when handling them.

Therapeutic Benefit of Ginkgo

Ginkgo extract is sold as the herbal supplement EGB761, which acts as an antioxidant.⁷ In France, Germany, and China, it is a commonly prescribed herbal medicine.⁸ It is purported to support memory and attention; studies have shown improvement in cognition and in involvement with activities of daily living for patients with dementia.^9,10 Ginkgo extract might lessen peripheral vascular disease and cerebral circulatory disease, having been shown in vitro and in animal models to prevent platelet aggregation induced by platelet-activating factor and to stimulate vasodilation by increasing production of nitric oxide.^11,12

Furthermore, purified ginkgo extract might have beneficial effects on skin. A study in rats showed that when intraperitoneal ginkgo extract was given prior to radiation therapy, 100% of rats receiving placebo developed radiation dermatitis vs 13% of those that received ginkgo extract (P<.0001). An excisional skin biopsy showed a decrease in markers of oxidative stress in rats that received ginkgo extract prior to radiation.⁷

A randomized, double-blind clinical trial showed a significant reduction in disease progression in vitiligo patients assigned to receive ginkgo extract orally compared to placebo (P=.006).¹³ Research for many possible uses of ginkgo extract is ongoing.

Cutaneous Manifestations

Contact with the fruit of the ginkgo tree can induce allergic contact dermatitis,¹⁴ most often as erythematous papules, vesicles, and in some cases edema.^5,15

Exposures While Picking Berries—In 1939, Bolus¹⁵ reported the case of a patient who presented with edema, erythema, and vesicular lesions involving the hands and face after picking berries from a ginkgo tree. Later, patch testing on this patient, using ginkgo fruit, resulted in burning and stinging that necessitated removal of the patch, suggesting an irritant reaction. This was followed by a vesicular reaction that then developed within 24 hours, which was more consistent with allergy. Similarly, in 1988, a case series of contact dermatitis was reported in 3 patients after gathering ginkgo fruit.⁵

Incidental Exposure While Walking—In 1965, dermatitis broke out in 35 high school students, mainly affecting exposed portions of the leg, after ginkgo fruit fell and its pulp was exposed on a path at their school.⁴ Subsequently, patch testing was performed on 29 volunteers—some who had been exposed to ginkgo on that path, others without prior exposure. It was established that testing with ginkgo pulp directly caused an irritant reaction in all students, regardless of prior ginkgo exposure, but all prior ginkgo-exposed students in this study reacted positively to an acetone extract of ginkgo pulp and either poison ivy extract or pentadecylcatechol.⁴

Systemic Contact After Eating Fruit—An illustrative case of dermatitis, stomatitis, and proctitis was reported in a man with history of poison oak contact dermatitis who had eaten fruit from a ginkgo tree, suggesting systemic contact dermatitis. Weeks after resolution of symptoms, he reacted positively to ginkgo fruit and poison ivy extracts on patch testing.¹⁶

Ginkgo dermatitis tends to resolve upon removal of the inciting agent and application of a topical steroid.^8,17 Although many reported cases involve the fruit, allergic contact dermatitis can result from exposure to any part of the plant. In a reported case, a woman developed airborne contact dermatitis from working with sarcotesta of the ginkgo plant.¹⁸ Despite wearing rubber gloves, she broke out 1 week after exposure with erythema on the face and arms and severe facial edema.

Ginkgo leaves also can cause allergic contact dermatitis.¹⁹ Precautions should be taken when handling any component of the ginkgo tree.

Oral ginkgo supplementation has been implicated in a variety of other cutaneous reactions—from benign to life-threatening. When the ginkgo allergen concentration is too high within the supplement, as has been noted in some formulations, patients have presented with a diffuse morbilliform eruption within 1 or 2 weeks after taking ginkgo.²⁰ One patient—who was not taking any other medication—experienced an episode of acute generalized exanthematous pustulosis 48 hours after taking ginkgo.²¹ Ingestion of ginkgo extract also has been associated with Stevens-Johnson syndrome.^22-24

Other Adverse Reactions

The adverse effects of ginkgo supplement vary widely. In addition to dermatitis, ginkgo supplement can cause headaches, palpitations, tachycardia, vasculitis, nausea, and other symptoms.¹⁴

Metabolic Disturbance—One patient taking ginkgo who died after a seizure was found to have subtherapeutic levels of valproate and phenytoin,²⁵ which could be due to ginkgo’s effect on cytochrome p450 enzyme CYP2C19.²⁶ Ginkgo interactions with many cytochrome enzymes have been studied for potential drug interactions. Any other direct effects remain variable and controversial.^27,28

Hemorrhage—Another serious effect associated with taking ginkgo supplements is hemorrhage, often in conjunction with warfarin¹⁴; however, a meta-analysis indicated that ginkgo generally does not increase the risk of bleeding.²⁹ Other studies have shown that taking ginkgo with warfarin showed no difference in clotting status, and ginkgo with aspirin resulted in no clinically significant difference in bruising, bleeding, or platelet function in an analysis over a period of 1 month.^30,31 These findings notwithstanding, pregnant women, surgical patients, and those taking a blood thinner are advised as a general precaution not to take ginkgo extract.

Carcinogenesis—Ginkgo extract has antioxidant properties, but there is evidence that it might act as a carcinogen. An animal study reported by the US National Toxicology Program found that ginkgo induced mutagenic activity in the liver, thyroid, and nose of mice and rats. Over time, rodent liver underwent changes consistent with hepatic enzyme induction.³² More research is needed to clarify the role of ginkgo in this process.

Toxicity by Ingestion—Ginkgo seeds can cause food poisoning due to the compound 4’-O-methylpyridoxine (also known as ginkgotoxin).³³ Because methylpyridoxine can cause depletion of pyridoxal phosphate (a form of vitamin B₆ necessary for the synthesis of γ-aminobutyric acid), overconsumption of ginkgo seeds, even when fully cooked, might result in convulsions and even death.³³

Nomenclature and Distribution of Plants

Gingko biloba belongs to the Ginkgoaceae family (class Ginkgophytes). The tree originated in China but might no longer exist in a truly wild form. It is grown worldwide for its beauty and longevity. The female ginkgo tree is a gymnosperm, producing fruit with seeds that are not coated by an ovary wall¹⁵; male (nonfruiting) trees are preferentially planted because the fruit is surrounded by a pulp that, when dropped, emits a sour smell described variously as rancid butter, vomit, or excrement.⁵

Identifying Features and Plant Facts

The deciduous ginkgo tree has unique fan-shaped leaves and is cultivated for its beauty and resistance to disease (Figure 2).^4,34 It is nicknamed the maidenhair tree because the leaves are similar to the pinnae of the maidenhair fern.³⁴ Because G biloba is resistant to pollution, it often is planted along city streets.¹⁷ The leaf—5- to 8-cm wide and a symbol of the city of Tokyo, Japan³⁴—grows in clusters (Figure 3)⁵ and is green but turns yellow before it falls in autumn.³⁴ Leaf veins branch out into the blade without anastomosing.³⁴

Male flowers grow in a catkinlike pattern; female flowers grow on long stems.⁵ The fruit is small, dark, and shriveled, with a hint of silver⁴; it typically is 2 to 2.5 cm in diameter and contains the ginkgo nut or seed. The kernel of the ginkgo nut is edible when roasted and is used in traditional Chinese and Japanese cuisine as a dish served on special occasions in autumn.³³

Final Thoughts

Given that G biloba is a beautiful, commonly planted ornamental tree, gardeners and landscapers should be aware of the risk for allergic contact dermatitis and use proper protection. Dermatologists should be aware of its cross-reactivity with other common plants such as poison ivy and poison oak to help patients identify the cause of their reactions and avoid the inciting agent. Because ginkgo extract also can cause a cutaneous reaction or interact with other medications, providers should remember to take a thorough medication history that includes herbal medicines and supplements.

No time of the year is more exciting than the unveiling of the American Contact Dermatitis Society Allergen of the Year. Sometimes the selected allergen represents a completely novel cause of allergic contact dermatitis (ACD) with an unpronounceable chemical name. Not this time! The 2022 Allergen of the Year is likely to be lurking in your kitchen drawer at this very moment, as this year aluminum was chosen for this most prestigious honor.¹ But do not throw out your aluminum foil just yet—aluminum allergy tends to be confined to specific scenarios. In this article, we highlight the growing recognition of aluminum contact allergy, particularly in the pediatric population, focusing on distinct presentations of aluminum ACD, unique sources of exposure, and nuances of patch testing to this metal.

Aluminum Is All Around Us

As the third most common element in the Earth’s crust, aluminum can be found quite literally everywhere.¹ However, aluminum rarely is found in its pure elemental form; instead, it reacts with other elements around it, most commonly oxygen, to form aluminum-containing compounds. Known for their stability and safety, aluminum and its salts are incorporated in myriad products ranging from electronic equipment to foods and their packaging, medications, cosmetics, orthopedic and dental implants, and even tattoos. Aluminum also is found in the air and water supply and may even be encountered in certain workplaces, such as aircraft and machine industries. As such, contact with aluminum is all but certain in modern life.

The use of aluminum in consumer products is widely accepted as safe by public health agencies in the United States.² Although there has been public concern that aluminum could be linked to development of breast cancer or Alzheimer disease, there is no clear evidence that these conditions are associated with routine aluminum exposure through ingestion or consumer products.^3-5

Aluminum Contact Allergy

In part because of its ubiquity and in part because of the stability of aluminum-containing compounds, it was long thought that aluminum was nonallergenic. Contact allergy to elemental aluminum is rare; on the other hand, aluminum salts (the forms we are likely to encounter in daily life) are now recognized in the field of contact dermatitis as allergens of significance, particularly in the pediatric population.^1,6

First reported as a possible occupational allergen in 1944,⁷ aluminum allergy came to prominence in the 1990s in association with vaccines. Aluminum is included in some vaccines as an adjuvant that bolsters the immune response⁸; the eTable lists currently available aluminum-containing vaccines in the United States; of note, none of the COVID-19 vaccines approved in the United States or Europe contain aluminum.¹¹ Although the use of aluminum in vaccines is considered to be safe by the US Food and Drug Administration and Centers for Disease Control and Prevention,^12,13 a small number of children become sensitized to aluminum through vaccines and may develop persistent pruritic subcutaneous nodules (also known as vaccination granulomas) at the injection site; however, the incidence of this adverse effect was less than 1% in large studies including as many as 76,000 children, suggesting that it is relatively rare.^14,15 Upon patch testing, aluminum allergy has been detected in 77% to 95% of such cases.¹⁴ There is wide variation in the onset of the nodules ranging from weeks to years following vaccination.¹⁵ Due to pruritus, the examination may reveal accompanying excoriations, hyperpigmentation, and sometimes hypertrichosis at the injection site. Aluminum allergy related to vaccination also can manifest with widespread eruptions representing systemic contact dermatitis.¹⁶

Along with vaccines, the second major source of aluminum sensitization is allergen-specific immunotherapies administered by allergists/immunologists, many of which contain aluminum hydroxide.^17,18

On the consumer product front, antiperspirants are the most common source of cutaneous exposure to aluminum. Aluminum complexes react with electrolytes in sweat to form plugs in eccrine ducts, thereby preventing sweat excretion.⁶ Allergic contact dermatitis to these products presents with axillary-vault dermatitis. There also have been reports of ACD to aluminum in sunscreen and toothpaste, with the latter implicated in causing systemic ACD.^19,20

Prevalence of Sensitization to Aluminum

There have been a few large-scale studies evaluating rates of sensitization to aluminum in general patch-test patient populations; additionally, because of the complexities of testing this metal, investigators have utilized differing formulations for patch testing. A recent Swedish study found that 0.9% of 5448 adults and 5.1% of 196 children showed positive reactions to aluminum chloride hexahydrate (ACH) 10% in petrolatum and/or aluminum lactate 12% in petrolatum.²¹ Notably, there was a significant association between aluminum allergy and history of atopy for both adults (P=.0056) and children (P=.046), which remains to be further explored. A systematic review and meta-analysis found comparable rates of aluminum allergy in 0.4% of adults and 5.6% of children without vaccine granulomas who were tested.²² With this evidence in mind, it has been recommended by contact dermatitis experts that aluminum be included in pediatric baseline patch test series and also investigated for potential inclusion in baseline series for adults.¹

Differential Diagnosis of Aluminum ACD

The differential diagnosis for subcutaneous nodules following vaccination is broad and includes various forms of panniculitis, sarcoidosis, foreign body reactions, vascular malformations, infections, and malignancies.^23-25 The diagnosis may be obscured in cases with delayed onset. Biopsy is not mandatory to establish the diagnosis; although variable histopathologic findings have been reported, a common feature is histiocytes with abundant granular cytoplasm.²⁶ It may be possible to demonstrate the presence of aluminum particles in tissue using electron microscopy and X-ray microanalysis.

For those patients who present with axillary-vault dermatitis, the differential includes ACD to more common allergens in antiperspirants (eg, fragrance), as well as other axillary dermatoses including inverse psoriasis, erythrasma, Hailey-Hailey disease, and various forms of intertrigo. Dermatitis localized to the axillary rim suggests textile allergy.

Patch Testing to Aluminum

Due to its physicochemical properties, patch testing for aluminum allergy is complicated, and historically there has been a lack of consensus on the ideal test formulation.^1,27,28 At this time, it appears that the most sensitive formulation for patch testing to aluminum is ACH 10% in petrolatum.¹ Some contact dermatitis experts recommend that children younger than 8 years should be tested with ACH 2% in petrolatum to minimize the risk of extreme patch test reactions.^29,30 In some patients sensitized to aluminum, the use of aluminum patch test chambers has been noted to produce false-positive reactions, taking the form of multiple ring-shaped reactions to the chambers themselves or reactions to certain allergens whose chemical properties cause corrosion of the aluminum within the chambers.^31-33 Therefore, when testing for suspected aluminum allergy, plastic chambers should be used; given the higher prevalence of aluminum allergy in children, some clinics routinely use plastic chambers for all pediatric patch testing.³⁴ Importantly, elemental aluminum, including empty aluminum test chambers or aluminum foil, alone is not sufficient for patch testing as it lacks sensitivity.¹ Additionally, nearly 20% of positive tests will be missed if a day 7 reading is not performed, making delayed reading a must in cases with high suspicion for aluminum allergy.²¹

Management of Aluminum Allergy

The development of pruritic subcutaneous nodules is uncomfortable for children and their guardians alike and may be associated with prolonged symptoms that negatively impact quality of life^35,36; nonetheless, expert authorities have determined that the preventive benefits of childhood vaccination far outweigh any risk posed by the presence of aluminum in vaccines.^12,13,37 Because aluminum-free formulations may not be available for all vaccines, it is essential to educate patients and families who may be at risk for developing vaccine hesitancy or avoidance.^35,36,38 Given the hypothesis that epidermal dendritic cells mediate aluminum sensitization, it has been proposed that vaccine administration via deep intramuscular rather than subcutaneous injection may mitigate the risk, but more evidence is needed to support this approach.^39,40 The good news is that the nodules tend to fade with age, with a median time to resolution of 18 to 49 months.¹⁴ In addition, patients may experience loss of sensitization to aluminum over time⁴¹; in one study, 77% of 241 children lost patch test reactivity when retested 5 to 9 years later.⁴² The exact reason for this diminishment of reactivity is not well understood. Adjunctive treatments to relieve symptoms of vaccine granulomas include topical and intralesional corticosteroids and antihistamines.

For patients reacting to aluminum in antiperspirants, there are many aluminum-free formulations on the market as well as recipes for homemade antiperspirants.⁶ On a case-by-case basis, patients may need to avoid aluminum-containing medications, permanent tattoos, and orthopedic or dental implants. To the best of our knowledge, there is no evidence suggesting a need to avoid aluminum in foods and their containers in routine daily life; although some patients report exacerbations of their symptoms associated with food-related aluminum exposures (eg, canned food, dried fruit) and improvement with dietary modification, further investigation is needed to confirm the relevance of these sources of contact.^36,38 For patients who require allergen-specific immunotherapy, aluminum-free allergen extracts are available.⁶

Final Interpretation

Exposure to aluminum is ubiquitous; although relatively uncommon, awareness of the potential for ACD to aluminum is increasingly important, particularly in children. Given the prevalence of aluminum contact allergy, it has been recommended by contact dermatitis experts for inclusion in baseline pediatric patch test series.¹ Although it is a complex issue, the development of ACD in a small proportion of children exposed to aluminum in vaccines does not outweigh the benefit of vaccination for almost all children. When conducting patch testing to aluminum, studies support testing to ACH 10% in petrolatum for adults, and consider reducing the concentration to ACH 2% for children.

Acknowledgment—The authors thank Ian Fritz, MD (South Portland, Maine), for his critical input during preparation of this article.

No time of the year is more exciting than the unveiling of the American Contact Dermatitis Society Allergen of the Year. Sometimes the selected allergen represents a completely novel cause of allergic contact dermatitis (ACD) with an unpronounceable chemical name. Not this time! The 2022 Allergen of the Year is likely to be lurking in your kitchen drawer at this very moment, as this year aluminum was chosen for this most prestigious honor.¹ But do not throw out your aluminum foil just yet—aluminum allergy tends to be confined to specific scenarios. In this article, we highlight the growing recognition of aluminum contact allergy, particularly in the pediatric population, focusing on distinct presentations of aluminum ACD, unique sources of exposure, and nuances of patch testing to this metal.

Aluminum Is All Around Us

As the third most common element in the Earth’s crust, aluminum can be found quite literally everywhere.¹ However, aluminum rarely is found in its pure elemental form; instead, it reacts with other elements around it, most commonly oxygen, to form aluminum-containing compounds. Known for their stability and safety, aluminum and its salts are incorporated in myriad products ranging from electronic equipment to foods and their packaging, medications, cosmetics, orthopedic and dental implants, and even tattoos. Aluminum also is found in the air and water supply and may even be encountered in certain workplaces, such as aircraft and machine industries. As such, contact with aluminum is all but certain in modern life.

The use of aluminum in consumer products is widely accepted as safe by public health agencies in the United States.² Although there has been public concern that aluminum could be linked to development of breast cancer or Alzheimer disease, there is no clear evidence that these conditions are associated with routine aluminum exposure through ingestion or consumer products.^3-5

Aluminum Contact Allergy

In part because of its ubiquity and in part because of the stability of aluminum-containing compounds, it was long thought that aluminum was nonallergenic. Contact allergy to elemental aluminum is rare; on the other hand, aluminum salts (the forms we are likely to encounter in daily life) are now recognized in the field of contact dermatitis as allergens of significance, particularly in the pediatric population.^1,6

First reported as a possible occupational allergen in 1944,⁷ aluminum allergy came to prominence in the 1990s in association with vaccines. Aluminum is included in some vaccines as an adjuvant that bolsters the immune response⁸; the eTable lists currently available aluminum-containing vaccines in the United States; of note, none of the COVID-19 vaccines approved in the United States or Europe contain aluminum.¹¹ Although the use of aluminum in vaccines is considered to be safe by the US Food and Drug Administration and Centers for Disease Control and Prevention,^12,13 a small number of children become sensitized to aluminum through vaccines and may develop persistent pruritic subcutaneous nodules (also known as vaccination granulomas) at the injection site; however, the incidence of this adverse effect was less than 1% in large studies including as many as 76,000 children, suggesting that it is relatively rare.^14,15 Upon patch testing, aluminum allergy has been detected in 77% to 95% of such cases.¹⁴ There is wide variation in the onset of the nodules ranging from weeks to years following vaccination.¹⁵ Due to pruritus, the examination may reveal accompanying excoriations, hyperpigmentation, and sometimes hypertrichosis at the injection site. Aluminum allergy related to vaccination also can manifest with widespread eruptions representing systemic contact dermatitis.¹⁶

Along with vaccines, the second major source of aluminum sensitization is allergen-specific immunotherapies administered by allergists/immunologists, many of which contain aluminum hydroxide.^17,18

On the consumer product front, antiperspirants are the most common source of cutaneous exposure to aluminum. Aluminum complexes react with electrolytes in sweat to form plugs in eccrine ducts, thereby preventing sweat excretion.⁶ Allergic contact dermatitis to these products presents with axillary-vault dermatitis. There also have been reports of ACD to aluminum in sunscreen and toothpaste, with the latter implicated in causing systemic ACD.^19,20

Prevalence of Sensitization to Aluminum

There have been a few large-scale studies evaluating rates of sensitization to aluminum in general patch-test patient populations; additionally, because of the complexities of testing this metal, investigators have utilized differing formulations for patch testing. A recent Swedish study found that 0.9% of 5448 adults and 5.1% of 196 children showed positive reactions to aluminum chloride hexahydrate (ACH) 10% in petrolatum and/or aluminum lactate 12% in petrolatum.²¹ Notably, there was a significant association between aluminum allergy and history of atopy for both adults (P=.0056) and children (P=.046), which remains to be further explored. A systematic review and meta-analysis found comparable rates of aluminum allergy in 0.4% of adults and 5.6% of children without vaccine granulomas who were tested.²² With this evidence in mind, it has been recommended by contact dermatitis experts that aluminum be included in pediatric baseline patch test series and also investigated for potential inclusion in baseline series for adults.¹

Differential Diagnosis of Aluminum ACD

The differential diagnosis for subcutaneous nodules following vaccination is broad and includes various forms of panniculitis, sarcoidosis, foreign body reactions, vascular malformations, infections, and malignancies.^23-25 The diagnosis may be obscured in cases with delayed onset. Biopsy is not mandatory to establish the diagnosis; although variable histopathologic findings have been reported, a common feature is histiocytes with abundant granular cytoplasm.²⁶ It may be possible to demonstrate the presence of aluminum particles in tissue using electron microscopy and X-ray microanalysis.

For those patients who present with axillary-vault dermatitis, the differential includes ACD to more common allergens in antiperspirants (eg, fragrance), as well as other axillary dermatoses including inverse psoriasis, erythrasma, Hailey-Hailey disease, and various forms of intertrigo. Dermatitis localized to the axillary rim suggests textile allergy.

Patch Testing to Aluminum

Due to its physicochemical properties, patch testing for aluminum allergy is complicated, and historically there has been a lack of consensus on the ideal test formulation.^1,27,28 At this time, it appears that the most sensitive formulation for patch testing to aluminum is ACH 10% in petrolatum.¹ Some contact dermatitis experts recommend that children younger than 8 years should be tested with ACH 2% in petrolatum to minimize the risk of extreme patch test reactions.^29,30 In some patients sensitized to aluminum, the use of aluminum patch test chambers has been noted to produce false-positive reactions, taking the form of multiple ring-shaped reactions to the chambers themselves or reactions to certain allergens whose chemical properties cause corrosion of the aluminum within the chambers.^31-33 Therefore, when testing for suspected aluminum allergy, plastic chambers should be used; given the higher prevalence of aluminum allergy in children, some clinics routinely use plastic chambers for all pediatric patch testing.³⁴ Importantly, elemental aluminum, including empty aluminum test chambers or aluminum foil, alone is not sufficient for patch testing as it lacks sensitivity.¹ Additionally, nearly 20% of positive tests will be missed if a day 7 reading is not performed, making delayed reading a must in cases with high suspicion for aluminum allergy.²¹

Management of Aluminum Allergy

The development of pruritic subcutaneous nodules is uncomfortable for children and their guardians alike and may be associated with prolonged symptoms that negatively impact quality of life^35,36; nonetheless, expert authorities have determined that the preventive benefits of childhood vaccination far outweigh any risk posed by the presence of aluminum in vaccines.^12,13,37 Because aluminum-free formulations may not be available for all vaccines, it is essential to educate patients and families who may be at risk for developing vaccine hesitancy or avoidance.^35,36,38 Given the hypothesis that epidermal dendritic cells mediate aluminum sensitization, it has been proposed that vaccine administration via deep intramuscular rather than subcutaneous injection may mitigate the risk, but more evidence is needed to support this approach.^39,40 The good news is that the nodules tend to fade with age, with a median time to resolution of 18 to 49 months.¹⁴ In addition, patients may experience loss of sensitization to aluminum over time⁴¹; in one study, 77% of 241 children lost patch test reactivity when retested 5 to 9 years later.⁴² The exact reason for this diminishment of reactivity is not well understood. Adjunctive treatments to relieve symptoms of vaccine granulomas include topical and intralesional corticosteroids and antihistamines.

For patients reacting to aluminum in antiperspirants, there are many aluminum-free formulations on the market as well as recipes for homemade antiperspirants.⁶ On a case-by-case basis, patients may need to avoid aluminum-containing medications, permanent tattoos, and orthopedic or dental implants. To the best of our knowledge, there is no evidence suggesting a need to avoid aluminum in foods and their containers in routine daily life; although some patients report exacerbations of their symptoms associated with food-related aluminum exposures (eg, canned food, dried fruit) and improvement with dietary modification, further investigation is needed to confirm the relevance of these sources of contact.^36,38 For patients who require allergen-specific immunotherapy, aluminum-free allergen extracts are available.⁶

Final Interpretation

Exposure to aluminum is ubiquitous; although relatively uncommon, awareness of the potential for ACD to aluminum is increasingly important, particularly in children. Given the prevalence of aluminum contact allergy, it has been recommended by contact dermatitis experts for inclusion in baseline pediatric patch test series.¹ Although it is a complex issue, the development of ACD in a small proportion of children exposed to aluminum in vaccines does not outweigh the benefit of vaccination for almost all children. When conducting patch testing to aluminum, studies support testing to ACH 10% in petrolatum for adults, and consider reducing the concentration to ACH 2% for children.

Acknowledgment—The authors thank Ian Fritz, MD (South Portland, Maine), for his critical input during preparation of this article.

No time of the year is more exciting than the unveiling of the American Contact Dermatitis Society Allergen of the Year. Sometimes the selected allergen represents a completely novel cause of allergic contact dermatitis (ACD) with an unpronounceable chemical name. Not this time! The 2022 Allergen of the Year is likely to be lurking in your kitchen drawer at this very moment, as this year aluminum was chosen for this most prestigious honor.¹ But do not throw out your aluminum foil just yet—aluminum allergy tends to be confined to specific scenarios. In this article, we highlight the growing recognition of aluminum contact allergy, particularly in the pediatric population, focusing on distinct presentations of aluminum ACD, unique sources of exposure, and nuances of patch testing to this metal.

Aluminum Is All Around Us

As the third most common element in the Earth’s crust, aluminum can be found quite literally everywhere.¹ However, aluminum rarely is found in its pure elemental form; instead, it reacts with other elements around it, most commonly oxygen, to form aluminum-containing compounds. Known for their stability and safety, aluminum and its salts are incorporated in myriad products ranging from electronic equipment to foods and their packaging, medications, cosmetics, orthopedic and dental implants, and even tattoos. Aluminum also is found in the air and water supply and may even be encountered in certain workplaces, such as aircraft and machine industries. As such, contact with aluminum is all but certain in modern life.

The use of aluminum in consumer products is widely accepted as safe by public health agencies in the United States.² Although there has been public concern that aluminum could be linked to development of breast cancer or Alzheimer disease, there is no clear evidence that these conditions are associated with routine aluminum exposure through ingestion or consumer products.^3-5

Aluminum Contact Allergy

In part because of its ubiquity and in part because of the stability of aluminum-containing compounds, it was long thought that aluminum was nonallergenic. Contact allergy to elemental aluminum is rare; on the other hand, aluminum salts (the forms we are likely to encounter in daily life) are now recognized in the field of contact dermatitis as allergens of significance, particularly in the pediatric population.^1,6

First reported as a possible occupational allergen in 1944,⁷ aluminum allergy came to prominence in the 1990s in association with vaccines. Aluminum is included in some vaccines as an adjuvant that bolsters the immune response⁸; the eTable lists currently available aluminum-containing vaccines in the United States; of note, none of the COVID-19 vaccines approved in the United States or Europe contain aluminum.¹¹ Although the use of aluminum in vaccines is considered to be safe by the US Food and Drug Administration and Centers for Disease Control and Prevention,^12,13 a small number of children become sensitized to aluminum through vaccines and may develop persistent pruritic subcutaneous nodules (also known as vaccination granulomas) at the injection site; however, the incidence of this adverse effect was less than 1% in large studies including as many as 76,000 children, suggesting that it is relatively rare.^14,15 Upon patch testing, aluminum allergy has been detected in 77% to 95% of such cases.¹⁴ There is wide variation in the onset of the nodules ranging from weeks to years following vaccination.¹⁵ Due to pruritus, the examination may reveal accompanying excoriations, hyperpigmentation, and sometimes hypertrichosis at the injection site. Aluminum allergy related to vaccination also can manifest with widespread eruptions representing systemic contact dermatitis.¹⁶

Along with vaccines, the second major source of aluminum sensitization is allergen-specific immunotherapies administered by allergists/immunologists, many of which contain aluminum hydroxide.^17,18

On the consumer product front, antiperspirants are the most common source of cutaneous exposure to aluminum. Aluminum complexes react with electrolytes in sweat to form plugs in eccrine ducts, thereby preventing sweat excretion.⁶ Allergic contact dermatitis to these products presents with axillary-vault dermatitis. There also have been reports of ACD to aluminum in sunscreen and toothpaste, with the latter implicated in causing systemic ACD.^19,20

Prevalence of Sensitization to Aluminum

There have been a few large-scale studies evaluating rates of sensitization to aluminum in general patch-test patient populations; additionally, because of the complexities of testing this metal, investigators have utilized differing formulations for patch testing. A recent Swedish study found that 0.9% of 5448 adults and 5.1% of 196 children showed positive reactions to aluminum chloride hexahydrate (ACH) 10% in petrolatum and/or aluminum lactate 12% in petrolatum.²¹ Notably, there was a significant association between aluminum allergy and history of atopy for both adults (P=.0056) and children (P=.046), which remains to be further explored. A systematic review and meta-analysis found comparable rates of aluminum allergy in 0.4% of adults and 5.6% of children without vaccine granulomas who were tested.²² With this evidence in mind, it has been recommended by contact dermatitis experts that aluminum be included in pediatric baseline patch test series and also investigated for potential inclusion in baseline series for adults.¹

Differential Diagnosis of Aluminum ACD

The differential diagnosis for subcutaneous nodules following vaccination is broad and includes various forms of panniculitis, sarcoidosis, foreign body reactions, vascular malformations, infections, and malignancies.^23-25 The diagnosis may be obscured in cases with delayed onset. Biopsy is not mandatory to establish the diagnosis; although variable histopathologic findings have been reported, a common feature is histiocytes with abundant granular cytoplasm.²⁶ It may be possible to demonstrate the presence of aluminum particles in tissue using electron microscopy and X-ray microanalysis.

For those patients who present with axillary-vault dermatitis, the differential includes ACD to more common allergens in antiperspirants (eg, fragrance), as well as other axillary dermatoses including inverse psoriasis, erythrasma, Hailey-Hailey disease, and various forms of intertrigo. Dermatitis localized to the axillary rim suggests textile allergy.

Patch Testing to Aluminum

Due to its physicochemical properties, patch testing for aluminum allergy is complicated, and historically there has been a lack of consensus on the ideal test formulation.^1,27,28 At this time, it appears that the most sensitive formulation for patch testing to aluminum is ACH 10% in petrolatum.¹ Some contact dermatitis experts recommend that children younger than 8 years should be tested with ACH 2% in petrolatum to minimize the risk of extreme patch test reactions.^29,30 In some patients sensitized to aluminum, the use of aluminum patch test chambers has been noted to produce false-positive reactions, taking the form of multiple ring-shaped reactions to the chambers themselves or reactions to certain allergens whose chemical properties cause corrosion of the aluminum within the chambers.^31-33 Therefore, when testing for suspected aluminum allergy, plastic chambers should be used; given the higher prevalence of aluminum allergy in children, some clinics routinely use plastic chambers for all pediatric patch testing.³⁴ Importantly, elemental aluminum, including empty aluminum test chambers or aluminum foil, alone is not sufficient for patch testing as it lacks sensitivity.¹ Additionally, nearly 20% of positive tests will be missed if a day 7 reading is not performed, making delayed reading a must in cases with high suspicion for aluminum allergy.²¹

Management of Aluminum Allergy

The development of pruritic subcutaneous nodules is uncomfortable for children and their guardians alike and may be associated with prolonged symptoms that negatively impact quality of life^35,36; nonetheless, expert authorities have determined that the preventive benefits of childhood vaccination far outweigh any risk posed by the presence of aluminum in vaccines.^12,13,37 Because aluminum-free formulations may not be available for all vaccines, it is essential to educate patients and families who may be at risk for developing vaccine hesitancy or avoidance.^35,36,38 Given the hypothesis that epidermal dendritic cells mediate aluminum sensitization, it has been proposed that vaccine administration via deep intramuscular rather than subcutaneous injection may mitigate the risk, but more evidence is needed to support this approach.^39,40 The good news is that the nodules tend to fade with age, with a median time to resolution of 18 to 49 months.¹⁴ In addition, patients may experience loss of sensitization to aluminum over time⁴¹; in one study, 77% of 241 children lost patch test reactivity when retested 5 to 9 years later.⁴² The exact reason for this diminishment of reactivity is not well understood. Adjunctive treatments to relieve symptoms of vaccine granulomas include topical and intralesional corticosteroids and antihistamines.

For patients reacting to aluminum in antiperspirants, there are many aluminum-free formulations on the market as well as recipes for homemade antiperspirants.⁶ On a case-by-case basis, patients may need to avoid aluminum-containing medications, permanent tattoos, and orthopedic or dental implants. To the best of our knowledge, there is no evidence suggesting a need to avoid aluminum in foods and their containers in routine daily life; although some patients report exacerbations of their symptoms associated with food-related aluminum exposures (eg, canned food, dried fruit) and improvement with dietary modification, further investigation is needed to confirm the relevance of these sources of contact.^36,38 For patients who require allergen-specific immunotherapy, aluminum-free allergen extracts are available.⁶

Final Interpretation

Exposure to aluminum is ubiquitous; although relatively uncommon, awareness of the potential for ACD to aluminum is increasingly important, particularly in children. Given the prevalence of aluminum contact allergy, it has been recommended by contact dermatitis experts for inclusion in baseline pediatric patch test series.¹ Although it is a complex issue, the development of ACD in a small proportion of children exposed to aluminum in vaccines does not outweigh the benefit of vaccination for almost all children. When conducting patch testing to aluminum, studies support testing to ACH 10% in petrolatum for adults, and consider reducing the concentration to ACH 2% for children.

Acknowledgment—The authors thank Ian Fritz, MD (South Portland, Maine), for his critical input during preparation of this article.

A patient presenting with a hand pustule is a phenomenon encountered worldwide requiring careful history-taking. Some occupations, activities, and various religious practices (eg, Eid al-Adha, Passover, Easter) have been implicated worldwide in orf infection. In the United States, orf virus usually is spread from infected animal hosts to humans. Herein, we review the differential for a single hand pustule, which includes both infectious and noninfectious causes. Recognizing orf virus as the etiology of a cutaneous hand pustule in patients is important, as misdiagnosis can lead to unnecessary invasive testing and/or treatments with suboptimal clinical outcomes.

Case Series

When conducting a search for orf virus cases at our institution (University of Iowa Hospitals and Clinics, Iowa City, Iowa), 5 patient cases were identified.

Patient 1—A 27-year-old otherwise healthy woman presented to clinic with a tender red bump on the right ring finger that had been slowly growing over the course of 2 weeks and had recently started to bleed. A social history revealed that she owned several goats, which she frequently milked; 1 of the goats had a cyst on the mouth, which she popped approximately 1 to 2 weeks prior to the appearance of the lesion on the finger. She also endorsed that she owned several cattle and various other animals with which she had frequent contact. A biopsy was obtained with features consistent with orf virus.

Patient 2—A 33-year-old man presented to clinic with a lesion of concern on the left index finger. Several days prior to presentation, the patient had visited the emergency department for swelling and erythema of the same finger after cutting himself with a knife while preparing sheep meat. Radiographs were normal, and the patient was referred to dermatology. In clinic, there was a 0.5-cm fluctuant mass on the distal interphalangeal joint of the third finger. The patient declined a biopsy, and the lesion healed over 4 to 6 weeks without complication.

Patient 3—A 38-year-old man presented to clinic with 2 painless, large, round nodules on the right proximal index finger, with open friable centers noted on physical examination (Figure 1). The patient reported cutting the finger while preparing sheep meat several days prior. The nodules had been present for a few weeks and continued to grow. A punch biopsy revealed evidence of parapoxvirus infection consistent with a diagnosis of orf.

Patient 4—A 48-year-old man was referred to our dermatology clinic for evaluation of a bleeding lesion on the left middle finger. Physical examination revealed an exophytic, friable, ulcerated nodule on the dorsal aspect of the left middle finger (Figure 2). Upon further questioning, the patient mentioned that he handled raw lamb meat after cutting the finger. A punch biopsy was obtained and was consistent with orf virus infection.

Patient 5—A 43-year-old woman presented to clinic with a chronic wound on the mid lower back that was noted to drain and crust over. She thought the lesion was improving, but it had become painful over the last few weeks. A shave biopsy of the lesion was consistent with orf virus. At follow-up, the patient was unable to identify any recent contact with animals.

Transmission From Animals to Humans—Orf virus is a member of the Parapoxvirus genus of the Poxviridae family.¹ This virus is highly contagious among animals and has been described around the globe. The resulting disease also is known as contagious pustular dermatitis,² soremuzzle,³ ecthyma contagiosum of sheep,⁴ and scabby mouth.⁵ This virus most commonly infects young lambs and manifests as raw to crusty papules, pustules, or vesicles around the mouth and nose of the animal.⁴ Additional signs include excessive salivation and weight loss or starvation from the inability to suckle because of the lesions.⁵ Although ecthyma contagiosum infection of sheep and goats has been well known for centuries, human infection was first reported in the literature in 1934.⁶

Transmission of orf to humans can occur when direct contact with an infected animal exhibiting active lesions occurs.⁷ Orf virus also can be transmitted through fomites (eg, from knives, wool, buildings, equipment) that previously were in contact with infected animals, making it relevant to ask all farmers about any animals with pustules around the mouth, nose, udders, or other commonly affected areas. Although sanitation efforts are important for prevention, orf virus is hardy, and fomites can remain on surfaces for many months.⁸ Transmission among animals and from animals to humans frequently occurs; however, human-to-human transmission is less common.⁹ Ecthyma contagiosum is considered an occupational hazard, with the disease being most prevalent in shepherds, veterinarians, and butchers.^1,8 Disease prevalence in these occupations has been reported to be as high as 50%.¹⁰ Infections also are seen in patients who attend petting zoos or who slaughter goats and sheep for cultural practices.⁸

Clinical Characteristics in Humans—The clinical diagnosis of orf is dependent on taking a thorough patient history that includes social, occupational, and religious activities. Development of a nodule or papule on a patient’s hand with recent exposure to fomites or direct contact with a goat or sheep up to 1 week prior is extremely suggestive of an orf virus infection.

Clinically, orf most often begins as an individual papule or nodule on the dorsal surface of the patient’s finger or hand and ranges from completely asymptomatic to pruritic or even painful.^1,8 Depending on how the infection was inoculated, lesions can vary in size and number. Other sites that have been reported less frequently include the genitals, legs, axillae, and head.^11,12 Lesions are roughly 1 cm in diameter but can vary in size. Ecthyma contagiosum is not a static disease but changes in appearance over the course of infection. Typically, lesions will appear 3 to 7 days after inoculation with the orf virus and will self-resolve 6 to 8 weeks later.

Orf lesions have been described to progress through 6 distinct phases before resolving: maculopapular (erythematous macule or papule forms), targetoid (formation of a necrotic center with red outer halo), acute (lesion begins to weep), regenerative (lesion becomes dry), papilloma (dry crust becomes papillomatous), and regression (skin returns to normal appearance).^1,8,9 Each phase of ecthyma contagiosum is unique and will last up to 1 week before progressing. Because of this prolonged clinical course, patients can present at any stage.

Reports of systemic symptoms are uncommon but can include lymphadenopathy, fever, and malaise.¹³ Although the disease course in immunocompetent individuals is quite mild, immunocompromised patients may experience persistent orf lesions that are painful and can be much larger, with reports of several centimeters in diameter.¹⁴

Dermatopathology and Molecular Studies—When a clinical diagnosis is not possible, biopsy or molecular studies can be helpful.⁸ Histopathology can vary depending on the phase of the lesion. Early stages are characterized by spongiform degeneration of the epidermis with variable vesiculation of the superficial epidermis and eosinophilic cytoplasmic inclusion bodies of keratinocytes (Figure 3). Later stages demonstrate full-thickness necrosis with epidermal balloon degeneration and dense inflammation of the dermis with edema and extravasated erythrocytes from dilated blood vessels. Both early- and late-stage disease commonly show characteristic elongated thin rete ridges.⁸

Molecular studies are another reliable method for diagnosis, though these are not always readily available. Polymerase chain reaction can be used for sensitive and rapid diagnosis.¹⁵ Less commonly, electron microscopy, Western blot, or enzyme-linked immunosorbent assays are used.¹⁶ Laboratory studies, such as complete blood cell count with differential, erythrocyte sedimentation rate, and C-reactive protein, often are unnecessary but may be helpful in ruling out other infectious causes. Tissue culture can be considered if bacterial, fungal, or acid-fast bacilli are in the differential; however, no growth will be seen in the case of orf viral infection.

Differential Diagnosis—The differential diagnosis for patients presenting with a large pustule on the hand or fingers can depend on geographic location, as the potential etiology may vary widely around the world. Several zoonotic viral infections other than orf can present with pustular lesions on the hands (Table).^17-24

Clinically, infection with these named viruses can be hard to distinguish; however, appropriate social history or polymerase chain reaction can be obtained to differentiate them. Other infectious entities include herpetic whitlow, giant molluscum, and anthrax (eTable).^24-26 Biopsy of the lesion with bacterial tissue culture may lead to definitive diagnosis.²⁶

Treatment—Because of the self-resolving nature of orf, treatment usually is not needed in immunocompetent patients with a solitary lesion. However, wound care is essential to prevent secondary infections of the lesion. If secondarily infected, topical or oral antibiotics may be prescribed. Immunocompromised individuals are at increased risk for developing large persistent lesions and sometimes require intervention for successful treatment. Several successful treatment methods have been described and include intralesional interferon injections, electrocautery, topical imiquimod, topical cidofovir, and cryotherapy.^8,14,27-30 Infections that continue to be refractory to less-invasive treatment can be considered for wide local excision; however, recurrence is possible.⁸ Vaccinations are available for animals to prevent the spread of infection in the flock, but there are no formulations of vaccines for human use. Prevention of spread to humans can be done through animal vaccination, careful handling of animal products while wearing nonporous gloves, and proper sanitation techniques.

Complications—Orf has an excellent long-term prognosis in immunocompetent patients, as the virus is epitheliotropic, and inoculation does not lead to viremia.² Although lesions typically are asymptomatic in most patients, complications can occur, especially in immunosuppressed individuals. These complications include systemic symptoms, giant persistent lesions prone to infection or scarring, erysipelas, lymphadenitis, and erythema multiforme.^8,31 Common systemic symptoms of ecthyma contagiosum include fever, fatigue, and myalgia. Lymphadenitis can occur along with local swelling and lymphatic streaking. Although erythema multiforme is a rare complication occurring after initial ecthyma contagiosum infection, this hypersensitivity reaction is postulated to be in response to the immunologic clearing of the orf virus.^32,33 Patients receiving systemic immunosuppressive medications are at an increased risk of developing complications from infection and may even be required to pause systemic treatment for complete resolution of orf lesions.³⁴ Other cutaneous diseases that decrease the skin’s barrier protection, such as bullous pemphigoid or eczema, also can place patients at an increased risk for complications.³⁵ Although human-to-human orf virus transmission is exceptionally rare, there is a case report of this phenomenon in immunosuppressed patients residing in a burn unit.³⁶ Transplant recipients on immunosuppressive medications also can experience orf lesions with exaggerated presentations that continue to grow up to several centimeters in diameter.³¹ Long-term prognosis is still good in these patients with appropriate disease recognition and treatment. Reinfection is not uncommon with repeated exposure to the source, but lesions are less severe and resolve faster than with initial infection.^1,8

Conclusion

The contagious hand pustule caused by orf virus is a distinct clinical entity that is prevalent worldwide and requires thorough evaluation of the clinical course of the lesion and the patient’s social history. Several zoonotic viral infections have been implicated in this presentation. Although biopsy and molecular studies can be helpful, the expert diagnostician can make a clinical diagnosis with careful attention to social history, geographic location, and cultural practices.

A patient presenting with a hand pustule is a phenomenon encountered worldwide requiring careful history-taking. Some occupations, activities, and various religious practices (eg, Eid al-Adha, Passover, Easter) have been implicated worldwide in orf infection. In the United States, orf virus usually is spread from infected animal hosts to humans. Herein, we review the differential for a single hand pustule, which includes both infectious and noninfectious causes. Recognizing orf virus as the etiology of a cutaneous hand pustule in patients is important, as misdiagnosis can lead to unnecessary invasive testing and/or treatments with suboptimal clinical outcomes.

Case Series

When conducting a search for orf virus cases at our institution (University of Iowa Hospitals and Clinics, Iowa City, Iowa), 5 patient cases were identified.

Patient 1—A 27-year-old otherwise healthy woman presented to clinic with a tender red bump on the right ring finger that had been slowly growing over the course of 2 weeks and had recently started to bleed. A social history revealed that she owned several goats, which she frequently milked; 1 of the goats had a cyst on the mouth, which she popped approximately 1 to 2 weeks prior to the appearance of the lesion on the finger. She also endorsed that she owned several cattle and various other animals with which she had frequent contact. A biopsy was obtained with features consistent with orf virus.

Patient 2—A 33-year-old man presented to clinic with a lesion of concern on the left index finger. Several days prior to presentation, the patient had visited the emergency department for swelling and erythema of the same finger after cutting himself with a knife while preparing sheep meat. Radiographs were normal, and the patient was referred to dermatology. In clinic, there was a 0.5-cm fluctuant mass on the distal interphalangeal joint of the third finger. The patient declined a biopsy, and the lesion healed over 4 to 6 weeks without complication.

Patient 3—A 38-year-old man presented to clinic with 2 painless, large, round nodules on the right proximal index finger, with open friable centers noted on physical examination (Figure 1). The patient reported cutting the finger while preparing sheep meat several days prior. The nodules had been present for a few weeks and continued to grow. A punch biopsy revealed evidence of parapoxvirus infection consistent with a diagnosis of orf.

Patient 4—A 48-year-old man was referred to our dermatology clinic for evaluation of a bleeding lesion on the left middle finger. Physical examination revealed an exophytic, friable, ulcerated nodule on the dorsal aspect of the left middle finger (Figure 2). Upon further questioning, the patient mentioned that he handled raw lamb meat after cutting the finger. A punch biopsy was obtained and was consistent with orf virus infection.

Patient 5—A 43-year-old woman presented to clinic with a chronic wound on the mid lower back that was noted to drain and crust over. She thought the lesion was improving, but it had become painful over the last few weeks. A shave biopsy of the lesion was consistent with orf virus. At follow-up, the patient was unable to identify any recent contact with animals.

Transmission From Animals to Humans—Orf virus is a member of the Parapoxvirus genus of the Poxviridae family.¹ This virus is highly contagious among animals and has been described around the globe. The resulting disease also is known as contagious pustular dermatitis,² soremuzzle,³ ecthyma contagiosum of sheep,⁴ and scabby mouth.⁵ This virus most commonly infects young lambs and manifests as raw to crusty papules, pustules, or vesicles around the mouth and nose of the animal.⁴ Additional signs include excessive salivation and weight loss or starvation from the inability to suckle because of the lesions.⁵ Although ecthyma contagiosum infection of sheep and goats has been well known for centuries, human infection was first reported in the literature in 1934.⁶

Transmission of orf to humans can occur when direct contact with an infected animal exhibiting active lesions occurs.⁷ Orf virus also can be transmitted through fomites (eg, from knives, wool, buildings, equipment) that previously were in contact with infected animals, making it relevant to ask all farmers about any animals with pustules around the mouth, nose, udders, or other commonly affected areas. Although sanitation efforts are important for prevention, orf virus is hardy, and fomites can remain on surfaces for many months.⁸ Transmission among animals and from animals to humans frequently occurs; however, human-to-human transmission is less common.⁹ Ecthyma contagiosum is considered an occupational hazard, with the disease being most prevalent in shepherds, veterinarians, and butchers.^1,8 Disease prevalence in these occupations has been reported to be as high as 50%.¹⁰ Infections also are seen in patients who attend petting zoos or who slaughter goats and sheep for cultural practices.⁸

Clinical Characteristics in Humans—The clinical diagnosis of orf is dependent on taking a thorough patient history that includes social, occupational, and religious activities. Development of a nodule or papule on a patient’s hand with recent exposure to fomites or direct contact with a goat or sheep up to 1 week prior is extremely suggestive of an orf virus infection.

Clinically, orf most often begins as an individual papule or nodule on the dorsal surface of the patient’s finger or hand and ranges from completely asymptomatic to pruritic or even painful.^1,8 Depending on how the infection was inoculated, lesions can vary in size and number. Other sites that have been reported less frequently include the genitals, legs, axillae, and head.^11,12 Lesions are roughly 1 cm in diameter but can vary in size. Ecthyma contagiosum is not a static disease but changes in appearance over the course of infection. Typically, lesions will appear 3 to 7 days after inoculation with the orf virus and will self-resolve 6 to 8 weeks later.

Orf lesions have been described to progress through 6 distinct phases before resolving: maculopapular (erythematous macule or papule forms), targetoid (formation of a necrotic center with red outer halo), acute (lesion begins to weep), regenerative (lesion becomes dry), papilloma (dry crust becomes papillomatous), and regression (skin returns to normal appearance).^1,8,9 Each phase of ecthyma contagiosum is unique and will last up to 1 week before progressing. Because of this prolonged clinical course, patients can present at any stage.

Reports of systemic symptoms are uncommon but can include lymphadenopathy, fever, and malaise.¹³ Although the disease course in immunocompetent individuals is quite mild, immunocompromised patients may experience persistent orf lesions that are painful and can be much larger, with reports of several centimeters in diameter.¹⁴

Dermatopathology and Molecular Studies—When a clinical diagnosis is not possible, biopsy or molecular studies can be helpful.⁸ Histopathology can vary depending on the phase of the lesion. Early stages are characterized by spongiform degeneration of the epidermis with variable vesiculation of the superficial epidermis and eosinophilic cytoplasmic inclusion bodies of keratinocytes (Figure 3). Later stages demonstrate full-thickness necrosis with epidermal balloon degeneration and dense inflammation of the dermis with edema and extravasated erythrocytes from dilated blood vessels. Both early- and late-stage disease commonly show characteristic elongated thin rete ridges.⁸

Molecular studies are another reliable method for diagnosis, though these are not always readily available. Polymerase chain reaction can be used for sensitive and rapid diagnosis.¹⁵ Less commonly, electron microscopy, Western blot, or enzyme-linked immunosorbent assays are used.¹⁶ Laboratory studies, such as complete blood cell count with differential, erythrocyte sedimentation rate, and C-reactive protein, often are unnecessary but may be helpful in ruling out other infectious causes. Tissue culture can be considered if bacterial, fungal, or acid-fast bacilli are in the differential; however, no growth will be seen in the case of orf viral infection.

Differential Diagnosis—The differential diagnosis for patients presenting with a large pustule on the hand or fingers can depend on geographic location, as the potential etiology may vary widely around the world. Several zoonotic viral infections other than orf can present with pustular lesions on the hands (Table).^17-24

Clinically, infection with these named viruses can be hard to distinguish; however, appropriate social history or polymerase chain reaction can be obtained to differentiate them. Other infectious entities include herpetic whitlow, giant molluscum, and anthrax (eTable).^24-26 Biopsy of the lesion with bacterial tissue culture may lead to definitive diagnosis.²⁶

Treatment—Because of the self-resolving nature of orf, treatment usually is not needed in immunocompetent patients with a solitary lesion. However, wound care is essential to prevent secondary infections of the lesion. If secondarily infected, topical or oral antibiotics may be prescribed. Immunocompromised individuals are at increased risk for developing large persistent lesions and sometimes require intervention for successful treatment. Several successful treatment methods have been described and include intralesional interferon injections, electrocautery, topical imiquimod, topical cidofovir, and cryotherapy.^8,14,27-30 Infections that continue to be refractory to less-invasive treatment can be considered for wide local excision; however, recurrence is possible.⁸ Vaccinations are available for animals to prevent the spread of infection in the flock, but there are no formulations of vaccines for human use. Prevention of spread to humans can be done through animal vaccination, careful handling of animal products while wearing nonporous gloves, and proper sanitation techniques.

Complications—Orf has an excellent long-term prognosis in immunocompetent patients, as the virus is epitheliotropic, and inoculation does not lead to viremia.² Although lesions typically are asymptomatic in most patients, complications can occur, especially in immunosuppressed individuals. These complications include systemic symptoms, giant persistent lesions prone to infection or scarring, erysipelas, lymphadenitis, and erythema multiforme.^8,31 Common systemic symptoms of ecthyma contagiosum include fever, fatigue, and myalgia. Lymphadenitis can occur along with local swelling and lymphatic streaking. Although erythema multiforme is a rare complication occurring after initial ecthyma contagiosum infection, this hypersensitivity reaction is postulated to be in response to the immunologic clearing of the orf virus.^32,33 Patients receiving systemic immunosuppressive medications are at an increased risk of developing complications from infection and may even be required to pause systemic treatment for complete resolution of orf lesions.³⁴ Other cutaneous diseases that decrease the skin’s barrier protection, such as bullous pemphigoid or eczema, also can place patients at an increased risk for complications.³⁵ Although human-to-human orf virus transmission is exceptionally rare, there is a case report of this phenomenon in immunosuppressed patients residing in a burn unit.³⁶ Transplant recipients on immunosuppressive medications also can experience orf lesions with exaggerated presentations that continue to grow up to several centimeters in diameter.³¹ Long-term prognosis is still good in these patients with appropriate disease recognition and treatment. Reinfection is not uncommon with repeated exposure to the source, but lesions are less severe and resolve faster than with initial infection.^1,8

Conclusion

The contagious hand pustule caused by orf virus is a distinct clinical entity that is prevalent worldwide and requires thorough evaluation of the clinical course of the lesion and the patient’s social history. Several zoonotic viral infections have been implicated in this presentation. Although biopsy and molecular studies can be helpful, the expert diagnostician can make a clinical diagnosis with careful attention to social history, geographic location, and cultural practices.

A patient presenting with a hand pustule is a phenomenon encountered worldwide requiring careful history-taking. Some occupations, activities, and various religious practices (eg, Eid al-Adha, Passover, Easter) have been implicated worldwide in orf infection. In the United States, orf virus usually is spread from infected animal hosts to humans. Herein, we review the differential for a single hand pustule, which includes both infectious and noninfectious causes. Recognizing orf virus as the etiology of a cutaneous hand pustule in patients is important, as misdiagnosis can lead to unnecessary invasive testing and/or treatments with suboptimal clinical outcomes.

Case Series

When conducting a search for orf virus cases at our institution (University of Iowa Hospitals and Clinics, Iowa City, Iowa), 5 patient cases were identified.

Patient 1—A 27-year-old otherwise healthy woman presented to clinic with a tender red bump on the right ring finger that had been slowly growing over the course of 2 weeks and had recently started to bleed. A social history revealed that she owned several goats, which she frequently milked; 1 of the goats had a cyst on the mouth, which she popped approximately 1 to 2 weeks prior to the appearance of the lesion on the finger. She also endorsed that she owned several cattle and various other animals with which she had frequent contact. A biopsy was obtained with features consistent with orf virus.

Patient 2—A 33-year-old man presented to clinic with a lesion of concern on the left index finger. Several days prior to presentation, the patient had visited the emergency department for swelling and erythema of the same finger after cutting himself with a knife while preparing sheep meat. Radiographs were normal, and the patient was referred to dermatology. In clinic, there was a 0.5-cm fluctuant mass on the distal interphalangeal joint of the third finger. The patient declined a biopsy, and the lesion healed over 4 to 6 weeks without complication.

Patient 3—A 38-year-old man presented to clinic with 2 painless, large, round nodules on the right proximal index finger, with open friable centers noted on physical examination (Figure 1). The patient reported cutting the finger while preparing sheep meat several days prior. The nodules had been present for a few weeks and continued to grow. A punch biopsy revealed evidence of parapoxvirus infection consistent with a diagnosis of orf.

Patient 4—A 48-year-old man was referred to our dermatology clinic for evaluation of a bleeding lesion on the left middle finger. Physical examination revealed an exophytic, friable, ulcerated nodule on the dorsal aspect of the left middle finger (Figure 2). Upon further questioning, the patient mentioned that he handled raw lamb meat after cutting the finger. A punch biopsy was obtained and was consistent with orf virus infection.

Patient 5—A 43-year-old woman presented to clinic with a chronic wound on the mid lower back that was noted to drain and crust over. She thought the lesion was improving, but it had become painful over the last few weeks. A shave biopsy of the lesion was consistent with orf virus. At follow-up, the patient was unable to identify any recent contact with animals.

Transmission From Animals to Humans—Orf virus is a member of the Parapoxvirus genus of the Poxviridae family.¹ This virus is highly contagious among animals and has been described around the globe. The resulting disease also is known as contagious pustular dermatitis,² soremuzzle,³ ecthyma contagiosum of sheep,⁴ and scabby mouth.⁵ This virus most commonly infects young lambs and manifests as raw to crusty papules, pustules, or vesicles around the mouth and nose of the animal.⁴ Additional signs include excessive salivation and weight loss or starvation from the inability to suckle because of the lesions.⁵ Although ecthyma contagiosum infection of sheep and goats has been well known for centuries, human infection was first reported in the literature in 1934.⁶

Transmission of orf to humans can occur when direct contact with an infected animal exhibiting active lesions occurs.⁷ Orf virus also can be transmitted through fomites (eg, from knives, wool, buildings, equipment) that previously were in contact with infected animals, making it relevant to ask all farmers about any animals with pustules around the mouth, nose, udders, or other commonly affected areas. Although sanitation efforts are important for prevention, orf virus is hardy, and fomites can remain on surfaces for many months.⁸ Transmission among animals and from animals to humans frequently occurs; however, human-to-human transmission is less common.⁹ Ecthyma contagiosum is considered an occupational hazard, with the disease being most prevalent in shepherds, veterinarians, and butchers.^1,8 Disease prevalence in these occupations has been reported to be as high as 50%.¹⁰ Infections also are seen in patients who attend petting zoos or who slaughter goats and sheep for cultural practices.⁸

Clinical Characteristics in Humans—The clinical diagnosis of orf is dependent on taking a thorough patient history that includes social, occupational, and religious activities. Development of a nodule or papule on a patient’s hand with recent exposure to fomites or direct contact with a goat or sheep up to 1 week prior is extremely suggestive of an orf virus infection.

Clinically, orf most often begins as an individual papule or nodule on the dorsal surface of the patient’s finger or hand and ranges from completely asymptomatic to pruritic or even painful.^1,8 Depending on how the infection was inoculated, lesions can vary in size and number. Other sites that have been reported less frequently include the genitals, legs, axillae, and head.^11,12 Lesions are roughly 1 cm in diameter but can vary in size. Ecthyma contagiosum is not a static disease but changes in appearance over the course of infection. Typically, lesions will appear 3 to 7 days after inoculation with the orf virus and will self-resolve 6 to 8 weeks later.

Orf lesions have been described to progress through 6 distinct phases before resolving: maculopapular (erythematous macule or papule forms), targetoid (formation of a necrotic center with red outer halo), acute (lesion begins to weep), regenerative (lesion becomes dry), papilloma (dry crust becomes papillomatous), and regression (skin returns to normal appearance).^1,8,9 Each phase of ecthyma contagiosum is unique and will last up to 1 week before progressing. Because of this prolonged clinical course, patients can present at any stage.

Reports of systemic symptoms are uncommon but can include lymphadenopathy, fever, and malaise.¹³ Although the disease course in immunocompetent individuals is quite mild, immunocompromised patients may experience persistent orf lesions that are painful and can be much larger, with reports of several centimeters in diameter.¹⁴

Dermatopathology and Molecular Studies—When a clinical diagnosis is not possible, biopsy or molecular studies can be helpful.⁸ Histopathology can vary depending on the phase of the lesion. Early stages are characterized by spongiform degeneration of the epidermis with variable vesiculation of the superficial epidermis and eosinophilic cytoplasmic inclusion bodies of keratinocytes (Figure 3). Later stages demonstrate full-thickness necrosis with epidermal balloon degeneration and dense inflammation of the dermis with edema and extravasated erythrocytes from dilated blood vessels. Both early- and late-stage disease commonly show characteristic elongated thin rete ridges.⁸

Molecular studies are another reliable method for diagnosis, though these are not always readily available. Polymerase chain reaction can be used for sensitive and rapid diagnosis.¹⁵ Less commonly, electron microscopy, Western blot, or enzyme-linked immunosorbent assays are used.¹⁶ Laboratory studies, such as complete blood cell count with differential, erythrocyte sedimentation rate, and C-reactive protein, often are unnecessary but may be helpful in ruling out other infectious causes. Tissue culture can be considered if bacterial, fungal, or acid-fast bacilli are in the differential; however, no growth will be seen in the case of orf viral infection.

Differential Diagnosis—The differential diagnosis for patients presenting with a large pustule on the hand or fingers can depend on geographic location, as the potential etiology may vary widely around the world. Several zoonotic viral infections other than orf can present with pustular lesions on the hands (Table).^17-24

Clinically, infection with these named viruses can be hard to distinguish; however, appropriate social history or polymerase chain reaction can be obtained to differentiate them. Other infectious entities include herpetic whitlow, giant molluscum, and anthrax (eTable).^24-26 Biopsy of the lesion with bacterial tissue culture may lead to definitive diagnosis.²⁶

Treatment—Because of the self-resolving nature of orf, treatment usually is not needed in immunocompetent patients with a solitary lesion. However, wound care is essential to prevent secondary infections of the lesion. If secondarily infected, topical or oral antibiotics may be prescribed. Immunocompromised individuals are at increased risk for developing large persistent lesions and sometimes require intervention for successful treatment. Several successful treatment methods have been described and include intralesional interferon injections, electrocautery, topical imiquimod, topical cidofovir, and cryotherapy.^8,14,27-30 Infections that continue to be refractory to less-invasive treatment can be considered for wide local excision; however, recurrence is possible.⁸ Vaccinations are available for animals to prevent the spread of infection in the flock, but there are no formulations of vaccines for human use. Prevention of spread to humans can be done through animal vaccination, careful handling of animal products while wearing nonporous gloves, and proper sanitation techniques.

Complications—Orf has an excellent long-term prognosis in immunocompetent patients, as the virus is epitheliotropic, and inoculation does not lead to viremia.² Although lesions typically are asymptomatic in most patients, complications can occur, especially in immunosuppressed individuals. These complications include systemic symptoms, giant persistent lesions prone to infection or scarring, erysipelas, lymphadenitis, and erythema multiforme.^8,31 Common systemic symptoms of ecthyma contagiosum include fever, fatigue, and myalgia. Lymphadenitis can occur along with local swelling and lymphatic streaking. Although erythema multiforme is a rare complication occurring after initial ecthyma contagiosum infection, this hypersensitivity reaction is postulated to be in response to the immunologic clearing of the orf virus.^32,33 Patients receiving systemic immunosuppressive medications are at an increased risk of developing complications from infection and may even be required to pause systemic treatment for complete resolution of orf lesions.³⁴ Other cutaneous diseases that decrease the skin’s barrier protection, such as bullous pemphigoid or eczema, also can place patients at an increased risk for complications.³⁵ Although human-to-human orf virus transmission is exceptionally rare, there is a case report of this phenomenon in immunosuppressed patients residing in a burn unit.³⁶ Transplant recipients on immunosuppressive medications also can experience orf lesions with exaggerated presentations that continue to grow up to several centimeters in diameter.³¹ Long-term prognosis is still good in these patients with appropriate disease recognition and treatment. Reinfection is not uncommon with repeated exposure to the source, but lesions are less severe and resolve faster than with initial infection.^1,8

Conclusion

The contagious hand pustule caused by orf virus is a distinct clinical entity that is prevalent worldwide and requires thorough evaluation of the clinical course of the lesion and the patient’s social history. Several zoonotic viral infections have been implicated in this presentation. Although biopsy and molecular studies can be helpful, the expert diagnostician can make a clinical diagnosis with careful attention to social history, geographic location, and cultural practices.

We have attended grand rounds presentations at which students announce that Mohs micrographic surgery evaluates 100% of the surgical margin, whereas standard excision samples 1% to 2% of the margin; we have even fielded questions from neighbors who have come across this information on the internet.^1-5 This statement describes a best-case scenario for Mohs surgery and a worst-case scenario for standard excision. We believe that it is important for clinicians to have a more nuanced understanding of how simple excisions are processed so that they can have pertinent discussions with patients, especially now that there is increasing access to personal health information along with increased agency in patient decision-making.

Margins for Mohs Surgery

Theoretically, Mohs surgery should sample all true surgical margins by complete circumferential, peripheral, and deep-margin assessment. Unfortunately, some sections are not cut full face—sections may not always sample a complete surface—when technicians make an error or lack expertise. Some sections may have small tissue folds or small gaps that prevent complete visualization. We estimate that the Mohs sections we review in consultation that are prepared by private practice Mohs surgeons in our communities visualize approximately 98% of surgical margins on average. Incomplete sections contribute to the rare tumor recurrences after Mohs surgery of approximately 2% to 3%.⁶

Standard Excision Margins

When we obtained the references cited in articles asserting that standard excision samples less than 0.5%, 1%, or 2% of the surgical margin, we did not find evidence-based information confirming this generally accepted conclusion. We believe the assertions are derived by comparing the sum of the thickness of all microscopic sections added together against the longitudinal length of the entire specimen.Sampling less than 0.5% of a margin has been described as providing the illusion of microscopic control.⁵ We have encountered medical students, nondermatologist physicians, and patients who have come across this information and have understandably concluded that standard margin assessment must be inadequate if only such a small amount of margin is assessed.

Here is a simple example to show that more margin is accessed in some cases. Consider this hypothetical situation: If a tumor can be readily visualized grossly and housed entirely within an imaginary cuboid (rectangular) prism that is removed in an elliptical specimen with a length of 6 cm, a width of 2 cm, and a height of 1 cm (Figure), then standard sectioning assesses a greater margin.

Bread-loaf sectioning would be expected to examine the complete surface of 2 sides (faces) of the cuboid. Assessing 2 of the 5 clinically relevant sides provides information for approximately 50% of the margins, as sections in the next parallel plane can be expected to be clear after the first clear section is identified. The clinically useful information is not limited to the sum of the widths of sections. Encountering a clear plane typically indicates that there will be no tumor in more distal parallel planes. Warne et al⁶ developed a formula that can accurately predict the percentage of the margin evaluated by proxy that considers the curvature of the ellipse.

Comparing Standard Excision and Mohs Surgery

Mohs surgery consistently results in the best outcomes, but standard excision is effective, too. Standard excision is relatively simple, requires less equipment, is less time consuming, and can provide good value when resources are finite. Data on recurrence of basal cell carcinoma after simple excision are limited, but the recurrence rate is reported to be approximately 3%.^7,8 A meta-analysis found that the recurrence rate of basal cell carcinoma treated with standard excision was 0.4%, 1.6%, 2.6%, and 4% with 5-mm, 4-mm, 3-mm, and 2-mm surgical margins, respectively.⁹

Mohs surgery is the best, most effective, and most tissue-sparing technique for certain nonmelanoma skin cancers. This observation is reflected in guidelines worldwide.¹⁰ The adequacy of standard approaches to margin evaluation depends on the capabilities and focus of the laboratory team. Dermatopathologists often are called to the laboratory to decide which technique will be best for a particular case.¹¹ Technicians are trained to take more sections in areas where abnormalities are seen, and some laboratories take photographs of specimens or provide sketches for correlation. Dermatopathologists also routinely request additional sections in areas where visible tumor extends close to surgical margins on microscopic examination.

It is not simply a matter of knowing how much of the margin is sampled but if the most pertinent areas are adequately sampled. Simple sectioning can work well and be cost effective. Many clinicians are unaware of how tissue processing can vary from laboratory to laboratory. There are no uniformly accepted standards for how tissue should be processed. Assiduous and thoughtful evaluation of specimens can affect results. As with any service, some laboratories provide more detailed and conscientious care while others focus more on immediate costs. Clinicians should understand how their specimens are processed by discussing margin evaluation with their dermatopathologist.

Final Thoughts

Used appropriately, Mohs surgery is an excellent technique that can provide outstanding results. Standard excision also has an important place in the dermatologist’s armamentarium and typically provides information about more than 1% to 2% of the margin. Understanding the techniques used to process specimens is critical to delivering the best possible care.

We have attended grand rounds presentations at which students announce that Mohs micrographic surgery evaluates 100% of the surgical margin, whereas standard excision samples 1% to 2% of the margin; we have even fielded questions from neighbors who have come across this information on the internet.^1-5 This statement describes a best-case scenario for Mohs surgery and a worst-case scenario for standard excision. We believe that it is important for clinicians to have a more nuanced understanding of how simple excisions are processed so that they can have pertinent discussions with patients, especially now that there is increasing access to personal health information along with increased agency in patient decision-making.

Margins for Mohs Surgery

Theoretically, Mohs surgery should sample all true surgical margins by complete circumferential, peripheral, and deep-margin assessment. Unfortunately, some sections are not cut full face—sections may not always sample a complete surface—when technicians make an error or lack expertise. Some sections may have small tissue folds or small gaps that prevent complete visualization. We estimate that the Mohs sections we review in consultation that are prepared by private practice Mohs surgeons in our communities visualize approximately 98% of surgical margins on average. Incomplete sections contribute to the rare tumor recurrences after Mohs surgery of approximately 2% to 3%.⁶

Standard Excision Margins

When we obtained the references cited in articles asserting that standard excision samples less than 0.5%, 1%, or 2% of the surgical margin, we did not find evidence-based information confirming this generally accepted conclusion. We believe the assertions are derived by comparing the sum of the thickness of all microscopic sections added together against the longitudinal length of the entire specimen.Sampling less than 0.5% of a margin has been described as providing the illusion of microscopic control.⁵ We have encountered medical students, nondermatologist physicians, and patients who have come across this information and have understandably concluded that standard margin assessment must be inadequate if only such a small amount of margin is assessed.

Here is a simple example to show that more margin is accessed in some cases. Consider this hypothetical situation: If a tumor can be readily visualized grossly and housed entirely within an imaginary cuboid (rectangular) prism that is removed in an elliptical specimen with a length of 6 cm, a width of 2 cm, and a height of 1 cm (Figure), then standard sectioning assesses a greater margin.

Bread-loaf sectioning would be expected to examine the complete surface of 2 sides (faces) of the cuboid. Assessing 2 of the 5 clinically relevant sides provides information for approximately 50% of the margins, as sections in the next parallel plane can be expected to be clear after the first clear section is identified. The clinically useful information is not limited to the sum of the widths of sections. Encountering a clear plane typically indicates that there will be no tumor in more distal parallel planes. Warne et al⁶ developed a formula that can accurately predict the percentage of the margin evaluated by proxy that considers the curvature of the ellipse.

Comparing Standard Excision and Mohs Surgery

Mohs surgery consistently results in the best outcomes, but standard excision is effective, too. Standard excision is relatively simple, requires less equipment, is less time consuming, and can provide good value when resources are finite. Data on recurrence of basal cell carcinoma after simple excision are limited, but the recurrence rate is reported to be approximately 3%.^7,8 A meta-analysis found that the recurrence rate of basal cell carcinoma treated with standard excision was 0.4%, 1.6%, 2.6%, and 4% with 5-mm, 4-mm, 3-mm, and 2-mm surgical margins, respectively.⁹

Mohs surgery is the best, most effective, and most tissue-sparing technique for certain nonmelanoma skin cancers. This observation is reflected in guidelines worldwide.¹⁰ The adequacy of standard approaches to margin evaluation depends on the capabilities and focus of the laboratory team. Dermatopathologists often are called to the laboratory to decide which technique will be best for a particular case.¹¹ Technicians are trained to take more sections in areas where abnormalities are seen, and some laboratories take photographs of specimens or provide sketches for correlation. Dermatopathologists also routinely request additional sections in areas where visible tumor extends close to surgical margins on microscopic examination.

It is not simply a matter of knowing how much of the margin is sampled but if the most pertinent areas are adequately sampled. Simple sectioning can work well and be cost effective. Many clinicians are unaware of how tissue processing can vary from laboratory to laboratory. There are no uniformly accepted standards for how tissue should be processed. Assiduous and thoughtful evaluation of specimens can affect results. As with any service, some laboratories provide more detailed and conscientious care while others focus more on immediate costs. Clinicians should understand how their specimens are processed by discussing margin evaluation with their dermatopathologist.

Final Thoughts

Used appropriately, Mohs surgery is an excellent technique that can provide outstanding results. Standard excision also has an important place in the dermatologist’s armamentarium and typically provides information about more than 1% to 2% of the margin. Understanding the techniques used to process specimens is critical to delivering the best possible care.

We have attended grand rounds presentations at which students announce that Mohs micrographic surgery evaluates 100% of the surgical margin, whereas standard excision samples 1% to 2% of the margin; we have even fielded questions from neighbors who have come across this information on the internet.^1-5 This statement describes a best-case scenario for Mohs surgery and a worst-case scenario for standard excision. We believe that it is important for clinicians to have a more nuanced understanding of how simple excisions are processed so that they can have pertinent discussions with patients, especially now that there is increasing access to personal health information along with increased agency in patient decision-making.

Margins for Mohs Surgery

Theoretically, Mohs surgery should sample all true surgical margins by complete circumferential, peripheral, and deep-margin assessment. Unfortunately, some sections are not cut full face—sections may not always sample a complete surface—when technicians make an error or lack expertise. Some sections may have small tissue folds or small gaps that prevent complete visualization. We estimate that the Mohs sections we review in consultation that are prepared by private practice Mohs surgeons in our communities visualize approximately 98% of surgical margins on average. Incomplete sections contribute to the rare tumor recurrences after Mohs surgery of approximately 2% to 3%.⁶

Standard Excision Margins

When we obtained the references cited in articles asserting that standard excision samples less than 0.5%, 1%, or 2% of the surgical margin, we did not find evidence-based information confirming this generally accepted conclusion. We believe the assertions are derived by comparing the sum of the thickness of all microscopic sections added together against the longitudinal length of the entire specimen.Sampling less than 0.5% of a margin has been described as providing the illusion of microscopic control.⁵ We have encountered medical students, nondermatologist physicians, and patients who have come across this information and have understandably concluded that standard margin assessment must be inadequate if only such a small amount of margin is assessed.

Here is a simple example to show that more margin is accessed in some cases. Consider this hypothetical situation: If a tumor can be readily visualized grossly and housed entirely within an imaginary cuboid (rectangular) prism that is removed in an elliptical specimen with a length of 6 cm, a width of 2 cm, and a height of 1 cm (Figure), then standard sectioning assesses a greater margin.

Bread-loaf sectioning would be expected to examine the complete surface of 2 sides (faces) of the cuboid. Assessing 2 of the 5 clinically relevant sides provides information for approximately 50% of the margins, as sections in the next parallel plane can be expected to be clear after the first clear section is identified. The clinically useful information is not limited to the sum of the widths of sections. Encountering a clear plane typically indicates that there will be no tumor in more distal parallel planes. Warne et al⁶ developed a formula that can accurately predict the percentage of the margin evaluated by proxy that considers the curvature of the ellipse.

Comparing Standard Excision and Mohs Surgery

Mohs surgery consistently results in the best outcomes, but standard excision is effective, too. Standard excision is relatively simple, requires less equipment, is less time consuming, and can provide good value when resources are finite. Data on recurrence of basal cell carcinoma after simple excision are limited, but the recurrence rate is reported to be approximately 3%.^7,8 A meta-analysis found that the recurrence rate of basal cell carcinoma treated with standard excision was 0.4%, 1.6%, 2.6%, and 4% with 5-mm, 4-mm, 3-mm, and 2-mm surgical margins, respectively.⁹

Mohs surgery is the best, most effective, and most tissue-sparing technique for certain nonmelanoma skin cancers. This observation is reflected in guidelines worldwide.¹⁰ The adequacy of standard approaches to margin evaluation depends on the capabilities and focus of the laboratory team. Dermatopathologists often are called to the laboratory to decide which technique will be best for a particular case.¹¹ Technicians are trained to take more sections in areas where abnormalities are seen, and some laboratories take photographs of specimens or provide sketches for correlation. Dermatopathologists also routinely request additional sections in areas where visible tumor extends close to surgical margins on microscopic examination.

It is not simply a matter of knowing how much of the margin is sampled but if the most pertinent areas are adequately sampled. Simple sectioning can work well and be cost effective. Many clinicians are unaware of how tissue processing can vary from laboratory to laboratory. There are no uniformly accepted standards for how tissue should be processed. Assiduous and thoughtful evaluation of specimens can affect results. As with any service, some laboratories provide more detailed and conscientious care while others focus more on immediate costs. Clinicians should understand how their specimens are processed by discussing margin evaluation with their dermatopathologist.

Final Thoughts

Used appropriately, Mohs surgery is an excellent technique that can provide outstanding results. Standard excision also has an important place in the dermatologist’s armamentarium and typically provides information about more than 1% to 2% of the margin. Understanding the techniques used to process specimens is critical to delivering the best possible care.

These findings are consistent with a type of heritable keratoderma called pachyonychia congenita (also called twenty-nails dystrophy). It is easy to mistake this unusual cause of thickening nails with a more common cause: onychomycosis.

Pachyonychia congenita describes a set of disorders driven by heritable defects in 1 of 5 keratin genes. The disorder is often transmitted in an autosomal dominant fashion, although a third of patients are thought to have a spontaneous mutation.¹ These gene changes can cause 1 or multiple dystrophic nails, thickened nail beds, natal teeth, thick plantar or palmar nodules or plaques, and hearing difficulties. Some patients may have symptoms at birth, while other patients do not develop symptoms until later in life.¹

There is currently no cure for pachyonychia congenita. Patients with suspected heritable keratoderma benefit from referral to Medical Genetics and a dermatologist who is comfortable treating keratodermas. Patients can obtain free genetic testing, educational material, and additional resources through pachyonychia.org.

This patient was prescribed topical urea 40% cream that was to be applied to the feet nightly, until the nodules became less painful. He was also evaluated for pressure-offloading orthotics. Nails may be treated with topical urea lacquer nightly until patients are satisfied with the appearance, although this patient chose to forgo the lacquer.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

These findings are consistent with a type of heritable keratoderma called pachyonychia congenita (also called twenty-nails dystrophy). It is easy to mistake this unusual cause of thickening nails with a more common cause: onychomycosis.

Pachyonychia congenita describes a set of disorders driven by heritable defects in 1 of 5 keratin genes. The disorder is often transmitted in an autosomal dominant fashion, although a third of patients are thought to have a spontaneous mutation.¹ These gene changes can cause 1 or multiple dystrophic nails, thickened nail beds, natal teeth, thick plantar or palmar nodules or plaques, and hearing difficulties. Some patients may have symptoms at birth, while other patients do not develop symptoms until later in life.¹

There is currently no cure for pachyonychia congenita. Patients with suspected heritable keratoderma benefit from referral to Medical Genetics and a dermatologist who is comfortable treating keratodermas. Patients can obtain free genetic testing, educational material, and additional resources through pachyonychia.org.

This patient was prescribed topical urea 40% cream that was to be applied to the feet nightly, until the nodules became less painful. He was also evaluated for pressure-offloading orthotics. Nails may be treated with topical urea lacquer nightly until patients are satisfied with the appearance, although this patient chose to forgo the lacquer.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

These findings are consistent with a type of heritable keratoderma called pachyonychia congenita (also called twenty-nails dystrophy). It is easy to mistake this unusual cause of thickening nails with a more common cause: onychomycosis.

Pachyonychia congenita describes a set of disorders driven by heritable defects in 1 of 5 keratin genes. The disorder is often transmitted in an autosomal dominant fashion, although a third of patients are thought to have a spontaneous mutation.¹ These gene changes can cause 1 or multiple dystrophic nails, thickened nail beds, natal teeth, thick plantar or palmar nodules or plaques, and hearing difficulties. Some patients may have symptoms at birth, while other patients do not develop symptoms until later in life.¹

There is currently no cure for pachyonychia congenita. Patients with suspected heritable keratoderma benefit from referral to Medical Genetics and a dermatologist who is comfortable treating keratodermas. Patients can obtain free genetic testing, educational material, and additional resources through pachyonychia.org.

This patient was prescribed topical urea 40% cream that was to be applied to the feet nightly, until the nodules became less painful. He was also evaluated for pressure-offloading orthotics. Nails may be treated with topical urea lacquer nightly until patients are satisfied with the appearance, although this patient chose to forgo the lacquer.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

To the Editor:

A 57-year-old woman presented to an outpatient clinic with severe pruritus and burning of the skin as well as subjective fevers and chills. She had been discharged from a psychiatric hospital for attempted suicide 1 day prior. There were no recent changes in the medication regimen, which consisted of linaclotide, fluoxetine, lorazepam, and gabapentin. While admitted, the patient was started on the atypical antipsychotic cariprazine. Within 24 hours of the first dose, she developed severe facial erythema that progressed to diffuse erythema over more than 60% of the body surface area. The attending psychiatrist promptly discontinued cariprazine. During the next 24 hours, there were no reports of fever, leukocytosis, or signs of systemic organ involvement. Given the patient’s mental and medical stability, she was discharged with instructions to follow up with the outpatient dermatology clinic.

At the current presentation, physical examination revealed innumerable 1- to 4-mm pustules coalescing to lakes of pus on an erythematous base over more than 60% of the body surface area (Figure 1). The mucous membranes were clear of lesions, the Nikolsky sign was negative, and the patient’s temperature was 99.6 °F in the office. Complete blood cell count and complete metabolic panel results were within reference range.

A 4-mm abdominal punch biopsy showed subcorneal neutrophilic pustules, papillary dermal edema, and superficial dermal lymphohistiocytic inflammation with numerous neutrophils, eosinophils, and extravasated red blood cells, consistent with acute generalized exanthematous pustulosis (AGEP)(Figure 2). The patient was started on wet wraps with triamcinolone cream 0.1%.

Two days later, physical examination revealed the erythema noted on initial examination had notably decreased, and the patient no longer reported burning or pruritus. One week after initial presentation to the clinic, the patient’s rash had resolved, and only a few small areas of desquamation remained.

Acute generalized exanthematous pustulosis is a severe cutaneous adverse reaction characterized by the development of numerous nonfollicular sterile pustules on an edematous and erythematous base. In almost 90% of reported cases, the cause is related to use of antibiotics, antifungals, antimalarials, or diltiazem (a calcium channel blocker). This rare cutaneous reaction occurs in 1 to 5 patients per million per year¹; it carries a 1% to 2% mortality rate with proper supportive treatment.

The clinical symptoms of AGEP typically present 24 to 48 hours after drug initiation with the rapid development of dozens to thousands of 1- to 4-mm pustules, typically localized to the flexor surfaces and face. In the setting of AGEP, acute onset of fever and leukocytosis typically occur at the time of the cutaneous eruption. These features were absent in this patient. The eruption usually starts on the face and then migrates to the trunk and extremities, sparing the palms and soles. Systemic involvement most commonly presents as hepatic, renal, or pulmonary insufficiency, which has been seen in 20% of cases.²

The immunologic response associated with the reaction has been studied in vitro. Drug-specific CD8 T cells use perforin/granzyme B and Fas ligand mechanisms to induce apoptosis of the keratinocytes within the epidermis, leading to vesicle formation.³ During the very first stages of formation, vesicles mainly comprise CD8 T cells and keratinocytes. These cells then begin producing CXC-18, a potent neutrophil chemokine, leading to extensive chemotaxis of neutrophils into vesicles, which then rapidly transform to pustules.³ This rapid transformation leads to the lakes of pustules, a description often associated with AGEP.

Treatment of AGEP is mainly supportive and consists of discontinuing use of the causative agent. Topical corticosteroids can be used during the pustular phase for symptom management. There is no evidence that systemic steroids reduce the duration of the disease.² Other supportive measures such as application of wet wraps can be used to provide comfort.

Cutaneous adverse drug reactions commonly are associated with psychiatric pharmacotherapy, but first-and second-generation antipsychotics rarely are associated with these types of reactions. In this patient, the causative agent of the AGEP was cariprazine, an atypical antipsychotic that had no reported association with AGEP or cutaneous adverse drug reactions prior to this presentation.

To the Editor:

A 57-year-old woman presented to an outpatient clinic with severe pruritus and burning of the skin as well as subjective fevers and chills. She had been discharged from a psychiatric hospital for attempted suicide 1 day prior. There were no recent changes in the medication regimen, which consisted of linaclotide, fluoxetine, lorazepam, and gabapentin. While admitted, the patient was started on the atypical antipsychotic cariprazine. Within 24 hours of the first dose, she developed severe facial erythema that progressed to diffuse erythema over more than 60% of the body surface area. The attending psychiatrist promptly discontinued cariprazine. During the next 24 hours, there were no reports of fever, leukocytosis, or signs of systemic organ involvement. Given the patient’s mental and medical stability, she was discharged with instructions to follow up with the outpatient dermatology clinic.

At the current presentation, physical examination revealed innumerable 1- to 4-mm pustules coalescing to lakes of pus on an erythematous base over more than 60% of the body surface area (Figure 1). The mucous membranes were clear of lesions, the Nikolsky sign was negative, and the patient’s temperature was 99.6 °F in the office. Complete blood cell count and complete metabolic panel results were within reference range.

A 4-mm abdominal punch biopsy showed subcorneal neutrophilic pustules, papillary dermal edema, and superficial dermal lymphohistiocytic inflammation with numerous neutrophils, eosinophils, and extravasated red blood cells, consistent with acute generalized exanthematous pustulosis (AGEP)(Figure 2). The patient was started on wet wraps with triamcinolone cream 0.1%.

Two days later, physical examination revealed the erythema noted on initial examination had notably decreased, and the patient no longer reported burning or pruritus. One week after initial presentation to the clinic, the patient’s rash had resolved, and only a few small areas of desquamation remained.

Acute generalized exanthematous pustulosis is a severe cutaneous adverse reaction characterized by the development of numerous nonfollicular sterile pustules on an edematous and erythematous base. In almost 90% of reported cases, the cause is related to use of antibiotics, antifungals, antimalarials, or diltiazem (a calcium channel blocker). This rare cutaneous reaction occurs in 1 to 5 patients per million per year¹; it carries a 1% to 2% mortality rate with proper supportive treatment.

The clinical symptoms of AGEP typically present 24 to 48 hours after drug initiation with the rapid development of dozens to thousands of 1- to 4-mm pustules, typically localized to the flexor surfaces and face. In the setting of AGEP, acute onset of fever and leukocytosis typically occur at the time of the cutaneous eruption. These features were absent in this patient. The eruption usually starts on the face and then migrates to the trunk and extremities, sparing the palms and soles. Systemic involvement most commonly presents as hepatic, renal, or pulmonary insufficiency, which has been seen in 20% of cases.²

The immunologic response associated with the reaction has been studied in vitro. Drug-specific CD8 T cells use perforin/granzyme B and Fas ligand mechanisms to induce apoptosis of the keratinocytes within the epidermis, leading to vesicle formation.³ During the very first stages of formation, vesicles mainly comprise CD8 T cells and keratinocytes. These cells then begin producing CXC-18, a potent neutrophil chemokine, leading to extensive chemotaxis of neutrophils into vesicles, which then rapidly transform to pustules.³ This rapid transformation leads to the lakes of pustules, a description often associated with AGEP.

Treatment of AGEP is mainly supportive and consists of discontinuing use of the causative agent. Topical corticosteroids can be used during the pustular phase for symptom management. There is no evidence that systemic steroids reduce the duration of the disease.² Other supportive measures such as application of wet wraps can be used to provide comfort.

Cutaneous adverse drug reactions commonly are associated with psychiatric pharmacotherapy, but first-and second-generation antipsychotics rarely are associated with these types of reactions. In this patient, the causative agent of the AGEP was cariprazine, an atypical antipsychotic that had no reported association with AGEP or cutaneous adverse drug reactions prior to this presentation.

To the Editor:

A 57-year-old woman presented to an outpatient clinic with severe pruritus and burning of the skin as well as subjective fevers and chills. She had been discharged from a psychiatric hospital for attempted suicide 1 day prior. There were no recent changes in the medication regimen, which consisted of linaclotide, fluoxetine, lorazepam, and gabapentin. While admitted, the patient was started on the atypical antipsychotic cariprazine. Within 24 hours of the first dose, she developed severe facial erythema that progressed to diffuse erythema over more than 60% of the body surface area. The attending psychiatrist promptly discontinued cariprazine. During the next 24 hours, there were no reports of fever, leukocytosis, or signs of systemic organ involvement. Given the patient’s mental and medical stability, she was discharged with instructions to follow up with the outpatient dermatology clinic.

At the current presentation, physical examination revealed innumerable 1- to 4-mm pustules coalescing to lakes of pus on an erythematous base over more than 60% of the body surface area (Figure 1). The mucous membranes were clear of lesions, the Nikolsky sign was negative, and the patient’s temperature was 99.6 °F in the office. Complete blood cell count and complete metabolic panel results were within reference range.

A 4-mm abdominal punch biopsy showed subcorneal neutrophilic pustules, papillary dermal edema, and superficial dermal lymphohistiocytic inflammation with numerous neutrophils, eosinophils, and extravasated red blood cells, consistent with acute generalized exanthematous pustulosis (AGEP)(Figure 2). The patient was started on wet wraps with triamcinolone cream 0.1%.

Two days later, physical examination revealed the erythema noted on initial examination had notably decreased, and the patient no longer reported burning or pruritus. One week after initial presentation to the clinic, the patient’s rash had resolved, and only a few small areas of desquamation remained.

Acute generalized exanthematous pustulosis is a severe cutaneous adverse reaction characterized by the development of numerous nonfollicular sterile pustules on an edematous and erythematous base. In almost 90% of reported cases, the cause is related to use of antibiotics, antifungals, antimalarials, or diltiazem (a calcium channel blocker). This rare cutaneous reaction occurs in 1 to 5 patients per million per year¹; it carries a 1% to 2% mortality rate with proper supportive treatment.

The clinical symptoms of AGEP typically present 24 to 48 hours after drug initiation with the rapid development of dozens to thousands of 1- to 4-mm pustules, typically localized to the flexor surfaces and face. In the setting of AGEP, acute onset of fever and leukocytosis typically occur at the time of the cutaneous eruption. These features were absent in this patient. The eruption usually starts on the face and then migrates to the trunk and extremities, sparing the palms and soles. Systemic involvement most commonly presents as hepatic, renal, or pulmonary insufficiency, which has been seen in 20% of cases.²

The immunologic response associated with the reaction has been studied in vitro. Drug-specific CD8 T cells use perforin/granzyme B and Fas ligand mechanisms to induce apoptosis of the keratinocytes within the epidermis, leading to vesicle formation.³ During the very first stages of formation, vesicles mainly comprise CD8 T cells and keratinocytes. These cells then begin producing CXC-18, a potent neutrophil chemokine, leading to extensive chemotaxis of neutrophils into vesicles, which then rapidly transform to pustules.³ This rapid transformation leads to the lakes of pustules, a description often associated with AGEP.

Treatment of AGEP is mainly supportive and consists of discontinuing use of the causative agent. Topical corticosteroids can be used during the pustular phase for symptom management. There is no evidence that systemic steroids reduce the duration of the disease.² Other supportive measures such as application of wet wraps can be used to provide comfort.

Cutaneous adverse drug reactions commonly are associated with psychiatric pharmacotherapy, but first-and second-generation antipsychotics rarely are associated with these types of reactions. In this patient, the causative agent of the AGEP was cariprazine, an atypical antipsychotic that had no reported association with AGEP or cutaneous adverse drug reactions prior to this presentation.

To the Editor:

A 47-year-old man presented at the dermatology clinic with a growing lesion on the left medial thigh. The patient traveled frequently for work. Although asymptomatic, the lesion was interfering with the patient’s ability to get through security because it routinely was getting detected by airport full-body scanners. These scanners use high-frequency radio waves or x-rays to detect nonmetallic objects under a traveler’s clothing. The patient would be frisked by security and had to explain that he had a growth in that location. He thankfully would be released by security on those occasions, but the delay in getting through security was becoming a nuisance.

Physical examination revealed a 5-cm, pedunculated, fatty nodule on the left medial thigh that was clinically consistent with nevus lipomatosis (NL)(Figure). Although benign, trouble traveling through airport security prompted the patient to request shave removal, which subsequently was performed. Histology showed a large pedunculated nodule with prominent adipose tissue, consistent with NL. At 3-month follow-up, the patient reported getting through airport security multiple times without incident.

Nevus lipomatosis is a benign fatty lesion most commonly found on the medial thighs or trunk of adults. The lesion usually is asymptomatic but can become irritated by rubbing or catching on clothing. Our patient had symptomatic NL that caused delays getting through airport security; he experienced full resolution after simple shave removal. In rare instances, both benign and malignant skin conditions have been seen on airport scanning devices since the introduction of increased security measures following September 11, 2001. In 2016, Heymann¹ reported a man with a 1.5-cm epidermal inclusion cyst detected by airport security scanners, prompting the traveler to request and carry a medically explanatory letter used to get through security. In 2015 Mayer and Adams² described a case of nodular melanoma that was detected 20 times over a period of 2 months by airport scanners, and in 2016, Caine et al³ reported a case of desmoplastic melanoma that was detected by airport security, but after its removal was not identified by security for the next 40 flights. Noncutaneous pathology also can be detected by airport scanners. In 2013, Naraynsingh et al⁴ reported a man with a large left reducible inguinal hernia who was stopped by airport security and subjected to an invasive physical examination of the area. These instances demonstrate the breadth of conditions that can be cumbersome when individuals are traveling by airplane in our current security climate.

Our patient had to go through the trouble of having the benign NL lesion removed to avoid the hassle of repeatedly being stopped by airport security. The patient had the lesion removed and is doing well, but the procedure could have been avoided if systems existed to help patients with dermatologic and medical conditions at airport security. Our patient likely will never be stopped again for the suspicious lump on the left inner thigh, but many others will be stopped for similar reasons.

To the Editor:

A 47-year-old man presented at the dermatology clinic with a growing lesion on the left medial thigh. The patient traveled frequently for work. Although asymptomatic, the lesion was interfering with the patient’s ability to get through security because it routinely was getting detected by airport full-body scanners. These scanners use high-frequency radio waves or x-rays to detect nonmetallic objects under a traveler’s clothing. The patient would be frisked by security and had to explain that he had a growth in that location. He thankfully would be released by security on those occasions, but the delay in getting through security was becoming a nuisance.

Physical examination revealed a 5-cm, pedunculated, fatty nodule on the left medial thigh that was clinically consistent with nevus lipomatosis (NL)(Figure). Although benign, trouble traveling through airport security prompted the patient to request shave removal, which subsequently was performed. Histology showed a large pedunculated nodule with prominent adipose tissue, consistent with NL. At 3-month follow-up, the patient reported getting through airport security multiple times without incident.

Nevus lipomatosis is a benign fatty lesion most commonly found on the medial thighs or trunk of adults. The lesion usually is asymptomatic but can become irritated by rubbing or catching on clothing. Our patient had symptomatic NL that caused delays getting through airport security; he experienced full resolution after simple shave removal. In rare instances, both benign and malignant skin conditions have been seen on airport scanning devices since the introduction of increased security measures following September 11, 2001. In 2016, Heymann¹ reported a man with a 1.5-cm epidermal inclusion cyst detected by airport security scanners, prompting the traveler to request and carry a medically explanatory letter used to get through security. In 2015 Mayer and Adams² described a case of nodular melanoma that was detected 20 times over a period of 2 months by airport scanners, and in 2016, Caine et al³ reported a case of desmoplastic melanoma that was detected by airport security, but after its removal was not identified by security for the next 40 flights. Noncutaneous pathology also can be detected by airport scanners. In 2013, Naraynsingh et al⁴ reported a man with a large left reducible inguinal hernia who was stopped by airport security and subjected to an invasive physical examination of the area. These instances demonstrate the breadth of conditions that can be cumbersome when individuals are traveling by airplane in our current security climate.

Our patient had to go through the trouble of having the benign NL lesion removed to avoid the hassle of repeatedly being stopped by airport security. The patient had the lesion removed and is doing well, but the procedure could have been avoided if systems existed to help patients with dermatologic and medical conditions at airport security. Our patient likely will never be stopped again for the suspicious lump on the left inner thigh, but many others will be stopped for similar reasons.

To the Editor:

A 47-year-old man presented at the dermatology clinic with a growing lesion on the left medial thigh. The patient traveled frequently for work. Although asymptomatic, the lesion was interfering with the patient’s ability to get through security because it routinely was getting detected by airport full-body scanners. These scanners use high-frequency radio waves or x-rays to detect nonmetallic objects under a traveler’s clothing. The patient would be frisked by security and had to explain that he had a growth in that location. He thankfully would be released by security on those occasions, but the delay in getting through security was becoming a nuisance.

Physical examination revealed a 5-cm, pedunculated, fatty nodule on the left medial thigh that was clinically consistent with nevus lipomatosis (NL)(Figure). Although benign, trouble traveling through airport security prompted the patient to request shave removal, which subsequently was performed. Histology showed a large pedunculated nodule with prominent adipose tissue, consistent with NL. At 3-month follow-up, the patient reported getting through airport security multiple times without incident.

Nevus lipomatosis is a benign fatty lesion most commonly found on the medial thighs or trunk of adults. The lesion usually is asymptomatic but can become irritated by rubbing or catching on clothing. Our patient had symptomatic NL that caused delays getting through airport security; he experienced full resolution after simple shave removal. In rare instances, both benign and malignant skin conditions have been seen on airport scanning devices since the introduction of increased security measures following September 11, 2001. In 2016, Heymann¹ reported a man with a 1.5-cm epidermal inclusion cyst detected by airport security scanners, prompting the traveler to request and carry a medically explanatory letter used to get through security. In 2015 Mayer and Adams² described a case of nodular melanoma that was detected 20 times over a period of 2 months by airport scanners, and in 2016, Caine et al³ reported a case of desmoplastic melanoma that was detected by airport security, but after its removal was not identified by security for the next 40 flights. Noncutaneous pathology also can be detected by airport scanners. In 2013, Naraynsingh et al⁴ reported a man with a large left reducible inguinal hernia who was stopped by airport security and subjected to an invasive physical examination of the area. These instances demonstrate the breadth of conditions that can be cumbersome when individuals are traveling by airplane in our current security climate.

Our patient had to go through the trouble of having the benign NL lesion removed to avoid the hassle of repeatedly being stopped by airport security. The patient had the lesion removed and is doing well, but the procedure could have been avoided if systems existed to help patients with dermatologic and medical conditions at airport security. Our patient likely will never be stopped again for the suspicious lump on the left inner thigh, but many others will be stopped for similar reasons.