Contact Dermatitis

To the Editor:

Allergic contact dermatitis (ACD) is a delayed-type hypersensitivity reaction against antigens to which the skin’s immune system was previously sensitized. The initial sensitization requires penetration of the antigen through the stratum corneum. Thus, the ability of a particle to cause ACD is related to its molecular structure and size, lipophilicity, and protein-binding affinity, as well as the dose and duration of exposure.¹ Psoriasis typically presents as well-demarcated areas of skin that may be erythematous, indurated, and scaly to variable degrees. Histologically, psoriasis plaques are characterized by epidermal hyperplasia in the presence of a T-cell infiltrate and neutrophilic microabscesses. We report a case of a patient with plaque-type psoriasis who experienced ACD with sparing of exposed psoriatic plaques.

A 45-year-old man with a 5-year history of generalized moderate to severe psoriasis undergoing therapy with ustekinumab 45 mg subcutaneously once every 12 weeks presented to the emergency department with intensely erythematous, pruritic, vesicular lesions on the trunk, arms, and legs within 24 hours of exposure to poison oak while hiking. The patient reported pruritus, pain, and swelling of the affected areas. On physical examination, he was afebrile. Widespread erythematous vesicular lesions were noted on the face, trunk, arms, and legs, sparing the well-demarcated scaly psoriatic plaques on the arms and legs (Figure). The patient was given intravenous fluids and intravenous diphenhydramine. After responding to initial treatment, the patient was discharged with ibuprofen and a tapering dose of oral prednisone from 60 mg 5 times daily, to 40 mg 5 times daily, to 20 mg 5 times daily over 15 days.

Plaque psoriasis is a chronic, immune-mediated, inflammatory disease that presents clinically as erythematous well-demarcated plaques with a micaceous scale. The immunologic environment of psoriasis plaques is characterized by infiltration of CD4⁺ T_H17 cells and elevated levels of IL-17, IL-23, tumor necrosis factor α, and IL-1β, which induce keratinocyte hyperproliferation through a complex mechanism resulting in hyperkeratosis composed of orthokeratosis and parakeratosis, a neutrophilic infiltrate, and Munro microabscesses.⁵

The predominant effector cells and the final effects on keratinocyte survival are divergent in psoriasis and ACD. The possibly antagonistic relationship between these immunologic processes is further supported by epidemiologic studies demonstrating a decreased incidence of ACD in patients with psoriasis.^6,7

Our patient demonstrated a typical ACD reaction in response to exposure to urushiol, the allergen present in poison oak, in areas unaffected by psoriasis plaques. Interestingly, the patient displayed this response even while undergoing therapy with ustekinumab, a fully humanized antibody that binds IL-12 and IL-23 and ultimately downregulates T_H17 cell-mediated release of IL-17 in the treatment of psoriasis. Although IL-17 also has been implicated in ACD, the lack of inhibition of ACD with ustekinumab treatment was previously demonstrated in a small retrospective study, indicating a potentially different source of IL-17 in ACD.⁸

Our patient did not demonstrate a typical ACD response in areas of active psoriasis plaques. This phenomenon was of great interest to us. It is possible that the presence of hyperkeratosis, manifested clinically as scaling, served as a mechanical barrier preventing the diffusion and exposure of cutaneous immune cells to urushiol. On the other hand, it is possible that the immunologic environment of the active psoriasis plaque was altered in such a way that it did not demonstrate the typical response to allergen exposure.

We hypothesize that the lack of a typical ACD response at sites of psoriatic plaques in our patient may be attributed to the intensity and duration of exposure to the allergen. Quaranta et al⁹ reported a typical ACD clinical response and a mixed immunohistologic response to nickel patch testing at sites of active plaques in nickel-sensitized psoriasis patients. Patch testing involves 48 hours of direct contact with an allergen, while our patient experienced an estimated 8 to 10 hours of exposure to the allergen prior to removal via washing. Supporting this line of reasoning, a proportion of patients who are responsive to nickel patch testing do not exhibit clinical symptoms in response to casual nickel exposure.¹⁰ Although a physical barrier effect due to hyperkeratosis may have contributed to the lack of ACD response in sites of psoriasis plaques in our patient, it remains possible that a more limited duration of exposure to the allergen is not sufficient to overcome the native immunologic milieu of the psoriasis plaque and induce the immunologic cascade resulting in ACD. Further research into the potentially antagonistic relationship of psoriasis and ACD should be performed to elucidate the interaction between these two common conditions.

To the Editor:

Allergic contact dermatitis (ACD) is a delayed-type hypersensitivity reaction against antigens to which the skin’s immune system was previously sensitized. The initial sensitization requires penetration of the antigen through the stratum corneum. Thus, the ability of a particle to cause ACD is related to its molecular structure and size, lipophilicity, and protein-binding affinity, as well as the dose and duration of exposure.¹ Psoriasis typically presents as well-demarcated areas of skin that may be erythematous, indurated, and scaly to variable degrees. Histologically, psoriasis plaques are characterized by epidermal hyperplasia in the presence of a T-cell infiltrate and neutrophilic microabscesses. We report a case of a patient with plaque-type psoriasis who experienced ACD with sparing of exposed psoriatic plaques.

A 45-year-old man with a 5-year history of generalized moderate to severe psoriasis undergoing therapy with ustekinumab 45 mg subcutaneously once every 12 weeks presented to the emergency department with intensely erythematous, pruritic, vesicular lesions on the trunk, arms, and legs within 24 hours of exposure to poison oak while hiking. The patient reported pruritus, pain, and swelling of the affected areas. On physical examination, he was afebrile. Widespread erythematous vesicular lesions were noted on the face, trunk, arms, and legs, sparing the well-demarcated scaly psoriatic plaques on the arms and legs (Figure). The patient was given intravenous fluids and intravenous diphenhydramine. After responding to initial treatment, the patient was discharged with ibuprofen and a tapering dose of oral prednisone from 60 mg 5 times daily, to 40 mg 5 times daily, to 20 mg 5 times daily over 15 days.

Plaque psoriasis is a chronic, immune-mediated, inflammatory disease that presents clinically as erythematous well-demarcated plaques with a micaceous scale. The immunologic environment of psoriasis plaques is characterized by infiltration of CD4⁺ T_H17 cells and elevated levels of IL-17, IL-23, tumor necrosis factor α, and IL-1β, which induce keratinocyte hyperproliferation through a complex mechanism resulting in hyperkeratosis composed of orthokeratosis and parakeratosis, a neutrophilic infiltrate, and Munro microabscesses.⁵

The predominant effector cells and the final effects on keratinocyte survival are divergent in psoriasis and ACD. The possibly antagonistic relationship between these immunologic processes is further supported by epidemiologic studies demonstrating a decreased incidence of ACD in patients with psoriasis.^6,7

Our patient demonstrated a typical ACD reaction in response to exposure to urushiol, the allergen present in poison oak, in areas unaffected by psoriasis plaques. Interestingly, the patient displayed this response even while undergoing therapy with ustekinumab, a fully humanized antibody that binds IL-12 and IL-23 and ultimately downregulates T_H17 cell-mediated release of IL-17 in the treatment of psoriasis. Although IL-17 also has been implicated in ACD, the lack of inhibition of ACD with ustekinumab treatment was previously demonstrated in a small retrospective study, indicating a potentially different source of IL-17 in ACD.⁸

Our patient did not demonstrate a typical ACD response in areas of active psoriasis plaques. This phenomenon was of great interest to us. It is possible that the presence of hyperkeratosis, manifested clinically as scaling, served as a mechanical barrier preventing the diffusion and exposure of cutaneous immune cells to urushiol. On the other hand, it is possible that the immunologic environment of the active psoriasis plaque was altered in such a way that it did not demonstrate the typical response to allergen exposure.

We hypothesize that the lack of a typical ACD response at sites of psoriatic plaques in our patient may be attributed to the intensity and duration of exposure to the allergen. Quaranta et al⁹ reported a typical ACD clinical response and a mixed immunohistologic response to nickel patch testing at sites of active plaques in nickel-sensitized psoriasis patients. Patch testing involves 48 hours of direct contact with an allergen, while our patient experienced an estimated 8 to 10 hours of exposure to the allergen prior to removal via washing. Supporting this line of reasoning, a proportion of patients who are responsive to nickel patch testing do not exhibit clinical symptoms in response to casual nickel exposure.¹⁰ Although a physical barrier effect due to hyperkeratosis may have contributed to the lack of ACD response in sites of psoriasis plaques in our patient, it remains possible that a more limited duration of exposure to the allergen is not sufficient to overcome the native immunologic milieu of the psoriasis plaque and induce the immunologic cascade resulting in ACD. Further research into the potentially antagonistic relationship of psoriasis and ACD should be performed to elucidate the interaction between these two common conditions.

To the Editor:

Allergic contact dermatitis (ACD) is a delayed-type hypersensitivity reaction against antigens to which the skin’s immune system was previously sensitized. The initial sensitization requires penetration of the antigen through the stratum corneum. Thus, the ability of a particle to cause ACD is related to its molecular structure and size, lipophilicity, and protein-binding affinity, as well as the dose and duration of exposure.¹ Psoriasis typically presents as well-demarcated areas of skin that may be erythematous, indurated, and scaly to variable degrees. Histologically, psoriasis plaques are characterized by epidermal hyperplasia in the presence of a T-cell infiltrate and neutrophilic microabscesses. We report a case of a patient with plaque-type psoriasis who experienced ACD with sparing of exposed psoriatic plaques.

A 45-year-old man with a 5-year history of generalized moderate to severe psoriasis undergoing therapy with ustekinumab 45 mg subcutaneously once every 12 weeks presented to the emergency department with intensely erythematous, pruritic, vesicular lesions on the trunk, arms, and legs within 24 hours of exposure to poison oak while hiking. The patient reported pruritus, pain, and swelling of the affected areas. On physical examination, he was afebrile. Widespread erythematous vesicular lesions were noted on the face, trunk, arms, and legs, sparing the well-demarcated scaly psoriatic plaques on the arms and legs (Figure). The patient was given intravenous fluids and intravenous diphenhydramine. After responding to initial treatment, the patient was discharged with ibuprofen and a tapering dose of oral prednisone from 60 mg 5 times daily, to 40 mg 5 times daily, to 20 mg 5 times daily over 15 days.

Plaque psoriasis is a chronic, immune-mediated, inflammatory disease that presents clinically as erythematous well-demarcated plaques with a micaceous scale. The immunologic environment of psoriasis plaques is characterized by infiltration of CD4⁺ T_H17 cells and elevated levels of IL-17, IL-23, tumor necrosis factor α, and IL-1β, which induce keratinocyte hyperproliferation through a complex mechanism resulting in hyperkeratosis composed of orthokeratosis and parakeratosis, a neutrophilic infiltrate, and Munro microabscesses.⁵

The predominant effector cells and the final effects on keratinocyte survival are divergent in psoriasis and ACD. The possibly antagonistic relationship between these immunologic processes is further supported by epidemiologic studies demonstrating a decreased incidence of ACD in patients with psoriasis.^6,7

Our patient demonstrated a typical ACD reaction in response to exposure to urushiol, the allergen present in poison oak, in areas unaffected by psoriasis plaques. Interestingly, the patient displayed this response even while undergoing therapy with ustekinumab, a fully humanized antibody that binds IL-12 and IL-23 and ultimately downregulates T_H17 cell-mediated release of IL-17 in the treatment of psoriasis. Although IL-17 also has been implicated in ACD, the lack of inhibition of ACD with ustekinumab treatment was previously demonstrated in a small retrospective study, indicating a potentially different source of IL-17 in ACD.⁸

Our patient did not demonstrate a typical ACD response in areas of active psoriasis plaques. This phenomenon was of great interest to us. It is possible that the presence of hyperkeratosis, manifested clinically as scaling, served as a mechanical barrier preventing the diffusion and exposure of cutaneous immune cells to urushiol. On the other hand, it is possible that the immunologic environment of the active psoriasis plaque was altered in such a way that it did not demonstrate the typical response to allergen exposure.

We hypothesize that the lack of a typical ACD response at sites of psoriatic plaques in our patient may be attributed to the intensity and duration of exposure to the allergen. Quaranta et al⁹ reported a typical ACD clinical response and a mixed immunohistologic response to nickel patch testing at sites of active plaques in nickel-sensitized psoriasis patients. Patch testing involves 48 hours of direct contact with an allergen, while our patient experienced an estimated 8 to 10 hours of exposure to the allergen prior to removal via washing. Supporting this line of reasoning, a proportion of patients who are responsive to nickel patch testing do not exhibit clinical symptoms in response to casual nickel exposure.¹⁰ Although a physical barrier effect due to hyperkeratosis may have contributed to the lack of ACD response in sites of psoriasis plaques in our patient, it remains possible that a more limited duration of exposure to the allergen is not sufficient to overcome the native immunologic milieu of the psoriasis plaque and induce the immunologic cascade resulting in ACD. Further research into the potentially antagonistic relationship of psoriasis and ACD should be performed to elucidate the interaction between these two common conditions.

Cardiac implantable electronic devices (CIEDs) – cardiac pacemakers and implantable cardioverter defibrillators –are an established treatment for the management of cardiac dysrhythmias in millions of patients. Complications occur in up to 15%, some of which may present first to the dermatologist.

The differential diagnosis of dermatoses overlying pacemakers includes infection, irritant or allergic contact dermatitis, reticular telangiectatic erythema (caused by local venous obstruction and pressure dermatitis), and impending skin erosion/device extrusion.

Erosion and extrusion is a major complication with significant morbidity and mortality. The two main causes are pressure necrosis and infection. Pressure necrosis is influenced by the size of the device, complexity of the connections, and technical skill with which the pacemaker chest wall pocket is created.

After extrusion, the pacemaker should be considered contaminated and removed, and the necrotic tissue debrided. If infected, a prolonged course of appropriate antibiotic therapy is indicated. A bacterial culture in the patient presented here was negative.

Pocket infection of CIEDs is rare and may manifest as erythema, tenderness, drainage, erosion, or pruritus above the site of the pacemaker, along with systemic symptoms and signs, including fever, chills, or malaise. Some may have just the systemic symptoms. Fewer than half of patients with CIED infection present within 1 year of their last procedure.

Ruptured epidermal cysts usually manifest as acute swelling, inflammation, and tenderness of previously long-standing asymptomatic epidermal cysts. There may be drainage of malodorous keratinous and purulent debris. They are typically not infected. Treatment includes incision and drainage for fluctuant lesions or intralesional corticosteroid injection for early, nonfluctuant cases.

Allergic contact dermatitis to metal may be seen with implantable devices. Patch testing to various metal allergens can be helpful in determining if any allergy is present.

This case and photo were submitted by Michael Stierstorfer, MD, East Penn Dermatology, North Wales, Pa.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

Cardiac implantable electronic devices (CIEDs) – cardiac pacemakers and implantable cardioverter defibrillators –are an established treatment for the management of cardiac dysrhythmias in millions of patients. Complications occur in up to 15%, some of which may present first to the dermatologist.

The differential diagnosis of dermatoses overlying pacemakers includes infection, irritant or allergic contact dermatitis, reticular telangiectatic erythema (caused by local venous obstruction and pressure dermatitis), and impending skin erosion/device extrusion.

Erosion and extrusion is a major complication with significant morbidity and mortality. The two main causes are pressure necrosis and infection. Pressure necrosis is influenced by the size of the device, complexity of the connections, and technical skill with which the pacemaker chest wall pocket is created.

After extrusion, the pacemaker should be considered contaminated and removed, and the necrotic tissue debrided. If infected, a prolonged course of appropriate antibiotic therapy is indicated. A bacterial culture in the patient presented here was negative.

Pocket infection of CIEDs is rare and may manifest as erythema, tenderness, drainage, erosion, or pruritus above the site of the pacemaker, along with systemic symptoms and signs, including fever, chills, or malaise. Some may have just the systemic symptoms. Fewer than half of patients with CIED infection present within 1 year of their last procedure.

Ruptured epidermal cysts usually manifest as acute swelling, inflammation, and tenderness of previously long-standing asymptomatic epidermal cysts. There may be drainage of malodorous keratinous and purulent debris. They are typically not infected. Treatment includes incision and drainage for fluctuant lesions or intralesional corticosteroid injection for early, nonfluctuant cases.

Allergic contact dermatitis to metal may be seen with implantable devices. Patch testing to various metal allergens can be helpful in determining if any allergy is present.

This case and photo were submitted by Michael Stierstorfer, MD, East Penn Dermatology, North Wales, Pa.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

Cardiac implantable electronic devices (CIEDs) – cardiac pacemakers and implantable cardioverter defibrillators –are an established treatment for the management of cardiac dysrhythmias in millions of patients. Complications occur in up to 15%, some of which may present first to the dermatologist.

The differential diagnosis of dermatoses overlying pacemakers includes infection, irritant or allergic contact dermatitis, reticular telangiectatic erythema (caused by local venous obstruction and pressure dermatitis), and impending skin erosion/device extrusion.

Erosion and extrusion is a major complication with significant morbidity and mortality. The two main causes are pressure necrosis and infection. Pressure necrosis is influenced by the size of the device, complexity of the connections, and technical skill with which the pacemaker chest wall pocket is created.

After extrusion, the pacemaker should be considered contaminated and removed, and the necrotic tissue debrided. If infected, a prolonged course of appropriate antibiotic therapy is indicated. A bacterial culture in the patient presented here was negative.

Pocket infection of CIEDs is rare and may manifest as erythema, tenderness, drainage, erosion, or pruritus above the site of the pacemaker, along with systemic symptoms and signs, including fever, chills, or malaise. Some may have just the systemic symptoms. Fewer than half of patients with CIED infection present within 1 year of their last procedure.

Ruptured epidermal cysts usually manifest as acute swelling, inflammation, and tenderness of previously long-standing asymptomatic epidermal cysts. There may be drainage of malodorous keratinous and purulent debris. They are typically not infected. Treatment includes incision and drainage for fluctuant lesions or intralesional corticosteroid injection for early, nonfluctuant cases.

Allergic contact dermatitis to metal may be seen with implantable devices. Patch testing to various metal allergens can be helpful in determining if any allergy is present.

This case and photo were submitted by Michael Stierstorfer, MD, East Penn Dermatology, North Wales, Pa.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

Heparin is a naturally occurring anticoagulant and is commonly used to treat or prevent venous thrombosis or the extension of thrombosis.¹ Heparin is composed of 15-kDa chains of complex polysaccharides with repeating pentasaccharide sequences. These high-affinity pentasaccharide subunits bind and activate antithrombin III, which exerts its dominant anticoagulant effects through the inhibition of factor Xa.²

Adverse effects of heparin administration include bleeding, injection-site pain, and thrombocytopenia. Heparin-induced thrombocytopenia (HIT) is a serious side effect wherein antibodies are formed against platelet antigens and predispose the patient to venous and arterial thrombosis.³ Dermatologic adverse effects of heparin range from commonly reported injection-site eruptions to the more rarely described distant or generalized cutaneous reactions.⁴

Bullous hemorrhagic dermatosis is a poorly understood idiosyncratic drug reaction characterized by tense, blood-filled blisters that arise following the administration of subcutaneous low-molecular-weight heparin or intravenous unfractionated heparin (UFH). First reported in 2006 by Perrinaud et al,⁵ only a few case reports describing this phenomenon exist in the literature.^6-8 We report a unique case of hemorrhagic bullae limited to the oral mucosa.

Case Report

An 84-year-old man was admitted to the cardiology service with severe substernal chest pain. An electrocardiogram did not show any ST-segment elevations; however, he had elevated troponin T levels. He had a medical history of coronary artery disease complicated by myocardial infarction (MI), as well as ischemic cardiomyopathy, hypertension, hyperlipidemia, ischemic stroke, and pulmonary embolism for which he was on long-term anticoagulation for years with warfarin, aspirin, and clopidogrel. The patient was diagnosed with a non–ST-segment elevation MI. Accordingly, the patient’s warfarin was discontinued, and he was administered a bolus and continuous infusion of UFH. He also was continued on aspirin and clopidogrel. Within 6 hours of initiation of UFH, the patient noted multiple discrete swollen lesions in the mouth. Dermatology consultation and biopsy of the lesions were deferred due to acute management of the patient’s MI.

Physical examination revealed a moist oral mucosa with 7 slightly raised, hemorrhagic bullae ranging from 2 to 7 mm in diameter (Figure, A and B). One oral lesion was tense and had become denuded prior to evaluation. Laboratory testing included a normal platelet count (160,000/µL), a nearly therapeutic international normalized ratio (1.9), and a partial thromboplastin time that was initially normal (27 seconds) prior to admission and development of the oral lesions but found to be elevated (176 seconds) after admission and initial UFH bolus.

Comment

Heparin-Induced Skin Lesions
The 2 most common types of heparin-induced skin lesions are delayed-type hypersensitivity reactions and immune-mediated HIT. A 2009 Canadian study found that the overwhelming majority of heparin-induced skin lesions are due to delayed-type hypersensitivity reactions.⁴ The majority of these reactions occurred at or near the injection site on the abdomen and presented as eczematous plaques. Distant cutaneous involvement and lesions of the buccal mucosa were not as commonly reported. Female sex, obesity, and heparin treatment exceeding 9 days were identified as risk factors in the development of delayed-type hypersensitivity reactions, but our patient did not have any of these risk factors.⁴

Types of HIT
Heparin-induced thrombocytopenia is one of the most serious adverse reactions to heparin administration. There are 2 subtypes of HIT, which differ in their clinical significance and pathophysiology.⁹ Type I HIT is a non–immune-mediated reaction that results from the direct effect of heparin on platelets, which causes platelet aggregation and thrombocytopenia. It presents within the first 2 days after heparin exposure.

Type II HIT is an immune-mediated response caused by the formation of IgG autoantibodies against the heparin–platelet factor 4 complex. Antibody formation and thrombocytopenia typically occur after 4 to 10 days of heparin exposure, and there can be devastating arterial and venous thrombotic complications.

Diagnosis of HIT
Heparin-induced thrombocytopenia should be suspected in patients with a lowered platelet count, particularly if the decrease is more than 50% from baseline, and in patients who develop stroke, MI, pulmonary embolism, or deep vein thrombosis while on heparin. Heparin-induced thrombocytopenia was not observed in our patient, as his platelet count remained stable between 160,000 and 164,000/µL throughout his hospital stay and he did not develop any evidence of thrombosis.

Differential Diagnosis
Our patient’s lesions appeared morphologically similar to angina bullosa haemorrhagica, but this condition was less likely based on other clinical features. Typically, angina bullosa haemorrhagica appears as a solitary, blood-filled blister due to oral mucosal trauma from the ingestion of hard or abrasive food.¹⁰ Angina bullosa haemorrhagica most often is located on the soft palate because of its susceptibility to injury during mastication, and this lesion tends to be painful.¹¹ In contrast, our patient developed 7 painless lesions on the buccal mucosa, sparing the soft palate, and without any history of preceding trauma.

Bullous pemphigoid also was considered given the presence of tense bullae in an elderly patient. However, the rapid and spontaneous resolution of these lesions with complete lack of skin involvement made this diagnosis less likely.¹²

Heparin-Induced Bullous Hemorrhagic Dermatosis
Because our patient described a similar reaction while taking enoxaparin in the past, this case represents an idiosyncratic drug reaction, possibly from antibodies to a heparin-antigen complex. Heparin-induced bullous hemorrhagic dermatosis is a rarely reported condition with the majority of lesions presenting on the extremities.

Conclusion

We describe a rare side effect of heparin therapy characterized by discrete blisters on the oral mucosa. However, familiarity with the spectrum of reactions to heparin allowed the patient to continue heparin therapy despite this side effect, as the eruption was not life-threatening and the benefit of continuing heparin outweighed this adverse effect.

Heparin is a naturally occurring anticoagulant and is commonly used to treat or prevent venous thrombosis or the extension of thrombosis.¹ Heparin is composed of 15-kDa chains of complex polysaccharides with repeating pentasaccharide sequences. These high-affinity pentasaccharide subunits bind and activate antithrombin III, which exerts its dominant anticoagulant effects through the inhibition of factor Xa.²

Adverse effects of heparin administration include bleeding, injection-site pain, and thrombocytopenia. Heparin-induced thrombocytopenia (HIT) is a serious side effect wherein antibodies are formed against platelet antigens and predispose the patient to venous and arterial thrombosis.³ Dermatologic adverse effects of heparin range from commonly reported injection-site eruptions to the more rarely described distant or generalized cutaneous reactions.⁴

Bullous hemorrhagic dermatosis is a poorly understood idiosyncratic drug reaction characterized by tense, blood-filled blisters that arise following the administration of subcutaneous low-molecular-weight heparin or intravenous unfractionated heparin (UFH). First reported in 2006 by Perrinaud et al,⁵ only a few case reports describing this phenomenon exist in the literature.^6-8 We report a unique case of hemorrhagic bullae limited to the oral mucosa.

Case Report

An 84-year-old man was admitted to the cardiology service with severe substernal chest pain. An electrocardiogram did not show any ST-segment elevations; however, he had elevated troponin T levels. He had a medical history of coronary artery disease complicated by myocardial infarction (MI), as well as ischemic cardiomyopathy, hypertension, hyperlipidemia, ischemic stroke, and pulmonary embolism for which he was on long-term anticoagulation for years with warfarin, aspirin, and clopidogrel. The patient was diagnosed with a non–ST-segment elevation MI. Accordingly, the patient’s warfarin was discontinued, and he was administered a bolus and continuous infusion of UFH. He also was continued on aspirin and clopidogrel. Within 6 hours of initiation of UFH, the patient noted multiple discrete swollen lesions in the mouth. Dermatology consultation and biopsy of the lesions were deferred due to acute management of the patient’s MI.

Physical examination revealed a moist oral mucosa with 7 slightly raised, hemorrhagic bullae ranging from 2 to 7 mm in diameter (Figure, A and B). One oral lesion was tense and had become denuded prior to evaluation. Laboratory testing included a normal platelet count (160,000/µL), a nearly therapeutic international normalized ratio (1.9), and a partial thromboplastin time that was initially normal (27 seconds) prior to admission and development of the oral lesions but found to be elevated (176 seconds) after admission and initial UFH bolus.

Comment

Heparin-Induced Skin Lesions
The 2 most common types of heparin-induced skin lesions are delayed-type hypersensitivity reactions and immune-mediated HIT. A 2009 Canadian study found that the overwhelming majority of heparin-induced skin lesions are due to delayed-type hypersensitivity reactions.⁴ The majority of these reactions occurred at or near the injection site on the abdomen and presented as eczematous plaques. Distant cutaneous involvement and lesions of the buccal mucosa were not as commonly reported. Female sex, obesity, and heparin treatment exceeding 9 days were identified as risk factors in the development of delayed-type hypersensitivity reactions, but our patient did not have any of these risk factors.⁴

Types of HIT
Heparin-induced thrombocytopenia is one of the most serious adverse reactions to heparin administration. There are 2 subtypes of HIT, which differ in their clinical significance and pathophysiology.⁹ Type I HIT is a non–immune-mediated reaction that results from the direct effect of heparin on platelets, which causes platelet aggregation and thrombocytopenia. It presents within the first 2 days after heparin exposure.

Type II HIT is an immune-mediated response caused by the formation of IgG autoantibodies against the heparin–platelet factor 4 complex. Antibody formation and thrombocytopenia typically occur after 4 to 10 days of heparin exposure, and there can be devastating arterial and venous thrombotic complications.

Diagnosis of HIT
Heparin-induced thrombocytopenia should be suspected in patients with a lowered platelet count, particularly if the decrease is more than 50% from baseline, and in patients who develop stroke, MI, pulmonary embolism, or deep vein thrombosis while on heparin. Heparin-induced thrombocytopenia was not observed in our patient, as his platelet count remained stable between 160,000 and 164,000/µL throughout his hospital stay and he did not develop any evidence of thrombosis.

Differential Diagnosis
Our patient’s lesions appeared morphologically similar to angina bullosa haemorrhagica, but this condition was less likely based on other clinical features. Typically, angina bullosa haemorrhagica appears as a solitary, blood-filled blister due to oral mucosal trauma from the ingestion of hard or abrasive food.¹⁰ Angina bullosa haemorrhagica most often is located on the soft palate because of its susceptibility to injury during mastication, and this lesion tends to be painful.¹¹ In contrast, our patient developed 7 painless lesions on the buccal mucosa, sparing the soft palate, and without any history of preceding trauma.

Bullous pemphigoid also was considered given the presence of tense bullae in an elderly patient. However, the rapid and spontaneous resolution of these lesions with complete lack of skin involvement made this diagnosis less likely.¹²

Heparin-Induced Bullous Hemorrhagic Dermatosis
Because our patient described a similar reaction while taking enoxaparin in the past, this case represents an idiosyncratic drug reaction, possibly from antibodies to a heparin-antigen complex. Heparin-induced bullous hemorrhagic dermatosis is a rarely reported condition with the majority of lesions presenting on the extremities.

Conclusion

We describe a rare side effect of heparin therapy characterized by discrete blisters on the oral mucosa. However, familiarity with the spectrum of reactions to heparin allowed the patient to continue heparin therapy despite this side effect, as the eruption was not life-threatening and the benefit of continuing heparin outweighed this adverse effect.

Heparin is a naturally occurring anticoagulant and is commonly used to treat or prevent venous thrombosis or the extension of thrombosis.¹ Heparin is composed of 15-kDa chains of complex polysaccharides with repeating pentasaccharide sequences. These high-affinity pentasaccharide subunits bind and activate antithrombin III, which exerts its dominant anticoagulant effects through the inhibition of factor Xa.²

Adverse effects of heparin administration include bleeding, injection-site pain, and thrombocytopenia. Heparin-induced thrombocytopenia (HIT) is a serious side effect wherein antibodies are formed against platelet antigens and predispose the patient to venous and arterial thrombosis.³ Dermatologic adverse effects of heparin range from commonly reported injection-site eruptions to the more rarely described distant or generalized cutaneous reactions.⁴

Bullous hemorrhagic dermatosis is a poorly understood idiosyncratic drug reaction characterized by tense, blood-filled blisters that arise following the administration of subcutaneous low-molecular-weight heparin or intravenous unfractionated heparin (UFH). First reported in 2006 by Perrinaud et al,⁵ only a few case reports describing this phenomenon exist in the literature.^6-8 We report a unique case of hemorrhagic bullae limited to the oral mucosa.

Case Report

An 84-year-old man was admitted to the cardiology service with severe substernal chest pain. An electrocardiogram did not show any ST-segment elevations; however, he had elevated troponin T levels. He had a medical history of coronary artery disease complicated by myocardial infarction (MI), as well as ischemic cardiomyopathy, hypertension, hyperlipidemia, ischemic stroke, and pulmonary embolism for which he was on long-term anticoagulation for years with warfarin, aspirin, and clopidogrel. The patient was diagnosed with a non–ST-segment elevation MI. Accordingly, the patient’s warfarin was discontinued, and he was administered a bolus and continuous infusion of UFH. He also was continued on aspirin and clopidogrel. Within 6 hours of initiation of UFH, the patient noted multiple discrete swollen lesions in the mouth. Dermatology consultation and biopsy of the lesions were deferred due to acute management of the patient’s MI.

Physical examination revealed a moist oral mucosa with 7 slightly raised, hemorrhagic bullae ranging from 2 to 7 mm in diameter (Figure, A and B). One oral lesion was tense and had become denuded prior to evaluation. Laboratory testing included a normal platelet count (160,000/µL), a nearly therapeutic international normalized ratio (1.9), and a partial thromboplastin time that was initially normal (27 seconds) prior to admission and development of the oral lesions but found to be elevated (176 seconds) after admission and initial UFH bolus.

Comment

Heparin-Induced Skin Lesions
The 2 most common types of heparin-induced skin lesions are delayed-type hypersensitivity reactions and immune-mediated HIT. A 2009 Canadian study found that the overwhelming majority of heparin-induced skin lesions are due to delayed-type hypersensitivity reactions.⁴ The majority of these reactions occurred at or near the injection site on the abdomen and presented as eczematous plaques. Distant cutaneous involvement and lesions of the buccal mucosa were not as commonly reported. Female sex, obesity, and heparin treatment exceeding 9 days were identified as risk factors in the development of delayed-type hypersensitivity reactions, but our patient did not have any of these risk factors.⁴

Types of HIT
Heparin-induced thrombocytopenia is one of the most serious adverse reactions to heparin administration. There are 2 subtypes of HIT, which differ in their clinical significance and pathophysiology.⁹ Type I HIT is a non–immune-mediated reaction that results from the direct effect of heparin on platelets, which causes platelet aggregation and thrombocytopenia. It presents within the first 2 days after heparin exposure.

Type II HIT is an immune-mediated response caused by the formation of IgG autoantibodies against the heparin–platelet factor 4 complex. Antibody formation and thrombocytopenia typically occur after 4 to 10 days of heparin exposure, and there can be devastating arterial and venous thrombotic complications.

Diagnosis of HIT
Heparin-induced thrombocytopenia should be suspected in patients with a lowered platelet count, particularly if the decrease is more than 50% from baseline, and in patients who develop stroke, MI, pulmonary embolism, or deep vein thrombosis while on heparin. Heparin-induced thrombocytopenia was not observed in our patient, as his platelet count remained stable between 160,000 and 164,000/µL throughout his hospital stay and he did not develop any evidence of thrombosis.

Differential Diagnosis
Our patient’s lesions appeared morphologically similar to angina bullosa haemorrhagica, but this condition was less likely based on other clinical features. Typically, angina bullosa haemorrhagica appears as a solitary, blood-filled blister due to oral mucosal trauma from the ingestion of hard or abrasive food.¹⁰ Angina bullosa haemorrhagica most often is located on the soft palate because of its susceptibility to injury during mastication, and this lesion tends to be painful.¹¹ In contrast, our patient developed 7 painless lesions on the buccal mucosa, sparing the soft palate, and without any history of preceding trauma.

Bullous pemphigoid also was considered given the presence of tense bullae in an elderly patient. However, the rapid and spontaneous resolution of these lesions with complete lack of skin involvement made this diagnosis less likely.¹²

Heparin-Induced Bullous Hemorrhagic Dermatosis
Because our patient described a similar reaction while taking enoxaparin in the past, this case represents an idiosyncratic drug reaction, possibly from antibodies to a heparin-antigen complex. Heparin-induced bullous hemorrhagic dermatosis is a rarely reported condition with the majority of lesions presenting on the extremities.

Conclusion

We describe a rare side effect of heparin therapy characterized by discrete blisters on the oral mucosa. However, familiarity with the spectrum of reactions to heparin allowed the patient to continue heparin therapy despite this side effect, as the eruption was not life-threatening and the benefit of continuing heparin outweighed this adverse effect.

In 2017, consumers spent an average of $8.53 billion on nail services.¹ This booming industry is set to grow to more than $15.5 billion by 2024.² Nail polishes and other nail cosmetic trends can present new exposures for consumers, including chemicals that can elicit allergic contact dermatitis. In this article, we discuss new nail trends and their associated allergens, the acrylates.

Tosylamide/Formaldehyde Resin

Traditionally, the most widely recognized nail polish allergen has been tosylamide/formaldehyde resin (TSFR). However, there now are many touted TSFR-free nail polishes on the market, and the rate of positive reactions to this chemical has been declining in recent years. The North American Contact Dermatitis Group reported a positive reaction rate of 1.3% from 2005 through 2006,³ and rates decreased to 0.9% from 2015 through 2016.⁴ An Australian study demonstrated a similar reduction in positive reaction rates to nail polish chemicals, with only 0.7% of patients reacting to TSFR from 2014 to 2016 and 0% in 2017. It is theorized that this reduction occurred from replacing TSFR in traditional nail polishes with other chemicals such as polyester resins and cellulose acetate butyrate.⁵

Acrylate-Based Nail Treatments

Consumers recently have been gravitating toward acrylate-based nail treatments vs traditional nail polishes for a variety of reasons. Often referred to as gels, dips, or shellac, acrylate-based nail treatments represent a hot new trend in nail cosmetics. These manicures are resistant to chipping and scratches, creating a like-new look that lasts for weeks after application. The long-lasting nature of acrylate-based nail polishes has made them wildly popular with consumers.

Traditional acrylic nails consist of a powder polymer mixed with a liquid monomer, which polymerizes when a catalyst is added.⁶ The procedure is time consuming and can take up to 2 hours for application. In contrast, the newer gel manicure can be completed faster and includes application of acrylate-based nail polish, including a base coat, 2 coats of color, and a top coat. Exposure to either a light-emitting diode (30–60 seconds) or UVA (2 minutes) lamp is necessary after each coat is applied for polymerization (Figure 1).⁶ This long-lasting, semipermanent manicure typically is what patients are referring to when they say they have “gel nails.”

Acrylate Allergy

Patients who are allergic to acrylates can present with different patterns of dermatitis. Although the majority of patients present with dermatitis on the hands, fingers, or wrists, up to 10% may only have facial and neck dermatitis.⁸ Less commonly, the abdomen and thighs can be involved.^6,8 Nail technicians most commonly present with pulpitis with cutaneous fissures.⁸ Other symptoms can include subungual hyperkeratosis, onycholysis, and nail dystrophy. Paresthesia, urticaria, and upper respiratory tract symptoms can occur but are less common.^6,8

Acrylate allergy typically is the result of sensitization to the acrylate monomers. In theory, gel nail acrylate materials are polymerized following exposure to a light-emitting diode or UVA lamp; however, there likely is some incomplete polymerization, which can increase the risk for development of allergy. Allergen exposure can occur due to incorrect application of the light source; inadvertent monomer exposure, which occurs when nail technicians wipe extra acrylate off of a client’s finger(s); or inadvertent application of acrylate monomers to objects in the nail technician’s work environment.^6,8

Several acrylate nail allergens have been reported. Many studies have identified 2-hydroxyethyl methacrylate (HEMA) as the most common nail acrylate allergen.^8,9 At least one study identified 2-hydroxypropyl methacrylate as the most common, with HEMA in second place.⁶ Other reported acrylate allergens have included ethylene glycol dimethacrylate, triethylene glycol dimethacrylate, methyl methacrylate, ethyl cyanoacrylate, 1,4-butanediol diacrylate, hydroxypropyl acrylate, and 2-hydroxyethyl acrylate.^8,9

The American Contact Dermatitis Society Core Allergen Series and the North American Contact Dermatitis Group screening series currently include HEMA, methyl methacrylate, ethyl acrylate, ethyl cyanoacrylate, and TSFR.^4,10 Of note, acrylates are not included in the thin-layer rapid use epicutaneous (T.R.U.E.) patch test (SmartPractice), so they will be missed if this series is used.¹¹ In the setting of suspected nail acrylate allergy, some authors recommend initial screening with HEMA and ethyl cyanoacrylate, with extended acrylate testing if both are negative.⁸

Upon patch testing with an acrylate series, patients frequently react to 2 or more acrylates and the reactions can be strong (++) or extreme (+++), which may represent cosensitization or cross-sensitization.⁸ The likelihood of cross-reactivity between acrylates is not clear, though it has been postulated that it is theoretically possible.⁶

An important pearl for patch testers using the chamber method is proper storage of acrylate allergens and assembly of trays prior to patch testing. Similar to all haptens, manufacturers recommend that acrylates should be stored in a refrigerator, but some authors suggest that acrylates should be stored in the freezer.¹² Acrylates are volatile chemicals and rapidly degrade when exposed to air. A methyl methacrylate preparation loaded into an inert quadrate (IQ) chamber and stored at room temperature showed a nearly undetectable amount of any residual methyl methacrylate 24 hours later. Refrigeration of allergens in chambers slowed but did not stop eventual degradation, with nearly all acrylate preparations reaching an undetectable level of allergen by day 8.¹³ Acrylates, along with other volatile allergens, should only be loaded into chambers immediately prior to placement on the patient.

Allergy Prevention

Prevention of nail acrylate allergy among consumers is simple: avoid contact with the offending allergen. Acrylate spillover (ie, applying the acrylate onto the skin) and direct contact with objects and working surfaces contaminated with acrylate-based nail products should be avoided.⁸ Avoidance is more complicated for nail technicians, but it is thought that nitrile gloves allow for the best dexterity and allergen avoidance when acrylate exposure is brief.¹⁴ Allowable exposure times with nitrile gloves may be 15 to 30 minutes. After this times passes, a glove change is required to avoid exposure.¹⁴ Wearing nitrile gloves for longer than 15 to 30 minutes will result in cutaneous exposure and risk for dermatitis in sensitized patients. If longer wear is desired, one option includes cutting the fingertips off of Silver Shield/4H gloves (Honeywell Safety Products USA, Inc), applying them to the distal fingers, and wearing a standard nitrile glove over top, known as the finger stall technique.⁶ In one study, this technique was recommended to nail technicians with acrylate allergy. A telephone survey conducted 4 to 43 months later confirmed that 36% (8/22) of participants were using the technique without symptoms. In this same study, 73% (16/22) had continued working as nail technicians.⁶

Acrylates are used for other medical purposes, including dental procedures, orthopedic procedures, surgical glues, wound dressings, and contact and intraocular lenses. They also have additional cosmetic applications, including eyelash and hair extensions.⁸ Therefore, it is vital that patients disclose any history of acrylate allergy to both their medical and cosmetic providers.

Our Final Interpretation

Acrylate allergy has become increasingly common, and long-lasting nail treatments often are the culprit. Whether through gels, dips, or shellac, repeated exposure to acrylates through nail treatments can increase the risk for allergy. The T.R.U.E. test alone will not make the diagnosis, as acrylates are not present in this patch test system. It is important to remind your allergic patients that acrylates are present in other compounds used for medical and cosmetic purposes. Avoidance is key, and for allergic patients who love to bedazzle their nails, we suggest less-permanent, acrylate-free nail polishes as alternatives.

In 2017, consumers spent an average of $8.53 billion on nail services.¹ This booming industry is set to grow to more than $15.5 billion by 2024.² Nail polishes and other nail cosmetic trends can present new exposures for consumers, including chemicals that can elicit allergic contact dermatitis. In this article, we discuss new nail trends and their associated allergens, the acrylates.

Tosylamide/Formaldehyde Resin

Traditionally, the most widely recognized nail polish allergen has been tosylamide/formaldehyde resin (TSFR). However, there now are many touted TSFR-free nail polishes on the market, and the rate of positive reactions to this chemical has been declining in recent years. The North American Contact Dermatitis Group reported a positive reaction rate of 1.3% from 2005 through 2006,³ and rates decreased to 0.9% from 2015 through 2016.⁴ An Australian study demonstrated a similar reduction in positive reaction rates to nail polish chemicals, with only 0.7% of patients reacting to TSFR from 2014 to 2016 and 0% in 2017. It is theorized that this reduction occurred from replacing TSFR in traditional nail polishes with other chemicals such as polyester resins and cellulose acetate butyrate.⁵

Acrylate-Based Nail Treatments

Consumers recently have been gravitating toward acrylate-based nail treatments vs traditional nail polishes for a variety of reasons. Often referred to as gels, dips, or shellac, acrylate-based nail treatments represent a hot new trend in nail cosmetics. These manicures are resistant to chipping and scratches, creating a like-new look that lasts for weeks after application. The long-lasting nature of acrylate-based nail polishes has made them wildly popular with consumers.

Traditional acrylic nails consist of a powder polymer mixed with a liquid monomer, which polymerizes when a catalyst is added.⁶ The procedure is time consuming and can take up to 2 hours for application. In contrast, the newer gel manicure can be completed faster and includes application of acrylate-based nail polish, including a base coat, 2 coats of color, and a top coat. Exposure to either a light-emitting diode (30–60 seconds) or UVA (2 minutes) lamp is necessary after each coat is applied for polymerization (Figure 1).⁶ This long-lasting, semipermanent manicure typically is what patients are referring to when they say they have “gel nails.”

Acrylate Allergy

Patients who are allergic to acrylates can present with different patterns of dermatitis. Although the majority of patients present with dermatitis on the hands, fingers, or wrists, up to 10% may only have facial and neck dermatitis.⁸ Less commonly, the abdomen and thighs can be involved.^6,8 Nail technicians most commonly present with pulpitis with cutaneous fissures.⁸ Other symptoms can include subungual hyperkeratosis, onycholysis, and nail dystrophy. Paresthesia, urticaria, and upper respiratory tract symptoms can occur but are less common.^6,8

Acrylate allergy typically is the result of sensitization to the acrylate monomers. In theory, gel nail acrylate materials are polymerized following exposure to a light-emitting diode or UVA lamp; however, there likely is some incomplete polymerization, which can increase the risk for development of allergy. Allergen exposure can occur due to incorrect application of the light source; inadvertent monomer exposure, which occurs when nail technicians wipe extra acrylate off of a client’s finger(s); or inadvertent application of acrylate monomers to objects in the nail technician’s work environment.^6,8

Several acrylate nail allergens have been reported. Many studies have identified 2-hydroxyethyl methacrylate (HEMA) as the most common nail acrylate allergen.^8,9 At least one study identified 2-hydroxypropyl methacrylate as the most common, with HEMA in second place.⁶ Other reported acrylate allergens have included ethylene glycol dimethacrylate, triethylene glycol dimethacrylate, methyl methacrylate, ethyl cyanoacrylate, 1,4-butanediol diacrylate, hydroxypropyl acrylate, and 2-hydroxyethyl acrylate.^8,9

The American Contact Dermatitis Society Core Allergen Series and the North American Contact Dermatitis Group screening series currently include HEMA, methyl methacrylate, ethyl acrylate, ethyl cyanoacrylate, and TSFR.^4,10 Of note, acrylates are not included in the thin-layer rapid use epicutaneous (T.R.U.E.) patch test (SmartPractice), so they will be missed if this series is used.¹¹ In the setting of suspected nail acrylate allergy, some authors recommend initial screening with HEMA and ethyl cyanoacrylate, with extended acrylate testing if both are negative.⁸

Upon patch testing with an acrylate series, patients frequently react to 2 or more acrylates and the reactions can be strong (++) or extreme (+++), which may represent cosensitization or cross-sensitization.⁸ The likelihood of cross-reactivity between acrylates is not clear, though it has been postulated that it is theoretically possible.⁶

An important pearl for patch testers using the chamber method is proper storage of acrylate allergens and assembly of trays prior to patch testing. Similar to all haptens, manufacturers recommend that acrylates should be stored in a refrigerator, but some authors suggest that acrylates should be stored in the freezer.¹² Acrylates are volatile chemicals and rapidly degrade when exposed to air. A methyl methacrylate preparation loaded into an inert quadrate (IQ) chamber and stored at room temperature showed a nearly undetectable amount of any residual methyl methacrylate 24 hours later. Refrigeration of allergens in chambers slowed but did not stop eventual degradation, with nearly all acrylate preparations reaching an undetectable level of allergen by day 8.¹³ Acrylates, along with other volatile allergens, should only be loaded into chambers immediately prior to placement on the patient.

Allergy Prevention

Prevention of nail acrylate allergy among consumers is simple: avoid contact with the offending allergen. Acrylate spillover (ie, applying the acrylate onto the skin) and direct contact with objects and working surfaces contaminated with acrylate-based nail products should be avoided.⁸ Avoidance is more complicated for nail technicians, but it is thought that nitrile gloves allow for the best dexterity and allergen avoidance when acrylate exposure is brief.¹⁴ Allowable exposure times with nitrile gloves may be 15 to 30 minutes. After this times passes, a glove change is required to avoid exposure.¹⁴ Wearing nitrile gloves for longer than 15 to 30 minutes will result in cutaneous exposure and risk for dermatitis in sensitized patients. If longer wear is desired, one option includes cutting the fingertips off of Silver Shield/4H gloves (Honeywell Safety Products USA, Inc), applying them to the distal fingers, and wearing a standard nitrile glove over top, known as the finger stall technique.⁶ In one study, this technique was recommended to nail technicians with acrylate allergy. A telephone survey conducted 4 to 43 months later confirmed that 36% (8/22) of participants were using the technique without symptoms. In this same study, 73% (16/22) had continued working as nail technicians.⁶

Acrylates are used for other medical purposes, including dental procedures, orthopedic procedures, surgical glues, wound dressings, and contact and intraocular lenses. They also have additional cosmetic applications, including eyelash and hair extensions.⁸ Therefore, it is vital that patients disclose any history of acrylate allergy to both their medical and cosmetic providers.

Our Final Interpretation

Acrylate allergy has become increasingly common, and long-lasting nail treatments often are the culprit. Whether through gels, dips, or shellac, repeated exposure to acrylates through nail treatments can increase the risk for allergy. The T.R.U.E. test alone will not make the diagnosis, as acrylates are not present in this patch test system. It is important to remind your allergic patients that acrylates are present in other compounds used for medical and cosmetic purposes. Avoidance is key, and for allergic patients who love to bedazzle their nails, we suggest less-permanent, acrylate-free nail polishes as alternatives.

In 2017, consumers spent an average of $8.53 billion on nail services.¹ This booming industry is set to grow to more than $15.5 billion by 2024.² Nail polishes and other nail cosmetic trends can present new exposures for consumers, including chemicals that can elicit allergic contact dermatitis. In this article, we discuss new nail trends and their associated allergens, the acrylates.

Tosylamide/Formaldehyde Resin

Traditionally, the most widely recognized nail polish allergen has been tosylamide/formaldehyde resin (TSFR). However, there now are many touted TSFR-free nail polishes on the market, and the rate of positive reactions to this chemical has been declining in recent years. The North American Contact Dermatitis Group reported a positive reaction rate of 1.3% from 2005 through 2006,³ and rates decreased to 0.9% from 2015 through 2016.⁴ An Australian study demonstrated a similar reduction in positive reaction rates to nail polish chemicals, with only 0.7% of patients reacting to TSFR from 2014 to 2016 and 0% in 2017. It is theorized that this reduction occurred from replacing TSFR in traditional nail polishes with other chemicals such as polyester resins and cellulose acetate butyrate.⁵

Acrylate-Based Nail Treatments

Consumers recently have been gravitating toward acrylate-based nail treatments vs traditional nail polishes for a variety of reasons. Often referred to as gels, dips, or shellac, acrylate-based nail treatments represent a hot new trend in nail cosmetics. These manicures are resistant to chipping and scratches, creating a like-new look that lasts for weeks after application. The long-lasting nature of acrylate-based nail polishes has made them wildly popular with consumers.

Traditional acrylic nails consist of a powder polymer mixed with a liquid monomer, which polymerizes when a catalyst is added.⁶ The procedure is time consuming and can take up to 2 hours for application. In contrast, the newer gel manicure can be completed faster and includes application of acrylate-based nail polish, including a base coat, 2 coats of color, and a top coat. Exposure to either a light-emitting diode (30–60 seconds) or UVA (2 minutes) lamp is necessary after each coat is applied for polymerization (Figure 1).⁶ This long-lasting, semipermanent manicure typically is what patients are referring to when they say they have “gel nails.”

Acrylate Allergy

Patients who are allergic to acrylates can present with different patterns of dermatitis. Although the majority of patients present with dermatitis on the hands, fingers, or wrists, up to 10% may only have facial and neck dermatitis.⁸ Less commonly, the abdomen and thighs can be involved.^6,8 Nail technicians most commonly present with pulpitis with cutaneous fissures.⁸ Other symptoms can include subungual hyperkeratosis, onycholysis, and nail dystrophy. Paresthesia, urticaria, and upper respiratory tract symptoms can occur but are less common.^6,8

Acrylate allergy typically is the result of sensitization to the acrylate monomers. In theory, gel nail acrylate materials are polymerized following exposure to a light-emitting diode or UVA lamp; however, there likely is some incomplete polymerization, which can increase the risk for development of allergy. Allergen exposure can occur due to incorrect application of the light source; inadvertent monomer exposure, which occurs when nail technicians wipe extra acrylate off of a client’s finger(s); or inadvertent application of acrylate monomers to objects in the nail technician’s work environment.^6,8

Several acrylate nail allergens have been reported. Many studies have identified 2-hydroxyethyl methacrylate (HEMA) as the most common nail acrylate allergen.^8,9 At least one study identified 2-hydroxypropyl methacrylate as the most common, with HEMA in second place.⁶ Other reported acrylate allergens have included ethylene glycol dimethacrylate, triethylene glycol dimethacrylate, methyl methacrylate, ethyl cyanoacrylate, 1,4-butanediol diacrylate, hydroxypropyl acrylate, and 2-hydroxyethyl acrylate.^8,9

The American Contact Dermatitis Society Core Allergen Series and the North American Contact Dermatitis Group screening series currently include HEMA, methyl methacrylate, ethyl acrylate, ethyl cyanoacrylate, and TSFR.^4,10 Of note, acrylates are not included in the thin-layer rapid use epicutaneous (T.R.U.E.) patch test (SmartPractice), so they will be missed if this series is used.¹¹ In the setting of suspected nail acrylate allergy, some authors recommend initial screening with HEMA and ethyl cyanoacrylate, with extended acrylate testing if both are negative.⁸

Upon patch testing with an acrylate series, patients frequently react to 2 or more acrylates and the reactions can be strong (++) or extreme (+++), which may represent cosensitization or cross-sensitization.⁸ The likelihood of cross-reactivity between acrylates is not clear, though it has been postulated that it is theoretically possible.⁶

An important pearl for patch testers using the chamber method is proper storage of acrylate allergens and assembly of trays prior to patch testing. Similar to all haptens, manufacturers recommend that acrylates should be stored in a refrigerator, but some authors suggest that acrylates should be stored in the freezer.¹² Acrylates are volatile chemicals and rapidly degrade when exposed to air. A methyl methacrylate preparation loaded into an inert quadrate (IQ) chamber and stored at room temperature showed a nearly undetectable amount of any residual methyl methacrylate 24 hours later. Refrigeration of allergens in chambers slowed but did not stop eventual degradation, with nearly all acrylate preparations reaching an undetectable level of allergen by day 8.¹³ Acrylates, along with other volatile allergens, should only be loaded into chambers immediately prior to placement on the patient.

Allergy Prevention

Prevention of nail acrylate allergy among consumers is simple: avoid contact with the offending allergen. Acrylate spillover (ie, applying the acrylate onto the skin) and direct contact with objects and working surfaces contaminated with acrylate-based nail products should be avoided.⁸ Avoidance is more complicated for nail technicians, but it is thought that nitrile gloves allow for the best dexterity and allergen avoidance when acrylate exposure is brief.¹⁴ Allowable exposure times with nitrile gloves may be 15 to 30 minutes. After this times passes, a glove change is required to avoid exposure.¹⁴ Wearing nitrile gloves for longer than 15 to 30 minutes will result in cutaneous exposure and risk for dermatitis in sensitized patients. If longer wear is desired, one option includes cutting the fingertips off of Silver Shield/4H gloves (Honeywell Safety Products USA, Inc), applying them to the distal fingers, and wearing a standard nitrile glove over top, known as the finger stall technique.⁶ In one study, this technique was recommended to nail technicians with acrylate allergy. A telephone survey conducted 4 to 43 months later confirmed that 36% (8/22) of participants were using the technique without symptoms. In this same study, 73% (16/22) had continued working as nail technicians.⁶

Acrylates are used for other medical purposes, including dental procedures, orthopedic procedures, surgical glues, wound dressings, and contact and intraocular lenses. They also have additional cosmetic applications, including eyelash and hair extensions.⁸ Therefore, it is vital that patients disclose any history of acrylate allergy to both their medical and cosmetic providers.

Our Final Interpretation

Acrylate allergy has become increasingly common, and long-lasting nail treatments often are the culprit. Whether through gels, dips, or shellac, repeated exposure to acrylates through nail treatments can increase the risk for allergy. The T.R.U.E. test alone will not make the diagnosis, as acrylates are not present in this patch test system. It is important to remind your allergic patients that acrylates are present in other compounds used for medical and cosmetic purposes. Avoidance is key, and for allergic patients who love to bedazzle their nails, we suggest less-permanent, acrylate-free nail polishes as alternatives.

The viscous homemade children’s plaything known as “slime” has been associated with allergic, as well as irritant, contact dermatitis of the hands thanks to an array of possible compounds with which it can be made, according to a case report in Pediatric Dermatology. The report details many possible compounds causing the dermatitis reactions seen by health care professionals.

In the case, which was reported by L. Elizabeth Anderson, MD, of the Children’s Hospital of Philadelphia and colleagues, an 11-year-old girl with a history of atopic dermatitis presented with hand dermatitis that was suspected to be related to playing with slime. After her dermatitis failed to respond to strong topical steroids, she was referred for patch testing, with positivity for methylchloroisothiazolinone/methylisothiazolinone (MCI/MI). After all contact with any products containing MCI/MI was eliminated, her hand dermatitis cleared, and bodywide atopic dermatitis improved some as well.

MCI/MI and MI are among the most commonly suspected culprits in cases of slime-related contact dermatitis. Although most cases are irritant contact dermatitis, some are allergic and can be detected using patch tests. MCI/MI is included in the T.R.U.E. Test, but according to the case report, 37% of patients with allergy to MI alone will not have positive response with the T.R.U.E. Test because of the low concentrations of MI in that test. The authors of this case report also listed many other the potential allergens in popular slime recipes; however, many are not included in the T.R.U.E. Test.

“While the T.R.U.E. Test does not capture most of the potential allergens in popular slime recipes, the recently published Pediatric Baseline Patch Test Series by Yu et al. [Dermatitis. 2018;29:206-12] does and is recommended for use in patients suspected of having dermatitis secondary to slime,” Dr. Anderson and associates wrote.

cpalmer@mdedge.com

SOURCE: Anderson LE et al. Pediatr Dermatol. 2019 Mar 13. doi: 10.1111/pde.13792.

The viscous homemade children’s plaything known as “slime” has been associated with allergic, as well as irritant, contact dermatitis of the hands thanks to an array of possible compounds with which it can be made, according to a case report in Pediatric Dermatology. The report details many possible compounds causing the dermatitis reactions seen by health care professionals.

In the case, which was reported by L. Elizabeth Anderson, MD, of the Children’s Hospital of Philadelphia and colleagues, an 11-year-old girl with a history of atopic dermatitis presented with hand dermatitis that was suspected to be related to playing with slime. After her dermatitis failed to respond to strong topical steroids, she was referred for patch testing, with positivity for methylchloroisothiazolinone/methylisothiazolinone (MCI/MI). After all contact with any products containing MCI/MI was eliminated, her hand dermatitis cleared, and bodywide atopic dermatitis improved some as well.

MCI/MI and MI are among the most commonly suspected culprits in cases of slime-related contact dermatitis. Although most cases are irritant contact dermatitis, some are allergic and can be detected using patch tests. MCI/MI is included in the T.R.U.E. Test, but according to the case report, 37% of patients with allergy to MI alone will not have positive response with the T.R.U.E. Test because of the low concentrations of MI in that test. The authors of this case report also listed many other the potential allergens in popular slime recipes; however, many are not included in the T.R.U.E. Test.

“While the T.R.U.E. Test does not capture most of the potential allergens in popular slime recipes, the recently published Pediatric Baseline Patch Test Series by Yu et al. [Dermatitis. 2018;29:206-12] does and is recommended for use in patients suspected of having dermatitis secondary to slime,” Dr. Anderson and associates wrote.

cpalmer@mdedge.com

SOURCE: Anderson LE et al. Pediatr Dermatol. 2019 Mar 13. doi: 10.1111/pde.13792.

The viscous homemade children’s plaything known as “slime” has been associated with allergic, as well as irritant, contact dermatitis of the hands thanks to an array of possible compounds with which it can be made, according to a case report in Pediatric Dermatology. The report details many possible compounds causing the dermatitis reactions seen by health care professionals.

In the case, which was reported by L. Elizabeth Anderson, MD, of the Children’s Hospital of Philadelphia and colleagues, an 11-year-old girl with a history of atopic dermatitis presented with hand dermatitis that was suspected to be related to playing with slime. After her dermatitis failed to respond to strong topical steroids, she was referred for patch testing, with positivity for methylchloroisothiazolinone/methylisothiazolinone (MCI/MI). After all contact with any products containing MCI/MI was eliminated, her hand dermatitis cleared, and bodywide atopic dermatitis improved some as well.

MCI/MI and MI are among the most commonly suspected culprits in cases of slime-related contact dermatitis. Although most cases are irritant contact dermatitis, some are allergic and can be detected using patch tests. MCI/MI is included in the T.R.U.E. Test, but according to the case report, 37% of patients with allergy to MI alone will not have positive response with the T.R.U.E. Test because of the low concentrations of MI in that test. The authors of this case report also listed many other the potential allergens in popular slime recipes; however, many are not included in the T.R.U.E. Test.

“While the T.R.U.E. Test does not capture most of the potential allergens in popular slime recipes, the recently published Pediatric Baseline Patch Test Series by Yu et al. [Dermatitis. 2018;29:206-12] does and is recommended for use in patients suspected of having dermatitis secondary to slime,” Dr. Anderson and associates wrote.

cpalmer@mdedge.com

SOURCE: Anderson LE et al. Pediatr Dermatol. 2019 Mar 13. doi: 10.1111/pde.13792.

To the Editor:

A 68-year-old white man presented with a firm, gradually enlarging, mildly tender, grayish black papule with central ulceration on the left dorsal wrist of 4 months’ duration (Figure 1). His relevant medical history included multiple basal cell carcinomas (BCCs) and squamous cell carcinomas, as well as a single-lung transplant 2 years prior, for which he was on chronic immunosuppressive therapy with azathioprine, everolimus, tacrolimus, and prednisone. The clinical differential diagnosis included pigmented BCC, malignant melanoma, and ulcerated squamous cell carcinoma.

Histologic examination of the lesion (Figure 2) demonstrated irregular nodules of basaloid tumor cells with rounded nuclei, visible nucleoli, and scant cytoplasm involving the dermis. The tumor produced abrupt matrical-type keratinization, forming ghost cells. The lesion also contained frequent mitotic figures, apoptotic cells, focal areas of necrosis, and abundant melanin pigment. Admixed throughout the lesion were pigmented and dendritic melanocytic cells. The overlying epidermis was focally ulcerated with an adjacent localized connection between the tumor and the epidermis. Keratinocyte atypia was found in the surrounding epidermis, which contained melanophages, solar elastosis, and scattered chronic inflammatory cells. An immunohistochemical study (Figure 3) for tyrosinase demonstrated abundant admixed melanocytic cells. β-Catenin expression was shown in both nuclear and cytoplasmic distributions, and there was focal labeling on BerEP4 staining. Based on these findings, a diagnosis of melanocytic matrical carcinoma (MMC) was made.

Melanocytic matricoma (MM), a rare adnexal tumor, was first described in 1999 by Carlson et al.¹ A PubMed search of articles indexed for MEDLINE using the terms melanocytic and matricoma yielded 24 reported cases in the English-language literature.^1-17 It consists of an admixed population of basaloid matrical and supramatrical cells, ghost cells, and dendritic melanocytes in a well-circumscribed dermal nodule, typically without epidermal or adnexal connection. In comparison to the more commonly described pilomatricoma, which can be uncommonly pigmented, MM typically has only focal areas of ghost cells and lacks cystic architecture.^1,9,10,18 A granulomatous reaction to keratinaceous debris is variably present.^1,9,10 Histologically, the scattered dendritic melanocytes are classically benign, but cases demonstrating melanocyte atypia have been reported.^10,13 Melanocytic matricoma appears most commonly as a black or gray papule on sun-damaged skin in older men and tends not to recur following complete excision; thus, MM is considered to be a clinically benign neoplasm. Given the demographics and distribution of the lesions, exposure to UV radiation is thought to play a contributory role in the pathogenesis.^2,10,19 Melanocytic matricoma is believed to recapitulate the hair follicle in the anagen phase, where there is close interplay between matrical keratinocytes and melanocytes prior to cessation of melanogenesis during the catagen phase.^5,6,8,20,21 Evidence demonstrating highly conserved β-catenin and downstream lymphoid enhancer binding factor 1 (LEF1) expression, as well as pleckstrin homology-like domain, family A, member 1 (PHLDA1) expression (as a marker for follicular stem cells), points to constitutive activity in the Wnt signaling pathway in follicular stem cells of the bulge area as a major agent of tumorigenesis.¹²

Melanocytic matrical carcinoma, also known as malignant MM or matrical carcinoma with melanocytic hyperplasia, may be considered the malignant counterpart to MM.²² A PubMed search of articles indexed for MEDLINE using the terms melanocytic matrical carcinoma, malignant melanocytic matricoma, and matrical carcinoma with melanocytic hyperplasia, with review of references to identify additional citations, yielded 13 reported cases of MMC in the English-language literature (Table).^19,22-30 As with MM, MMC is a biphasic tumor with basaloid matrical and supramatrical cells; focal areas of ghost cells; and admixed, banal-appearing dendritic melanocytes. However, the basaloid component also demonstrates nuclear atypia, mitoses, occasional ulceration, and variably poor circumscription. Clinically these lesions can mimic pigmented BCC, malignant melanoma, or other malignant adnexal tumors.²⁵ Their natural history is unknown due to few reported cases, but they can be correlated with matrical carcinomas, which were first described by Weedon et al³¹ in 1980. A summary of more than 130 cases of matrical carcinomas in the English-language literature found that MMCs have high rates of local recurrence and metastasize in approximately 13% of cases. Wide local excision demonstrated lower rates of recurrence than simple excision (23% vs 83%), but there were insufficient cases to determine the incidence following Mohs micrographic surgery.³² Melanocytic matrical carcinomas also demonstrate mutations in the β-catenin pathway,pointing to a similar pathogenesis as their benign counterparts or perhaps direct malignant transformation.^25,33,34

A subset of MMCs are combined cutaneous tumors (CCTs) consisting of epithelial neoplasms in close association with malignant melanocytes. Two of the more common variants include dermal squamomelanocytic tumors, a term first used by Pool et al,³⁵ and malignant basomelanocytic tumors, as named by Erickson et al,³⁶ but trichoblastomelanomas and other types have been documented.³⁷ Although CCTs typically occur in the same patient populations as MMCs, namely elderly white men with chronically sun-damaged skin,they exhibit several important distinctions.^37-39 By definition, CCTs have a malignant melanocytic component, whereas melanocytes are nonneoplastic in MMCs. The pathogenesis may differ as well. Various mechanisms for the close association of epithelial tumors and melanoma have been proposed, including field cancerization, tumor collision, tumor-tumor metastases, tumor colonization, and others, though CCTs likely arise through combinations of these processes depending upon their subtype.^37-39 Paracrine signaling may play an important role in the pathogenesis of both tumors.^5,6,8,38 As with MMCs, the prognosis of CCTs is limited by relatively few reported cases. Despite advanced Breslow depths in many cases, these tumors display more indolent behavior suggestive of melanoma in situ rather than invasive melanoma, perhaps due to dependence upon epithelial paracrine factors.^37,39-42

Solid-organ transplant recipients have higher rates of more aggressive malignancies, of which skin cancer is the most common.^43-49 Squamous cell carcinoma of the skin accounts for 95% of cutaneous malignancies in this population and occurs at approximately 65 times the rate of the general population.⁵⁰ The risk of other skin cancers also is increased, though less dramatically, including BCC (10-fold increased risk) and melanoma (2- to 8-fold increased risk).^46,50-53 The cause likely is multifactorial, including older age, history of skin cancer pretransplant, more than 5 years posttransplant, male sex, and incrementally as Fitzpatrick skin type decreases from VI to I.^54-56 Immunosuppressive therapy also plays a role in tumorigenesis. Azathioprine metabolites have specifically been implicated in UVA radiation–induced promutagenic oxidative damage to DNA.⁵⁷ Other studies have found no significant differences in the type of immunosuppressant used but instead have correlated rates of skin cancer to overall immunosuppression.^48,55,58 Lung transplant recipients in particular demonstrate high rates of cutaneous malignancy, likely due in part to the necessity of more potent immunosuppressive regimens. Nearly one-third of patients develop a cutaneous malignancy by 5 years and nearly half by 10 years posttransplant.⁵⁵

We report a rare case of MMC in a solid-organ transplant recipient. We hypothesize that the combination of UV radiation exposure–induced photodamage acquired pretransplant in addition to an aggressive immunosuppressive regimen with azathioprine and other agents posttransplant contributed to the development of this patient’s rare malignancy. Although rare, these tumors should remain in the differential diagnosis of clinicians and pathologists caring for this unique patient population.

To the Editor:

A 68-year-old white man presented with a firm, gradually enlarging, mildly tender, grayish black papule with central ulceration on the left dorsal wrist of 4 months’ duration (Figure 1). His relevant medical history included multiple basal cell carcinomas (BCCs) and squamous cell carcinomas, as well as a single-lung transplant 2 years prior, for which he was on chronic immunosuppressive therapy with azathioprine, everolimus, tacrolimus, and prednisone. The clinical differential diagnosis included pigmented BCC, malignant melanoma, and ulcerated squamous cell carcinoma.

Histologic examination of the lesion (Figure 2) demonstrated irregular nodules of basaloid tumor cells with rounded nuclei, visible nucleoli, and scant cytoplasm involving the dermis. The tumor produced abrupt matrical-type keratinization, forming ghost cells. The lesion also contained frequent mitotic figures, apoptotic cells, focal areas of necrosis, and abundant melanin pigment. Admixed throughout the lesion were pigmented and dendritic melanocytic cells. The overlying epidermis was focally ulcerated with an adjacent localized connection between the tumor and the epidermis. Keratinocyte atypia was found in the surrounding epidermis, which contained melanophages, solar elastosis, and scattered chronic inflammatory cells. An immunohistochemical study (Figure 3) for tyrosinase demonstrated abundant admixed melanocytic cells. β-Catenin expression was shown in both nuclear and cytoplasmic distributions, and there was focal labeling on BerEP4 staining. Based on these findings, a diagnosis of melanocytic matrical carcinoma (MMC) was made.

Melanocytic matricoma (MM), a rare adnexal tumor, was first described in 1999 by Carlson et al.¹ A PubMed search of articles indexed for MEDLINE using the terms melanocytic and matricoma yielded 24 reported cases in the English-language literature.^1-17 It consists of an admixed population of basaloid matrical and supramatrical cells, ghost cells, and dendritic melanocytes in a well-circumscribed dermal nodule, typically without epidermal or adnexal connection. In comparison to the more commonly described pilomatricoma, which can be uncommonly pigmented, MM typically has only focal areas of ghost cells and lacks cystic architecture.^1,9,10,18 A granulomatous reaction to keratinaceous debris is variably present.^1,9,10 Histologically, the scattered dendritic melanocytes are classically benign, but cases demonstrating melanocyte atypia have been reported.^10,13 Melanocytic matricoma appears most commonly as a black or gray papule on sun-damaged skin in older men and tends not to recur following complete excision; thus, MM is considered to be a clinically benign neoplasm. Given the demographics and distribution of the lesions, exposure to UV radiation is thought to play a contributory role in the pathogenesis.^2,10,19 Melanocytic matricoma is believed to recapitulate the hair follicle in the anagen phase, where there is close interplay between matrical keratinocytes and melanocytes prior to cessation of melanogenesis during the catagen phase.^5,6,8,20,21 Evidence demonstrating highly conserved β-catenin and downstream lymphoid enhancer binding factor 1 (LEF1) expression, as well as pleckstrin homology-like domain, family A, member 1 (PHLDA1) expression (as a marker for follicular stem cells), points to constitutive activity in the Wnt signaling pathway in follicular stem cells of the bulge area as a major agent of tumorigenesis.¹²

Melanocytic matrical carcinoma, also known as malignant MM or matrical carcinoma with melanocytic hyperplasia, may be considered the malignant counterpart to MM.²² A PubMed search of articles indexed for MEDLINE using the terms melanocytic matrical carcinoma, malignant melanocytic matricoma, and matrical carcinoma with melanocytic hyperplasia, with review of references to identify additional citations, yielded 13 reported cases of MMC in the English-language literature (Table).^19,22-30 As with MM, MMC is a biphasic tumor with basaloid matrical and supramatrical cells; focal areas of ghost cells; and admixed, banal-appearing dendritic melanocytes. However, the basaloid component also demonstrates nuclear atypia, mitoses, occasional ulceration, and variably poor circumscription. Clinically these lesions can mimic pigmented BCC, malignant melanoma, or other malignant adnexal tumors.²⁵ Their natural history is unknown due to few reported cases, but they can be correlated with matrical carcinomas, which were first described by Weedon et al³¹ in 1980. A summary of more than 130 cases of matrical carcinomas in the English-language literature found that MMCs have high rates of local recurrence and metastasize in approximately 13% of cases. Wide local excision demonstrated lower rates of recurrence than simple excision (23% vs 83%), but there were insufficient cases to determine the incidence following Mohs micrographic surgery.³² Melanocytic matrical carcinomas also demonstrate mutations in the β-catenin pathway,pointing to a similar pathogenesis as their benign counterparts or perhaps direct malignant transformation.^25,33,34

A subset of MMCs are combined cutaneous tumors (CCTs) consisting of epithelial neoplasms in close association with malignant melanocytes. Two of the more common variants include dermal squamomelanocytic tumors, a term first used by Pool et al,³⁵ and malignant basomelanocytic tumors, as named by Erickson et al,³⁶ but trichoblastomelanomas and other types have been documented.³⁷ Although CCTs typically occur in the same patient populations as MMCs, namely elderly white men with chronically sun-damaged skin,they exhibit several important distinctions.^37-39 By definition, CCTs have a malignant melanocytic component, whereas melanocytes are nonneoplastic in MMCs. The pathogenesis may differ as well. Various mechanisms for the close association of epithelial tumors and melanoma have been proposed, including field cancerization, tumor collision, tumor-tumor metastases, tumor colonization, and others, though CCTs likely arise through combinations of these processes depending upon their subtype.^37-39 Paracrine signaling may play an important role in the pathogenesis of both tumors.^5,6,8,38 As with MMCs, the prognosis of CCTs is limited by relatively few reported cases. Despite advanced Breslow depths in many cases, these tumors display more indolent behavior suggestive of melanoma in situ rather than invasive melanoma, perhaps due to dependence upon epithelial paracrine factors.^37,39-42

Solid-organ transplant recipients have higher rates of more aggressive malignancies, of which skin cancer is the most common.^43-49 Squamous cell carcinoma of the skin accounts for 95% of cutaneous malignancies in this population and occurs at approximately 65 times the rate of the general population.⁵⁰ The risk of other skin cancers also is increased, though less dramatically, including BCC (10-fold increased risk) and melanoma (2- to 8-fold increased risk).^46,50-53 The cause likely is multifactorial, including older age, history of skin cancer pretransplant, more than 5 years posttransplant, male sex, and incrementally as Fitzpatrick skin type decreases from VI to I.^54-56 Immunosuppressive therapy also plays a role in tumorigenesis. Azathioprine metabolites have specifically been implicated in UVA radiation–induced promutagenic oxidative damage to DNA.⁵⁷ Other studies have found no significant differences in the type of immunosuppressant used but instead have correlated rates of skin cancer to overall immunosuppression.^48,55,58 Lung transplant recipients in particular demonstrate high rates of cutaneous malignancy, likely due in part to the necessity of more potent immunosuppressive regimens. Nearly one-third of patients develop a cutaneous malignancy by 5 years and nearly half by 10 years posttransplant.⁵⁵

We report a rare case of MMC in a solid-organ transplant recipient. We hypothesize that the combination of UV radiation exposure–induced photodamage acquired pretransplant in addition to an aggressive immunosuppressive regimen with azathioprine and other agents posttransplant contributed to the development of this patient’s rare malignancy. Although rare, these tumors should remain in the differential diagnosis of clinicians and pathologists caring for this unique patient population.

To the Editor:

A 68-year-old white man presented with a firm, gradually enlarging, mildly tender, grayish black papule with central ulceration on the left dorsal wrist of 4 months’ duration (Figure 1). His relevant medical history included multiple basal cell carcinomas (BCCs) and squamous cell carcinomas, as well as a single-lung transplant 2 years prior, for which he was on chronic immunosuppressive therapy with azathioprine, everolimus, tacrolimus, and prednisone. The clinical differential diagnosis included pigmented BCC, malignant melanoma, and ulcerated squamous cell carcinoma.

Histologic examination of the lesion (Figure 2) demonstrated irregular nodules of basaloid tumor cells with rounded nuclei, visible nucleoli, and scant cytoplasm involving the dermis. The tumor produced abrupt matrical-type keratinization, forming ghost cells. The lesion also contained frequent mitotic figures, apoptotic cells, focal areas of necrosis, and abundant melanin pigment. Admixed throughout the lesion were pigmented and dendritic melanocytic cells. The overlying epidermis was focally ulcerated with an adjacent localized connection between the tumor and the epidermis. Keratinocyte atypia was found in the surrounding epidermis, which contained melanophages, solar elastosis, and scattered chronic inflammatory cells. An immunohistochemical study (Figure 3) for tyrosinase demonstrated abundant admixed melanocytic cells. β-Catenin expression was shown in both nuclear and cytoplasmic distributions, and there was focal labeling on BerEP4 staining. Based on these findings, a diagnosis of melanocytic matrical carcinoma (MMC) was made.

Melanocytic matricoma (MM), a rare adnexal tumor, was first described in 1999 by Carlson et al.¹ A PubMed search of articles indexed for MEDLINE using the terms melanocytic and matricoma yielded 24 reported cases in the English-language literature.^1-17 It consists of an admixed population of basaloid matrical and supramatrical cells, ghost cells, and dendritic melanocytes in a well-circumscribed dermal nodule, typically without epidermal or adnexal connection. In comparison to the more commonly described pilomatricoma, which can be uncommonly pigmented, MM typically has only focal areas of ghost cells and lacks cystic architecture.^1,9,10,18 A granulomatous reaction to keratinaceous debris is variably present.^1,9,10 Histologically, the scattered dendritic melanocytes are classically benign, but cases demonstrating melanocyte atypia have been reported.^10,13 Melanocytic matricoma appears most commonly as a black or gray papule on sun-damaged skin in older men and tends not to recur following complete excision; thus, MM is considered to be a clinically benign neoplasm. Given the demographics and distribution of the lesions, exposure to UV radiation is thought to play a contributory role in the pathogenesis.^2,10,19 Melanocytic matricoma is believed to recapitulate the hair follicle in the anagen phase, where there is close interplay between matrical keratinocytes and melanocytes prior to cessation of melanogenesis during the catagen phase.^5,6,8,20,21 Evidence demonstrating highly conserved β-catenin and downstream lymphoid enhancer binding factor 1 (LEF1) expression, as well as pleckstrin homology-like domain, family A, member 1 (PHLDA1) expression (as a marker for follicular stem cells), points to constitutive activity in the Wnt signaling pathway in follicular stem cells of the bulge area as a major agent of tumorigenesis.¹²

Melanocytic matrical carcinoma, also known as malignant MM or matrical carcinoma with melanocytic hyperplasia, may be considered the malignant counterpart to MM.²² A PubMed search of articles indexed for MEDLINE using the terms melanocytic matrical carcinoma, malignant melanocytic matricoma, and matrical carcinoma with melanocytic hyperplasia, with review of references to identify additional citations, yielded 13 reported cases of MMC in the English-language literature (Table).^19,22-30 As with MM, MMC is a biphasic tumor with basaloid matrical and supramatrical cells; focal areas of ghost cells; and admixed, banal-appearing dendritic melanocytes. However, the basaloid component also demonstrates nuclear atypia, mitoses, occasional ulceration, and variably poor circumscription. Clinically these lesions can mimic pigmented BCC, malignant melanoma, or other malignant adnexal tumors.²⁵ Their natural history is unknown due to few reported cases, but they can be correlated with matrical carcinomas, which were first described by Weedon et al³¹ in 1980. A summary of more than 130 cases of matrical carcinomas in the English-language literature found that MMCs have high rates of local recurrence and metastasize in approximately 13% of cases. Wide local excision demonstrated lower rates of recurrence than simple excision (23% vs 83%), but there were insufficient cases to determine the incidence following Mohs micrographic surgery.³² Melanocytic matrical carcinomas also demonstrate mutations in the β-catenin pathway,pointing to a similar pathogenesis as their benign counterparts or perhaps direct malignant transformation.^25,33,34

A subset of MMCs are combined cutaneous tumors (CCTs) consisting of epithelial neoplasms in close association with malignant melanocytes. Two of the more common variants include dermal squamomelanocytic tumors, a term first used by Pool et al,³⁵ and malignant basomelanocytic tumors, as named by Erickson et al,³⁶ but trichoblastomelanomas and other types have been documented.³⁷ Although CCTs typically occur in the same patient populations as MMCs, namely elderly white men with chronically sun-damaged skin,they exhibit several important distinctions.^37-39 By definition, CCTs have a malignant melanocytic component, whereas melanocytes are nonneoplastic in MMCs. The pathogenesis may differ as well. Various mechanisms for the close association of epithelial tumors and melanoma have been proposed, including field cancerization, tumor collision, tumor-tumor metastases, tumor colonization, and others, though CCTs likely arise through combinations of these processes depending upon their subtype.^37-39 Paracrine signaling may play an important role in the pathogenesis of both tumors.^5,6,8,38 As with MMCs, the prognosis of CCTs is limited by relatively few reported cases. Despite advanced Breslow depths in many cases, these tumors display more indolent behavior suggestive of melanoma in situ rather than invasive melanoma, perhaps due to dependence upon epithelial paracrine factors.^37,39-42

Solid-organ transplant recipients have higher rates of more aggressive malignancies, of which skin cancer is the most common.^43-49 Squamous cell carcinoma of the skin accounts for 95% of cutaneous malignancies in this population and occurs at approximately 65 times the rate of the general population.⁵⁰ The risk of other skin cancers also is increased, though less dramatically, including BCC (10-fold increased risk) and melanoma (2- to 8-fold increased risk).^46,50-53 The cause likely is multifactorial, including older age, history of skin cancer pretransplant, more than 5 years posttransplant, male sex, and incrementally as Fitzpatrick skin type decreases from VI to I.^54-56 Immunosuppressive therapy also plays a role in tumorigenesis. Azathioprine metabolites have specifically been implicated in UVA radiation–induced promutagenic oxidative damage to DNA.⁵⁷ Other studies have found no significant differences in the type of immunosuppressant used but instead have correlated rates of skin cancer to overall immunosuppression.^48,55,58 Lung transplant recipients in particular demonstrate high rates of cutaneous malignancy, likely due in part to the necessity of more potent immunosuppressive regimens. Nearly one-third of patients develop a cutaneous malignancy by 5 years and nearly half by 10 years posttransplant.⁵⁵

We report a rare case of MMC in a solid-organ transplant recipient. We hypothesize that the combination of UV radiation exposure–induced photodamage acquired pretransplant in addition to an aggressive immunosuppressive regimen with azathioprine and other agents posttransplant contributed to the development of this patient’s rare malignancy. Although rare, these tumors should remain in the differential diagnosis of clinicians and pathologists caring for this unique patient population.

WAIKOLOA, HAWAII – The prevalence of allergic contact dermatitis is elevated among patients with atopic dermatitis – and it pays to know their major sources of risk, according to Jonathan I. Silverberg, MD, PhD.

photorobot/Getty Images

“What are atopic dermatitis patients allergic to? It’s all coming from their personal care products and the things being used to treat their atopic dermatitis,” Dr. Silverberg said at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

Dr. Silverberg, of the department of dermatology at Northwestern University, Chicago, coauthored a systematic review and meta-analysis that examined the association between AD and contact sensitization. In their examination of 74 published studies, the investigators found that the likelihood of allergic contact dermatitis was 1.5-fold greater in adults and children with AD than in healthy individuals from the general population (J Am Acad Dermatol. 2017 Jul;77[1]:70-8).

This finding is at odds with an earlier widespread belief that AD patients should not be at increased risk because the immune profile of their primarily Th2-mediated disease would have a suppressant effect on Th1-mediated hypersensitivity.

“Recent data are calling into question old dogmas and reshaping the way we think about this. And this is not just an academic exercise, this is highly clinically relevant,” the dermatologist asserted.

The results of the meta-analysis prompted Dr. Silverberg and colleagues to conduct a retrospective study of more than 500 adults patch tested to an expanded allergen series at Northwestern’s patch test clinic with the purpose of identifying the common offending allergens in patients with AD. The key finding: The patients with AD were significantly more likely to have positive patch test reactions to ingredients in their repetitively used personal care products, topical corticosteroids, and topical antibiotics than the individuals without AD. The probable explanation for this results is that the skin barrier disruption inherent in AD allows for easier passage of weak allergens through the skin (J Am Acad Dermatol. 2018 Dec;79[6]:1028-33.e6).

Bruce Jancin/MDedge News

Lanolin was identified as a particularly common allergen in the AD group. “Lanolin is found in one of the most commonly used moisturizers we recommend to patients: Aquaphor. It’s also found in tons of lip balms and emollients. Pretty much every soft soap out there contains lanolin, and it’s in a variety of other personal care products,” Dr. Silverberg noted.

Other common offenders in the AD population included fragrance mix II, cinnamal, quaternium-15, budesonide, tixocortol, carba mix, neomycin, bacitracin, rubber mix, and chlorhexidine. Relevance was established in more than 90% of the positive reactions.

“You can patch test them directly to their personal care products and make that connection beautifully and see how they’re reacting to them,” he said.


 

When to patch test atopic dermatitis patients

Dr. Silverberg was a coauthor of multidisciplinary expert consensus guidelines on when to consider patch testing in AD (Dermatitis. 2016 Jul-Aug;27[4]:186-92). “We had to go consensus because we don’t have nearly enough studies to provide true evidence-based recommendations,” he explained.

Because allergic contact dermatitis is a potentially curable comorbid condition in AD patients, it’s important to recognize the scenarios in which patch testing should be considered. These include AD refractory to topical therapy; adolescent- or adult-onset atopic dermatitis; and in AD patients with an atypical or evolving lesional distribution, such as localized dermatitis on the eyelids, head and neck, or hands and feet. Patch testing is also warranted before initiating systemic therapy for AD.

“If you’re about to put a patient on a biologic or phototherapy and step them up to a whole new class of risk of adverse events, that’s an ideal time to think about reversible options,” Dr. Silverberg advised.

Another situation in which he considers patch testing advisable, although this one isn’t covered in the consensus guidelines, is in AD patients with prominent nummular eczema lesions. “Widespread nummular eczema lesions may be a sign of allergic contact dermatitis in atopic dermatitis patients. I’m not saying everyone with nummular lesions is going to have a positive patch test, but it’s definitely a situation you want to think about,” he said.
 

How to patch test atopic dermatitis patients

Most of the common topical allergens in AD patients are not included in the T.R.U.E. Test. An expanded allergen series, such as the American Contact Dermatitis Society core 80 series, is the better way to go.

Once the dermatologist determines that a patient’s positive patch test reaction is relevant, it’s important to recommend the use of personal care products that are “pretty clean,” Dr. Silverberg said.

“Clean in my opinion is not a matter of ‘It should be all organic and all natural,’ ” he emphasized. “I’m not anti- any of that, but clean means having the fewest ingredients possible and trying to steer clear of those really common allergens that patients are highly likely to have been exposed to and potentially sensitized to over the many years of their tenure of atopic dermatitis.”

Dr. Silverberg reported receiving research grants from Galderma and GlaxoSmithKline and serving as a consultant to more than a dozen pharmaceutical companies.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

bjancin@mdedge.com

WAIKOLOA, HAWAII – The prevalence of allergic contact dermatitis is elevated among patients with atopic dermatitis – and it pays to know their major sources of risk, according to Jonathan I. Silverberg, MD, PhD.

photorobot/Getty Images

“What are atopic dermatitis patients allergic to? It’s all coming from their personal care products and the things being used to treat their atopic dermatitis,” Dr. Silverberg said at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

Dr. Silverberg, of the department of dermatology at Northwestern University, Chicago, coauthored a systematic review and meta-analysis that examined the association between AD and contact sensitization. In their examination of 74 published studies, the investigators found that the likelihood of allergic contact dermatitis was 1.5-fold greater in adults and children with AD than in healthy individuals from the general population (J Am Acad Dermatol. 2017 Jul;77[1]:70-8).

This finding is at odds with an earlier widespread belief that AD patients should not be at increased risk because the immune profile of their primarily Th2-mediated disease would have a suppressant effect on Th1-mediated hypersensitivity.

“Recent data are calling into question old dogmas and reshaping the way we think about this. And this is not just an academic exercise, this is highly clinically relevant,” the dermatologist asserted.

The results of the meta-analysis prompted Dr. Silverberg and colleagues to conduct a retrospective study of more than 500 adults patch tested to an expanded allergen series at Northwestern’s patch test clinic with the purpose of identifying the common offending allergens in patients with AD. The key finding: The patients with AD were significantly more likely to have positive patch test reactions to ingredients in their repetitively used personal care products, topical corticosteroids, and topical antibiotics than the individuals without AD. The probable explanation for this results is that the skin barrier disruption inherent in AD allows for easier passage of weak allergens through the skin (J Am Acad Dermatol. 2018 Dec;79[6]:1028-33.e6).

Bruce Jancin/MDedge News

Lanolin was identified as a particularly common allergen in the AD group. “Lanolin is found in one of the most commonly used moisturizers we recommend to patients: Aquaphor. It’s also found in tons of lip balms and emollients. Pretty much every soft soap out there contains lanolin, and it’s in a variety of other personal care products,” Dr. Silverberg noted.

Other common offenders in the AD population included fragrance mix II, cinnamal, quaternium-15, budesonide, tixocortol, carba mix, neomycin, bacitracin, rubber mix, and chlorhexidine. Relevance was established in more than 90% of the positive reactions.

“You can patch test them directly to their personal care products and make that connection beautifully and see how they’re reacting to them,” he said.


 

When to patch test atopic dermatitis patients

Dr. Silverberg was a coauthor of multidisciplinary expert consensus guidelines on when to consider patch testing in AD (Dermatitis. 2016 Jul-Aug;27[4]:186-92). “We had to go consensus because we don’t have nearly enough studies to provide true evidence-based recommendations,” he explained.

Because allergic contact dermatitis is a potentially curable comorbid condition in AD patients, it’s important to recognize the scenarios in which patch testing should be considered. These include AD refractory to topical therapy; adolescent- or adult-onset atopic dermatitis; and in AD patients with an atypical or evolving lesional distribution, such as localized dermatitis on the eyelids, head and neck, or hands and feet. Patch testing is also warranted before initiating systemic therapy for AD.

“If you’re about to put a patient on a biologic or phototherapy and step them up to a whole new class of risk of adverse events, that’s an ideal time to think about reversible options,” Dr. Silverberg advised.

Another situation in which he considers patch testing advisable, although this one isn’t covered in the consensus guidelines, is in AD patients with prominent nummular eczema lesions. “Widespread nummular eczema lesions may be a sign of allergic contact dermatitis in atopic dermatitis patients. I’m not saying everyone with nummular lesions is going to have a positive patch test, but it’s definitely a situation you want to think about,” he said.
 

How to patch test atopic dermatitis patients

Most of the common topical allergens in AD patients are not included in the T.R.U.E. Test. An expanded allergen series, such as the American Contact Dermatitis Society core 80 series, is the better way to go.

Once the dermatologist determines that a patient’s positive patch test reaction is relevant, it’s important to recommend the use of personal care products that are “pretty clean,” Dr. Silverberg said.

“Clean in my opinion is not a matter of ‘It should be all organic and all natural,’ ” he emphasized. “I’m not anti- any of that, but clean means having the fewest ingredients possible and trying to steer clear of those really common allergens that patients are highly likely to have been exposed to and potentially sensitized to over the many years of their tenure of atopic dermatitis.”

Dr. Silverberg reported receiving research grants from Galderma and GlaxoSmithKline and serving as a consultant to more than a dozen pharmaceutical companies.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

bjancin@mdedge.com

WAIKOLOA, HAWAII – The prevalence of allergic contact dermatitis is elevated among patients with atopic dermatitis – and it pays to know their major sources of risk, according to Jonathan I. Silverberg, MD, PhD.

photorobot/Getty Images

“What are atopic dermatitis patients allergic to? It’s all coming from their personal care products and the things being used to treat their atopic dermatitis,” Dr. Silverberg said at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

Dr. Silverberg, of the department of dermatology at Northwestern University, Chicago, coauthored a systematic review and meta-analysis that examined the association between AD and contact sensitization. In their examination of 74 published studies, the investigators found that the likelihood of allergic contact dermatitis was 1.5-fold greater in adults and children with AD than in healthy individuals from the general population (J Am Acad Dermatol. 2017 Jul;77[1]:70-8).

This finding is at odds with an earlier widespread belief that AD patients should not be at increased risk because the immune profile of their primarily Th2-mediated disease would have a suppressant effect on Th1-mediated hypersensitivity.

“Recent data are calling into question old dogmas and reshaping the way we think about this. And this is not just an academic exercise, this is highly clinically relevant,” the dermatologist asserted.

The results of the meta-analysis prompted Dr. Silverberg and colleagues to conduct a retrospective study of more than 500 adults patch tested to an expanded allergen series at Northwestern’s patch test clinic with the purpose of identifying the common offending allergens in patients with AD. The key finding: The patients with AD were significantly more likely to have positive patch test reactions to ingredients in their repetitively used personal care products, topical corticosteroids, and topical antibiotics than the individuals without AD. The probable explanation for this results is that the skin barrier disruption inherent in AD allows for easier passage of weak allergens through the skin (J Am Acad Dermatol. 2018 Dec;79[6]:1028-33.e6).

Bruce Jancin/MDedge News

Lanolin was identified as a particularly common allergen in the AD group. “Lanolin is found in one of the most commonly used moisturizers we recommend to patients: Aquaphor. It’s also found in tons of lip balms and emollients. Pretty much every soft soap out there contains lanolin, and it’s in a variety of other personal care products,” Dr. Silverberg noted.

Other common offenders in the AD population included fragrance mix II, cinnamal, quaternium-15, budesonide, tixocortol, carba mix, neomycin, bacitracin, rubber mix, and chlorhexidine. Relevance was established in more than 90% of the positive reactions.

“You can patch test them directly to their personal care products and make that connection beautifully and see how they’re reacting to them,” he said.


 

When to patch test atopic dermatitis patients

Dr. Silverberg was a coauthor of multidisciplinary expert consensus guidelines on when to consider patch testing in AD (Dermatitis. 2016 Jul-Aug;27[4]:186-92). “We had to go consensus because we don’t have nearly enough studies to provide true evidence-based recommendations,” he explained.

Because allergic contact dermatitis is a potentially curable comorbid condition in AD patients, it’s important to recognize the scenarios in which patch testing should be considered. These include AD refractory to topical therapy; adolescent- or adult-onset atopic dermatitis; and in AD patients with an atypical or evolving lesional distribution, such as localized dermatitis on the eyelids, head and neck, or hands and feet. Patch testing is also warranted before initiating systemic therapy for AD.

“If you’re about to put a patient on a biologic or phototherapy and step them up to a whole new class of risk of adverse events, that’s an ideal time to think about reversible options,” Dr. Silverberg advised.

Another situation in which he considers patch testing advisable, although this one isn’t covered in the consensus guidelines, is in AD patients with prominent nummular eczema lesions. “Widespread nummular eczema lesions may be a sign of allergic contact dermatitis in atopic dermatitis patients. I’m not saying everyone with nummular lesions is going to have a positive patch test, but it’s definitely a situation you want to think about,” he said.
 

How to patch test atopic dermatitis patients

Most of the common topical allergens in AD patients are not included in the T.R.U.E. Test. An expanded allergen series, such as the American Contact Dermatitis Society core 80 series, is the better way to go.

Once the dermatologist determines that a patient’s positive patch test reaction is relevant, it’s important to recommend the use of personal care products that are “pretty clean,” Dr. Silverberg said.

“Clean in my opinion is not a matter of ‘It should be all organic and all natural,’ ” he emphasized. “I’m not anti- any of that, but clean means having the fewest ingredients possible and trying to steer clear of those really common allergens that patients are highly likely to have been exposed to and potentially sensitized to over the many years of their tenure of atopic dermatitis.”

Dr. Silverberg reported receiving research grants from Galderma and GlaxoSmithKline and serving as a consultant to more than a dozen pharmaceutical companies.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

bjancin@mdedge.com

Each year, the American Contact Dermatitis Society (ACDS) names an allergen of the year with the purpose of promoting greater awareness of a key allergen and its impact on patients. Often, the allergen of the year is an emerging allergen that may represent an underrecognized or novel cause of allergic contact dermatitis (ACD). In 2019, the ACDS chose parabens as the “nonallergen” of the year to draw attention to their low rate of associated ACD despite high public interest in limiting exposure to parabens.¹

What types of products contain parabens?

Parabens are preservatives commonly found in many different categories of personal care products. Preservatives inhibit microbial growth and are necessary ingredients in water-based products. The 4 most common parabens used in personal care products are methylparaben, ethylparaben, propylparaben, and butylparaben.¹ Parabens are metabolized to 4-hydroxybenzoic acid and are excreted in urine. When parabens are applied topically, there is minimal penetration through intact human skin.² In the United States, parabens are allowed as preservatives in cosmetics at concentrations up to 0.4% when used alone or up to 0.8% when used in combination with other parabens.³

Consumers are exposed to parabens in a wide variety of personal care products. The Contact Allergen Management Program (CAMP) is a system owned and managed by the ACDS that typically is used to generate lists of safe personal care products for patients and also can be queried for the presence of individual chemicals in products. According to a 2018 query of the CAMP, parabens were found in 19% of all products.¹ A more recent query of CAMP (http://www.contactderm.org/resources/acds-camp) in March 2019 showed parabens were present in 39.3% of makeup products, especially in eye products, foundations, and concealers; parabens also were found in 34% of moisturizers, 11.5% of soaps, and 19% of sunscreens. Notably, 14.8% of prescription topical steroids listed in the CAMP contained a paraben. Another method for evaluating chemical contents of personal care products is a review of the Voluntary Cosmetic Registration Program, a US Food and Drug Administration–based registry for cosmetic products. Survey data from the Voluntary Cosmetic Registration Program in 2018 documented methylparaben in 11,626 formulations.⁴ Other parabens included propylparaben (8885 products), butylparaben (3915 products), and ethylparaben (3860 products). Parabens were reported more frequently in leave-on rather than rinse-off products.⁴

In medications, parabens are recommended at concentrations of no more than 0.1%.¹ Fransway et al¹ compiled a list of medications that contain parabens, including commonly prescribed dermatologic topical medications such as corticosteroids, several acne preparations, eflornithine, fluorouracil, hydroquinone, imiquimod, urea, and sertaconazole. Oral and parenteral medications including local anesthetics and corticosteroids also may contain parabens.

Consumers also may be exposed to parabens through foodstuffs. Methylparaben and propylparaben have been classified as generally recognized as safe in foods by the US Food and Drug Administration.⁵ The acceptable daily intake of parabens in food is 0 to 10 mg/kg of body weight,¹ and the estimated dietary intake for a typical adult is 307 mg/kg of body weight daily.⁶ Several studies on paraben content in foodstuffs have confirmed their presence in both natural and processed foods.^1,6 Systemic contact dermatitis caused by ingestion of parabens is rare. In general, individuals with positive patch test reactions to parabens should not routinely avoid them in foods or oral medications,¹ but they should, of course, be avoided in topical medications.

What is the rate of ACD with parabens?

One of the main reasons that parabens were designated as the ACDS nonallergen of the year is the very low rate of ACD associated with parabens. The North American Contact Dermatitis Group, a research group with members in the United States and Canada, reported a 0.6% positive reaction rate when patch testing with paraben mix 12%,⁷ which closely compares with a 0.8% positive reaction rate when patch testing with paraben mix 16% using the Mayo Clinic standard series.⁸ From the standpoint of ACD, this very low patch test reaction rate makes parabens one of the safest preservative options for use in cosmetic products.

Are there health risks associated with parabens?

The paraben controversy in the scientific literature and in the lay press centers around potential health risks and endocrine disruption. We will focus on the conversation regarding parabens and the risk for endocrine disruption and association with breast cancer.

Parabens have been reported to have estrogenic effects; however, the bulk of the data is limited to in vitro and animal studies, with less evidence of endocrine disruption in humans.² In vitro studies have demonstrated that the estrogenic potency of parabens is much less than that of estrogen. In one study, parabens were shown to be 10,000-fold less potent than 17β-estradiol⁹; in a separate study, they had a maximum potency of only 1/4000 that of estrogen.¹⁰ Additionally, an in vitro study showed varying ability for parabens to bind estrogen receptors, with a greater ability to bind with longer alkyl side chains.¹¹ The result is decreased or increased estrogen activity, dependent on side chain length and type of receptor.² Finally, some studies add conflicting results that parabens may actually create an antiestrogenic effect in human breast cancer cells.¹² From the standpoint of estrogen mimicry, there are no known studies in humans confirming harmful effects associated with paraben exposure.

The reported association between parabens and breast cancer is closely related to their theoretical estrogenic effects. The conversation regarding parabens and breast cancer has been fueled by the identification of parabens in human breast tumors and their presence in concentrations similar to what is needed to stimulate in vitro breast cancer cells.² The existing data do not confirm causation. An association with parabens in topical axillary personal care products has been theorized but not confirmed; for example, it was shown that paraben levels were highest in the axillary region of breast cancer tissue, including women who had never used deodorant. It was concluded that the presence of axillary parabens was due to sources other than topical axillary personal care products.¹³ Another study confirmed there was not an increased risk for breast cancer in patients who applied personal care products to the axillary area within an hour of shaving.¹⁴ The existing data do not support topical paraben exposure as a risk for breast cancer.

Final Thoughts

Parabens are preservatives frequently found in personal care products and exhibit a very low rate of associated ACD. Consumers may be exposed to parabens through foods, cosmetics, and medications. Although there have been consumer concerns regarding endocrine disruption or carcinogenicity associated with parabens, definite evidence of their harm is lacking in the scientific literature, and many studies confirm their safety.² With their high prevalence in personal care products and low rates of associated contact allergy, parabens remain ideal preservative agents.

Ultimately, contact dermatitis is a common yet often underrecognized dermatologic condition. To address this knowledge gap in clinical practice, we are proud to launch Final Interpretation, a new column in Cutis covering emerging trends in contact dermatitis. We will address pearls, pitfalls, and updates in contact dermatitis. Although our primary focus will be ACD, other important causes of contact dermatitis will be highlighted. Look for the inaugural column in the June 2019 issue of Cutis.

Each year, the American Contact Dermatitis Society (ACDS) names an allergen of the year with the purpose of promoting greater awareness of a key allergen and its impact on patients. Often, the allergen of the year is an emerging allergen that may represent an underrecognized or novel cause of allergic contact dermatitis (ACD). In 2019, the ACDS chose parabens as the “nonallergen” of the year to draw attention to their low rate of associated ACD despite high public interest in limiting exposure to parabens.¹

What types of products contain parabens?

Parabens are preservatives commonly found in many different categories of personal care products. Preservatives inhibit microbial growth and are necessary ingredients in water-based products. The 4 most common parabens used in personal care products are methylparaben, ethylparaben, propylparaben, and butylparaben.¹ Parabens are metabolized to 4-hydroxybenzoic acid and are excreted in urine. When parabens are applied topically, there is minimal penetration through intact human skin.² In the United States, parabens are allowed as preservatives in cosmetics at concentrations up to 0.4% when used alone or up to 0.8% when used in combination with other parabens.³

Consumers are exposed to parabens in a wide variety of personal care products. The Contact Allergen Management Program (CAMP) is a system owned and managed by the ACDS that typically is used to generate lists of safe personal care products for patients and also can be queried for the presence of individual chemicals in products. According to a 2018 query of the CAMP, parabens were found in 19% of all products.¹ A more recent query of CAMP (http://www.contactderm.org/resources/acds-camp) in March 2019 showed parabens were present in 39.3% of makeup products, especially in eye products, foundations, and concealers; parabens also were found in 34% of moisturizers, 11.5% of soaps, and 19% of sunscreens. Notably, 14.8% of prescription topical steroids listed in the CAMP contained a paraben. Another method for evaluating chemical contents of personal care products is a review of the Voluntary Cosmetic Registration Program, a US Food and Drug Administration–based registry for cosmetic products. Survey data from the Voluntary Cosmetic Registration Program in 2018 documented methylparaben in 11,626 formulations.⁴ Other parabens included propylparaben (8885 products), butylparaben (3915 products), and ethylparaben (3860 products). Parabens were reported more frequently in leave-on rather than rinse-off products.⁴

In medications, parabens are recommended at concentrations of no more than 0.1%.¹ Fransway et al¹ compiled a list of medications that contain parabens, including commonly prescribed dermatologic topical medications such as corticosteroids, several acne preparations, eflornithine, fluorouracil, hydroquinone, imiquimod, urea, and sertaconazole. Oral and parenteral medications including local anesthetics and corticosteroids also may contain parabens.

Consumers also may be exposed to parabens through foodstuffs. Methylparaben and propylparaben have been classified as generally recognized as safe in foods by the US Food and Drug Administration.⁵ The acceptable daily intake of parabens in food is 0 to 10 mg/kg of body weight,¹ and the estimated dietary intake for a typical adult is 307 mg/kg of body weight daily.⁶ Several studies on paraben content in foodstuffs have confirmed their presence in both natural and processed foods.^1,6 Systemic contact dermatitis caused by ingestion of parabens is rare. In general, individuals with positive patch test reactions to parabens should not routinely avoid them in foods or oral medications,¹ but they should, of course, be avoided in topical medications.

What is the rate of ACD with parabens?

One of the main reasons that parabens were designated as the ACDS nonallergen of the year is the very low rate of ACD associated with parabens. The North American Contact Dermatitis Group, a research group with members in the United States and Canada, reported a 0.6% positive reaction rate when patch testing with paraben mix 12%,⁷ which closely compares with a 0.8% positive reaction rate when patch testing with paraben mix 16% using the Mayo Clinic standard series.⁸ From the standpoint of ACD, this very low patch test reaction rate makes parabens one of the safest preservative options for use in cosmetic products.

Are there health risks associated with parabens?

The paraben controversy in the scientific literature and in the lay press centers around potential health risks and endocrine disruption. We will focus on the conversation regarding parabens and the risk for endocrine disruption and association with breast cancer.

Parabens have been reported to have estrogenic effects; however, the bulk of the data is limited to in vitro and animal studies, with less evidence of endocrine disruption in humans.² In vitro studies have demonstrated that the estrogenic potency of parabens is much less than that of estrogen. In one study, parabens were shown to be 10,000-fold less potent than 17β-estradiol⁹; in a separate study, they had a maximum potency of only 1/4000 that of estrogen.¹⁰ Additionally, an in vitro study showed varying ability for parabens to bind estrogen receptors, with a greater ability to bind with longer alkyl side chains.¹¹ The result is decreased or increased estrogen activity, dependent on side chain length and type of receptor.² Finally, some studies add conflicting results that parabens may actually create an antiestrogenic effect in human breast cancer cells.¹² From the standpoint of estrogen mimicry, there are no known studies in humans confirming harmful effects associated with paraben exposure.

The reported association between parabens and breast cancer is closely related to their theoretical estrogenic effects. The conversation regarding parabens and breast cancer has been fueled by the identification of parabens in human breast tumors and their presence in concentrations similar to what is needed to stimulate in vitro breast cancer cells.² The existing data do not confirm causation. An association with parabens in topical axillary personal care products has been theorized but not confirmed; for example, it was shown that paraben levels were highest in the axillary region of breast cancer tissue, including women who had never used deodorant. It was concluded that the presence of axillary parabens was due to sources other than topical axillary personal care products.¹³ Another study confirmed there was not an increased risk for breast cancer in patients who applied personal care products to the axillary area within an hour of shaving.¹⁴ The existing data do not support topical paraben exposure as a risk for breast cancer.

Final Thoughts

Parabens are preservatives frequently found in personal care products and exhibit a very low rate of associated ACD. Consumers may be exposed to parabens through foods, cosmetics, and medications. Although there have been consumer concerns regarding endocrine disruption or carcinogenicity associated with parabens, definite evidence of their harm is lacking in the scientific literature, and many studies confirm their safety.² With their high prevalence in personal care products and low rates of associated contact allergy, parabens remain ideal preservative agents.

Ultimately, contact dermatitis is a common yet often underrecognized dermatologic condition. To address this knowledge gap in clinical practice, we are proud to launch Final Interpretation, a new column in Cutis covering emerging trends in contact dermatitis. We will address pearls, pitfalls, and updates in contact dermatitis. Although our primary focus will be ACD, other important causes of contact dermatitis will be highlighted. Look for the inaugural column in the June 2019 issue of Cutis.

Each year, the American Contact Dermatitis Society (ACDS) names an allergen of the year with the purpose of promoting greater awareness of a key allergen and its impact on patients. Often, the allergen of the year is an emerging allergen that may represent an underrecognized or novel cause of allergic contact dermatitis (ACD). In 2019, the ACDS chose parabens as the “nonallergen” of the year to draw attention to their low rate of associated ACD despite high public interest in limiting exposure to parabens.¹

What types of products contain parabens?

Parabens are preservatives commonly found in many different categories of personal care products. Preservatives inhibit microbial growth and are necessary ingredients in water-based products. The 4 most common parabens used in personal care products are methylparaben, ethylparaben, propylparaben, and butylparaben.¹ Parabens are metabolized to 4-hydroxybenzoic acid and are excreted in urine. When parabens are applied topically, there is minimal penetration through intact human skin.² In the United States, parabens are allowed as preservatives in cosmetics at concentrations up to 0.4% when used alone or up to 0.8% when used in combination with other parabens.³

Consumers are exposed to parabens in a wide variety of personal care products. The Contact Allergen Management Program (CAMP) is a system owned and managed by the ACDS that typically is used to generate lists of safe personal care products for patients and also can be queried for the presence of individual chemicals in products. According to a 2018 query of the CAMP, parabens were found in 19% of all products.¹ A more recent query of CAMP (http://www.contactderm.org/resources/acds-camp) in March 2019 showed parabens were present in 39.3% of makeup products, especially in eye products, foundations, and concealers; parabens also were found in 34% of moisturizers, 11.5% of soaps, and 19% of sunscreens. Notably, 14.8% of prescription topical steroids listed in the CAMP contained a paraben. Another method for evaluating chemical contents of personal care products is a review of the Voluntary Cosmetic Registration Program, a US Food and Drug Administration–based registry for cosmetic products. Survey data from the Voluntary Cosmetic Registration Program in 2018 documented methylparaben in 11,626 formulations.⁴ Other parabens included propylparaben (8885 products), butylparaben (3915 products), and ethylparaben (3860 products). Parabens were reported more frequently in leave-on rather than rinse-off products.⁴

In medications, parabens are recommended at concentrations of no more than 0.1%.¹ Fransway et al¹ compiled a list of medications that contain parabens, including commonly prescribed dermatologic topical medications such as corticosteroids, several acne preparations, eflornithine, fluorouracil, hydroquinone, imiquimod, urea, and sertaconazole. Oral and parenteral medications including local anesthetics and corticosteroids also may contain parabens.

Consumers also may be exposed to parabens through foodstuffs. Methylparaben and propylparaben have been classified as generally recognized as safe in foods by the US Food and Drug Administration.⁵ The acceptable daily intake of parabens in food is 0 to 10 mg/kg of body weight,¹ and the estimated dietary intake for a typical adult is 307 mg/kg of body weight daily.⁶ Several studies on paraben content in foodstuffs have confirmed their presence in both natural and processed foods.^1,6 Systemic contact dermatitis caused by ingestion of parabens is rare. In general, individuals with positive patch test reactions to parabens should not routinely avoid them in foods or oral medications,¹ but they should, of course, be avoided in topical medications.

What is the rate of ACD with parabens?

One of the main reasons that parabens were designated as the ACDS nonallergen of the year is the very low rate of ACD associated with parabens. The North American Contact Dermatitis Group, a research group with members in the United States and Canada, reported a 0.6% positive reaction rate when patch testing with paraben mix 12%,⁷ which closely compares with a 0.8% positive reaction rate when patch testing with paraben mix 16% using the Mayo Clinic standard series.⁸ From the standpoint of ACD, this very low patch test reaction rate makes parabens one of the safest preservative options for use in cosmetic products.

Are there health risks associated with parabens?

The paraben controversy in the scientific literature and in the lay press centers around potential health risks and endocrine disruption. We will focus on the conversation regarding parabens and the risk for endocrine disruption and association with breast cancer.

Parabens have been reported to have estrogenic effects; however, the bulk of the data is limited to in vitro and animal studies, with less evidence of endocrine disruption in humans.² In vitro studies have demonstrated that the estrogenic potency of parabens is much less than that of estrogen. In one study, parabens were shown to be 10,000-fold less potent than 17β-estradiol⁹; in a separate study, they had a maximum potency of only 1/4000 that of estrogen.¹⁰ Additionally, an in vitro study showed varying ability for parabens to bind estrogen receptors, with a greater ability to bind with longer alkyl side chains.¹¹ The result is decreased or increased estrogen activity, dependent on side chain length and type of receptor.² Finally, some studies add conflicting results that parabens may actually create an antiestrogenic effect in human breast cancer cells.¹² From the standpoint of estrogen mimicry, there are no known studies in humans confirming harmful effects associated with paraben exposure.

The reported association between parabens and breast cancer is closely related to their theoretical estrogenic effects. The conversation regarding parabens and breast cancer has been fueled by the identification of parabens in human breast tumors and their presence in concentrations similar to what is needed to stimulate in vitro breast cancer cells.² The existing data do not confirm causation. An association with parabens in topical axillary personal care products has been theorized but not confirmed; for example, it was shown that paraben levels were highest in the axillary region of breast cancer tissue, including women who had never used deodorant. It was concluded that the presence of axillary parabens was due to sources other than topical axillary personal care products.¹³ Another study confirmed there was not an increased risk for breast cancer in patients who applied personal care products to the axillary area within an hour of shaving.¹⁴ The existing data do not support topical paraben exposure as a risk for breast cancer.

Final Thoughts

Parabens are preservatives frequently found in personal care products and exhibit a very low rate of associated ACD. Consumers may be exposed to parabens through foods, cosmetics, and medications. Although there have been consumer concerns regarding endocrine disruption or carcinogenicity associated with parabens, definite evidence of their harm is lacking in the scientific literature, and many studies confirm their safety.² With their high prevalence in personal care products and low rates of associated contact allergy, parabens remain ideal preservative agents.

Ultimately, contact dermatitis is a common yet often underrecognized dermatologic condition. To address this knowledge gap in clinical practice, we are proud to launch Final Interpretation, a new column in Cutis covering emerging trends in contact dermatitis. We will address pearls, pitfalls, and updates in contact dermatitis. Although our primary focus will be ACD, other important causes of contact dermatitis will be highlighted. Look for the inaugural column in the June 2019 issue of Cutis.

WASHINGTON – The American Contact Dermatitis Society has selected isobornyl acrylate the contact allergen of the year. It is an acrylic monomer used as an adhesive.

Vidyard Video

Among other applications, isobornyl acrylate is often used in medical devices. The selection was made based in part on multiple case reports of diabetes patients developing contact allergies to their diabetes devices, such as insulin pumps, explained Golara Honari, MD, of Stanford (Calif.) University, who presented the selection at the ACDS annual meeting.

The significance of this allergen is that testing through routine panels does not identify it, so clinician awareness is especially important, Dr. Honari noted in a video interview at the meeting.

Most of the reported contact allergen cases have been in patients with diabetes, but clinicians should think about other possible sources, such as acrylic nails, she said. As for treatment, clinicians and patients can consider alternative diabetes devices without isobornyl acrylate, she said.

In the future, close collaboration between clinicians and the medical device industry to develop appropriate labeling can help increase awareness of the potential for allergic reactions, she added.

Dr. Honari had no relevant financial conflicts to disclose.

WASHINGTON – The American Contact Dermatitis Society has selected isobornyl acrylate the contact allergen of the year. It is an acrylic monomer used as an adhesive.

Vidyard Video

Among other applications, isobornyl acrylate is often used in medical devices. The selection was made based in part on multiple case reports of diabetes patients developing contact allergies to their diabetes devices, such as insulin pumps, explained Golara Honari, MD, of Stanford (Calif.) University, who presented the selection at the ACDS annual meeting.

The significance of this allergen is that testing through routine panels does not identify it, so clinician awareness is especially important, Dr. Honari noted in a video interview at the meeting.

Most of the reported contact allergen cases have been in patients with diabetes, but clinicians should think about other possible sources, such as acrylic nails, she said. As for treatment, clinicians and patients can consider alternative diabetes devices without isobornyl acrylate, she said.

In the future, close collaboration between clinicians and the medical device industry to develop appropriate labeling can help increase awareness of the potential for allergic reactions, she added.

Dr. Honari had no relevant financial conflicts to disclose.

WASHINGTON – The American Contact Dermatitis Society has selected isobornyl acrylate the contact allergen of the year. It is an acrylic monomer used as an adhesive.

Vidyard Video

Among other applications, isobornyl acrylate is often used in medical devices. The selection was made based in part on multiple case reports of diabetes patients developing contact allergies to their diabetes devices, such as insulin pumps, explained Golara Honari, MD, of Stanford (Calif.) University, who presented the selection at the ACDS annual meeting.

The significance of this allergen is that testing through routine panels does not identify it, so clinician awareness is especially important, Dr. Honari noted in a video interview at the meeting.

Most of the reported contact allergen cases have been in patients with diabetes, but clinicians should think about other possible sources, such as acrylic nails, she said. As for treatment, clinicians and patients can consider alternative diabetes devices without isobornyl acrylate, she said.

In the future, close collaboration between clinicians and the medical device industry to develop appropriate labeling can help increase awareness of the potential for allergic reactions, she added.

Dr. Honari had no relevant financial conflicts to disclose.

To the Editor:

Specific characteristics of a lymphocytic infiltrate noted on frozen section histologic examination during Mohs micrographic surgery (MMS) tumor excision should raise suspicion of an underlying chronic lymphocytic leukemia (CLL). This infiltrate may be the presenting sign of the underlying leukemia and has variable presentation that may mimic aggressive features. The following 3 cases highlight this phenomenon.

A 74-year-old man (patient 1) with a medical history of multiple nonmelanoma skin cancers (NMSCs) presented for definitive treatment of a biopsy-proven infiltrative basal cell carcinoma involving the right infra-auricular region. Mohs section histologic evaluation revealed patches of lymphocytic infiltrates so dense they obscured the tumor margins. The lymphocytic infiltrates persisted even after 3 MMS stages, though they were moderately less dense compared to the initial MMS stage. Clinical interpretation determined no relationship between the lymphocytic infiltrates and residual tumor. Due to concerns that this lymphocytic infiltrate may indicate an underlying leukemic process, preoperative laboratory tests were ordered prior to closure of the surgical wound, which demonstrated an elevated white blood cell count of 65,000/µL (reference range, 4500–11,000/µL) with 93% lymphocytes. A follow-up complete blood cell count (CBC) and blood smear confirmed the diagnosis of CLL. The patient was referred to a hematologist/oncologist.

An 84-year old man (patient 2) with a medical history of numerous precancerous lesions and 1 squamous cell carcinoma (SCC) presented for a biopsy, which determined moderately differentiated SCC. Mohs micrographic surgery was performed. The initial stage of MMS histologic examination demonstrated basosquamous carcinoma in the specimen margins, including perineural growth, with an extensive lymphoid infiltrate surrounding the tumor (Figure 1). A second stage of MMS was performed, and although margins appeared to be clear of the basosquamous histology, complete assessment was difficult due to areas of dense inflammatory infiltrate (Figure 2), including perineural infiltration that remained and appeared to extend deeper into the tissues. Pathology was consulted and it was determined that the perineural infiltration was unlikely related to tumor spread but rather secondary to an unknown cause. Further investigation of the patient’s medical history revealed previously diagnosed CLL, which had been omitted by the patient, as he had forgotten this diagnosis and denied a history of cancer, lymphoma, and even leukemia. A query to the patient’s primary care physician found the most recent CBC demonstrated an elevated white blood cell count of 37,600/µL with 78% lymphocytes.

An 84-year-old man (patient 3) with a known history of CLL was referred for MMS excision of a 3.5×4.0-cm SCC on the right anterior temple extending onto the lateral upper and lower eyelids. Mohs frozen section histologic examination of excised tissue revealed patches of heavy lymphocytic infiltrates not found exclusively around the residual tumor but additionally around superficial and deep neurovascular bundles. The second stage of MMS appeared to be clear of tumor cells, but lymphocytic infiltrates remained. Because this patient had a clear history of CLL, the decision was made in conjunction with a dermatopathologist to conclude the surgery at this point. However, secondary to the aggressive, deeply invasive growth of this SCC, the patient was referred for adjunctive radiation therapy to the surgical site after wound reconstruction.

Chronic lymphocytic leukemia is the most common leukemia in the Western world¹ and is estimated to account for 27% of all new cases of leukemia. An individual’s lifetime risk is 0.5%. Chronic lymphocytic leukemia is predominantly a disease of the elderly, with an average age at diagnosis of 71 years. It is more common among males, North American and European populations, and those with a positive family history. Although epidemiologic factors including farming, prolonged pesticide exposure, and contact with Agent Orange have tentative links to CLL, the relationships are poorly established.²

Symptoms associated with acute leukemia only rarely manifest in patients with CLL.³ If present, symptoms are vague and include weakness, fatigue, weight loss, fever, night sweats, and a feeling of abdominal fullness.^2,3 On clinical examination, patients also may have lymphadenopathy, splenomegaly, or hepatomegaly. Increasing severity of symptoms at time of presentation directly correlates with the severity and staging at the time of diagnosis.⁴ Not only do patients with CLL have a greater incidence of NMSCs with more notable subclinical tumor extension than the average person, but these individuals also have a greatly increased risk for skin cancer recurrence posttreatment.^5,6

Although tissue pathology is not routinely part of the diagnosis of patients with CLL, findings can add to clinical suspicion. Smudge cells, which are cell debris, are characteristic morphologic features found in CLL. Most CLL cells are characteristically small mature lymphocytes with a dense nucleus.³ The presence of aggregates of these cells may obscure tumor margins during resection of NMSCs.⁷ This infiltrate is present in more than one-third of patients with CLL, as described in one retrospective cohort. This study simultaneously demonstrated the relationship between CLL and a 2-fold increase in postoperative defect size, which was attributed to either subclinical tumor spread or extra tissue removal to ensure clearance due to the leukemic infiltrates themselves.⁸ The presence of perineural tumor growth, which can occur with aggressive SCC and basal cell carcinoma, may be mimicked by perineural involvement of CLL cells rather than the reactive inflammation associated with continued tumor margins.⁷

When evaluating a patient with suspected CLL, laboratory tests should include a CBC with differential and examination of the peripheral smear. If abnormal, immunophenotyping of lymphocytes by flow cytometry will rule out other lymphoproliferative diseases and verify CLL as the diagnosis.³ Diagnosis of CLL requires the presence of monoclonal B lymphocytes (≥5×10⁹/L) in the peripheral blood as confirmed by flow cytometry.³ Clonality of circulating B lymphocytes must be confirmed, and immunophenotyping will establish a diagnosis with leukemic cells having positive expression of CD20 (Figure 3A) and CD23 (Figure 3B)(characteristic of B-cell lineage) with coexpression of CD43 and CD5 (Figure 3C)(characteristic of T-cell lineage).^7,9 This pattern of immunohistochemical markers can be differentiated from the normal immune response to cutaneous malignancies, which have the pattern of being CD3⁺, CD5⁺, and CD43⁺ with absence of B-cell markers (ie, CD20, CD23)(Table).⁷

The pathogenesis of this peritumoral infiltrate is unknown, though multiple theories exist. One theory is that the neoplastic lymphocytes are responding as a dysfunctional arm of the immune system to tumor-specific antigens. In patients with CLL, leukemic lymphocytes comprise a large portion of the circulating leukocyte population and this peritumoral infiltrate may simply be a reflection of the circulating leukocytic population. Another theory contends that neoplastic lymphocytes are simply nonspecific aggregations secondary to tumor neovascularization and increased vascular permeability.¹⁰

This neoplastic infiltrate seen incidentally during MMS excision of NMSCs not only provides a unique opportunity to diagnose and intervene in those with unknown CLL but also to be aware of complicating features that can spare the patient from unnecessary tissue removal, thereby maximizing the benefit of MMS. This infiltrate can obscure tumor margins; is unusually dense and patchy, with or without infiltrating perineural or perivascular components; and persists beyond what would seem to be an adequate margin to clear a tumor. These cases show these findings, which exemplify the peritumoral infiltrate of CLL and should prompt further workup.

To the Editor:

Specific characteristics of a lymphocytic infiltrate noted on frozen section histologic examination during Mohs micrographic surgery (MMS) tumor excision should raise suspicion of an underlying chronic lymphocytic leukemia (CLL). This infiltrate may be the presenting sign of the underlying leukemia and has variable presentation that may mimic aggressive features. The following 3 cases highlight this phenomenon.

A 74-year-old man (patient 1) with a medical history of multiple nonmelanoma skin cancers (NMSCs) presented for definitive treatment of a biopsy-proven infiltrative basal cell carcinoma involving the right infra-auricular region. Mohs section histologic evaluation revealed patches of lymphocytic infiltrates so dense they obscured the tumor margins. The lymphocytic infiltrates persisted even after 3 MMS stages, though they were moderately less dense compared to the initial MMS stage. Clinical interpretation determined no relationship between the lymphocytic infiltrates and residual tumor. Due to concerns that this lymphocytic infiltrate may indicate an underlying leukemic process, preoperative laboratory tests were ordered prior to closure of the surgical wound, which demonstrated an elevated white blood cell count of 65,000/µL (reference range, 4500–11,000/µL) with 93% lymphocytes. A follow-up complete blood cell count (CBC) and blood smear confirmed the diagnosis of CLL. The patient was referred to a hematologist/oncologist.

An 84-year old man (patient 2) with a medical history of numerous precancerous lesions and 1 squamous cell carcinoma (SCC) presented for a biopsy, which determined moderately differentiated SCC. Mohs micrographic surgery was performed. The initial stage of MMS histologic examination demonstrated basosquamous carcinoma in the specimen margins, including perineural growth, with an extensive lymphoid infiltrate surrounding the tumor (Figure 1). A second stage of MMS was performed, and although margins appeared to be clear of the basosquamous histology, complete assessment was difficult due to areas of dense inflammatory infiltrate (Figure 2), including perineural infiltration that remained and appeared to extend deeper into the tissues. Pathology was consulted and it was determined that the perineural infiltration was unlikely related to tumor spread but rather secondary to an unknown cause. Further investigation of the patient’s medical history revealed previously diagnosed CLL, which had been omitted by the patient, as he had forgotten this diagnosis and denied a history of cancer, lymphoma, and even leukemia. A query to the patient’s primary care physician found the most recent CBC demonstrated an elevated white blood cell count of 37,600/µL with 78% lymphocytes.

An 84-year-old man (patient 3) with a known history of CLL was referred for MMS excision of a 3.5×4.0-cm SCC on the right anterior temple extending onto the lateral upper and lower eyelids. Mohs frozen section histologic examination of excised tissue revealed patches of heavy lymphocytic infiltrates not found exclusively around the residual tumor but additionally around superficial and deep neurovascular bundles. The second stage of MMS appeared to be clear of tumor cells, but lymphocytic infiltrates remained. Because this patient had a clear history of CLL, the decision was made in conjunction with a dermatopathologist to conclude the surgery at this point. However, secondary to the aggressive, deeply invasive growth of this SCC, the patient was referred for adjunctive radiation therapy to the surgical site after wound reconstruction.

Chronic lymphocytic leukemia is the most common leukemia in the Western world¹ and is estimated to account for 27% of all new cases of leukemia. An individual’s lifetime risk is 0.5%. Chronic lymphocytic leukemia is predominantly a disease of the elderly, with an average age at diagnosis of 71 years. It is more common among males, North American and European populations, and those with a positive family history. Although epidemiologic factors including farming, prolonged pesticide exposure, and contact with Agent Orange have tentative links to CLL, the relationships are poorly established.²

Symptoms associated with acute leukemia only rarely manifest in patients with CLL.³ If present, symptoms are vague and include weakness, fatigue, weight loss, fever, night sweats, and a feeling of abdominal fullness.^2,3 On clinical examination, patients also may have lymphadenopathy, splenomegaly, or hepatomegaly. Increasing severity of symptoms at time of presentation directly correlates with the severity and staging at the time of diagnosis.⁴ Not only do patients with CLL have a greater incidence of NMSCs with more notable subclinical tumor extension than the average person, but these individuals also have a greatly increased risk for skin cancer recurrence posttreatment.^5,6

Although tissue pathology is not routinely part of the diagnosis of patients with CLL, findings can add to clinical suspicion. Smudge cells, which are cell debris, are characteristic morphologic features found in CLL. Most CLL cells are characteristically small mature lymphocytes with a dense nucleus.³ The presence of aggregates of these cells may obscure tumor margins during resection of NMSCs.⁷ This infiltrate is present in more than one-third of patients with CLL, as described in one retrospective cohort. This study simultaneously demonstrated the relationship between CLL and a 2-fold increase in postoperative defect size, which was attributed to either subclinical tumor spread or extra tissue removal to ensure clearance due to the leukemic infiltrates themselves.⁸ The presence of perineural tumor growth, which can occur with aggressive SCC and basal cell carcinoma, may be mimicked by perineural involvement of CLL cells rather than the reactive inflammation associated with continued tumor margins.⁷

When evaluating a patient with suspected CLL, laboratory tests should include a CBC with differential and examination of the peripheral smear. If abnormal, immunophenotyping of lymphocytes by flow cytometry will rule out other lymphoproliferative diseases and verify CLL as the diagnosis.³ Diagnosis of CLL requires the presence of monoclonal B lymphocytes (≥5×10⁹/L) in the peripheral blood as confirmed by flow cytometry.³ Clonality of circulating B lymphocytes must be confirmed, and immunophenotyping will establish a diagnosis with leukemic cells having positive expression of CD20 (Figure 3A) and CD23 (Figure 3B)(characteristic of B-cell lineage) with coexpression of CD43 and CD5 (Figure 3C)(characteristic of T-cell lineage).^7,9 This pattern of immunohistochemical markers can be differentiated from the normal immune response to cutaneous malignancies, which have the pattern of being CD3⁺, CD5⁺, and CD43⁺ with absence of B-cell markers (ie, CD20, CD23)(Table).⁷

The pathogenesis of this peritumoral infiltrate is unknown, though multiple theories exist. One theory is that the neoplastic lymphocytes are responding as a dysfunctional arm of the immune system to tumor-specific antigens. In patients with CLL, leukemic lymphocytes comprise a large portion of the circulating leukocyte population and this peritumoral infiltrate may simply be a reflection of the circulating leukocytic population. Another theory contends that neoplastic lymphocytes are simply nonspecific aggregations secondary to tumor neovascularization and increased vascular permeability.¹⁰

This neoplastic infiltrate seen incidentally during MMS excision of NMSCs not only provides a unique opportunity to diagnose and intervene in those with unknown CLL but also to be aware of complicating features that can spare the patient from unnecessary tissue removal, thereby maximizing the benefit of MMS. This infiltrate can obscure tumor margins; is unusually dense and patchy, with or without infiltrating perineural or perivascular components; and persists beyond what would seem to be an adequate margin to clear a tumor. These cases show these findings, which exemplify the peritumoral infiltrate of CLL and should prompt further workup.

To the Editor:

Specific characteristics of a lymphocytic infiltrate noted on frozen section histologic examination during Mohs micrographic surgery (MMS) tumor excision should raise suspicion of an underlying chronic lymphocytic leukemia (CLL). This infiltrate may be the presenting sign of the underlying leukemia and has variable presentation that may mimic aggressive features. The following 3 cases highlight this phenomenon.

A 74-year-old man (patient 1) with a medical history of multiple nonmelanoma skin cancers (NMSCs) presented for definitive treatment of a biopsy-proven infiltrative basal cell carcinoma involving the right infra-auricular region. Mohs section histologic evaluation revealed patches of lymphocytic infiltrates so dense they obscured the tumor margins. The lymphocytic infiltrates persisted even after 3 MMS stages, though they were moderately less dense compared to the initial MMS stage. Clinical interpretation determined no relationship between the lymphocytic infiltrates and residual tumor. Due to concerns that this lymphocytic infiltrate may indicate an underlying leukemic process, preoperative laboratory tests were ordered prior to closure of the surgical wound, which demonstrated an elevated white blood cell count of 65,000/µL (reference range, 4500–11,000/µL) with 93% lymphocytes. A follow-up complete blood cell count (CBC) and blood smear confirmed the diagnosis of CLL. The patient was referred to a hematologist/oncologist.

An 84-year old man (patient 2) with a medical history of numerous precancerous lesions and 1 squamous cell carcinoma (SCC) presented for a biopsy, which determined moderately differentiated SCC. Mohs micrographic surgery was performed. The initial stage of MMS histologic examination demonstrated basosquamous carcinoma in the specimen margins, including perineural growth, with an extensive lymphoid infiltrate surrounding the tumor (Figure 1). A second stage of MMS was performed, and although margins appeared to be clear of the basosquamous histology, complete assessment was difficult due to areas of dense inflammatory infiltrate (Figure 2), including perineural infiltration that remained and appeared to extend deeper into the tissues. Pathology was consulted and it was determined that the perineural infiltration was unlikely related to tumor spread but rather secondary to an unknown cause. Further investigation of the patient’s medical history revealed previously diagnosed CLL, which had been omitted by the patient, as he had forgotten this diagnosis and denied a history of cancer, lymphoma, and even leukemia. A query to the patient’s primary care physician found the most recent CBC demonstrated an elevated white blood cell count of 37,600/µL with 78% lymphocytes.

An 84-year-old man (patient 3) with a known history of CLL was referred for MMS excision of a 3.5×4.0-cm SCC on the right anterior temple extending onto the lateral upper and lower eyelids. Mohs frozen section histologic examination of excised tissue revealed patches of heavy lymphocytic infiltrates not found exclusively around the residual tumor but additionally around superficial and deep neurovascular bundles. The second stage of MMS appeared to be clear of tumor cells, but lymphocytic infiltrates remained. Because this patient had a clear history of CLL, the decision was made in conjunction with a dermatopathologist to conclude the surgery at this point. However, secondary to the aggressive, deeply invasive growth of this SCC, the patient was referred for adjunctive radiation therapy to the surgical site after wound reconstruction.

Chronic lymphocytic leukemia is the most common leukemia in the Western world¹ and is estimated to account for 27% of all new cases of leukemia. An individual’s lifetime risk is 0.5%. Chronic lymphocytic leukemia is predominantly a disease of the elderly, with an average age at diagnosis of 71 years. It is more common among males, North American and European populations, and those with a positive family history. Although epidemiologic factors including farming, prolonged pesticide exposure, and contact with Agent Orange have tentative links to CLL, the relationships are poorly established.²

Symptoms associated with acute leukemia only rarely manifest in patients with CLL.³ If present, symptoms are vague and include weakness, fatigue, weight loss, fever, night sweats, and a feeling of abdominal fullness.^2,3 On clinical examination, patients also may have lymphadenopathy, splenomegaly, or hepatomegaly. Increasing severity of symptoms at time of presentation directly correlates with the severity and staging at the time of diagnosis.⁴ Not only do patients with CLL have a greater incidence of NMSCs with more notable subclinical tumor extension than the average person, but these individuals also have a greatly increased risk for skin cancer recurrence posttreatment.^5,6

Although tissue pathology is not routinely part of the diagnosis of patients with CLL, findings can add to clinical suspicion. Smudge cells, which are cell debris, are characteristic morphologic features found in CLL. Most CLL cells are characteristically small mature lymphocytes with a dense nucleus.³ The presence of aggregates of these cells may obscure tumor margins during resection of NMSCs.⁷ This infiltrate is present in more than one-third of patients with CLL, as described in one retrospective cohort. This study simultaneously demonstrated the relationship between CLL and a 2-fold increase in postoperative defect size, which was attributed to either subclinical tumor spread or extra tissue removal to ensure clearance due to the leukemic infiltrates themselves.⁸ The presence of perineural tumor growth, which can occur with aggressive SCC and basal cell carcinoma, may be mimicked by perineural involvement of CLL cells rather than the reactive inflammation associated with continued tumor margins.⁷

When evaluating a patient with suspected CLL, laboratory tests should include a CBC with differential and examination of the peripheral smear. If abnormal, immunophenotyping of lymphocytes by flow cytometry will rule out other lymphoproliferative diseases and verify CLL as the diagnosis.³ Diagnosis of CLL requires the presence of monoclonal B lymphocytes (≥5×10⁹/L) in the peripheral blood as confirmed by flow cytometry.³ Clonality of circulating B lymphocytes must be confirmed, and immunophenotyping will establish a diagnosis with leukemic cells having positive expression of CD20 (Figure 3A) and CD23 (Figure 3B)(characteristic of B-cell lineage) with coexpression of CD43 and CD5 (Figure 3C)(characteristic of T-cell lineage).^7,9 This pattern of immunohistochemical markers can be differentiated from the normal immune response to cutaneous malignancies, which have the pattern of being CD3⁺, CD5⁺, and CD43⁺ with absence of B-cell markers (ie, CD20, CD23)(Table).⁷

The pathogenesis of this peritumoral infiltrate is unknown, though multiple theories exist. One theory is that the neoplastic lymphocytes are responding as a dysfunctional arm of the immune system to tumor-specific antigens. In patients with CLL, leukemic lymphocytes comprise a large portion of the circulating leukocyte population and this peritumoral infiltrate may simply be a reflection of the circulating leukocytic population. Another theory contends that neoplastic lymphocytes are simply nonspecific aggregations secondary to tumor neovascularization and increased vascular permeability.¹⁰

This neoplastic infiltrate seen incidentally during MMS excision of NMSCs not only provides a unique opportunity to diagnose and intervene in those with unknown CLL but also to be aware of complicating features that can spare the patient from unnecessary tissue removal, thereby maximizing the benefit of MMS. This infiltrate can obscure tumor margins; is unusually dense and patchy, with or without infiltrating perineural or perivascular components; and persists beyond what would seem to be an adequate margin to clear a tumor. These cases show these findings, which exemplify the peritumoral infiltrate of CLL and should prompt further workup.