Dermatopathology

The Diagnosis: Inverted Follicular Keratosis

The differential diagnosis for endophytic squamous neoplasms encompasses benign and malignant entities. The histologic findings of our patient's lesion were compatible with the diagnosis of inverted follicular keratosis (IFK), a benign neoplasm that usually presents as a keratotic papule on the head or neck. Histologically, IFK is characterized by an endophytic growth pattern with squamous eddies (quiz images). Inverted follicular keratosis may represent an irritated seborrheic keratosis or a distinct neoplasm derived from the infundibular portion of the hair follicle; the exact etiology is uncertain.^1,2 No relationship between IFK and human papillomavirus (HPV) has been established.³ Inverted follicular keratosis can mimic squamous cell carcinoma (SCC). Important clues to the diagnosis of IFK are the presence of squamous eddies and the lack of squamous pearls or cytologic atypia.⁴ Squamous eddies consist of whorled keratinocytes without keratinization or atypia. Superficial shave biopsies may fail to demonstrate the characteristic well-circumscribed architecture and may lead to an erroneous diagnosis.

Acantholytic SCC is characterized by atypical keratinocytes that have lost cohesive properties, resulting in acantholysis (Figure 1).⁵ This histologic variant was once categorized as an aggressive variant of SCC, but studies have failed to support this assertion.^5,6 Acantholytic SCC has a discohesive nature producing a pseudoglandular appearance sometimes mistaken for adenosquamous carcinoma or metastatic carcinoma. Recent literature has suggested that acantholytic SCCs, similar to IFKs, are derived from the follicular infundibulum.^5,6 Also similar to IFKs, acantholytic SCCs often are located on the face. The invasive architecture and atypical cytology of acantholytic SCCs can differentiate them from IFKs. Acantholytic SCCs can contain keratin pearls with concentric keratinocytes showing incomplete keratinization centrally, often with retained nuclei, but rare to no squamous eddies unless irritated.

Trichilemmoma is an endophytic benign neoplasm derived from the outer sheath of the pilosebaceous follicle characterized by lobules of clear cells hanging from the epidermis.⁷ A study investigating the relationship between HPV and trichilemmomas failed to definitively detect HPV in trichilemmomas and this relationship remains unclear.⁸ Desmoplastic trichilemmoma is a subtype histologically characterized by jagged islands of epithelial cells separated by dense pink stroma and encased in a glassy basement membrane (Figure 2). The presence of desmoplasia and a jagged growth pattern can mimic invasive SCC, but the absence of cytologic atypia and the surrounding basement membrane differs from SCC.^4,7 Trichilemmomas typically are solitary, but multiple lesions are associated with Cowden syndrome. Cowden syndrome is a rare autosomal-dominant condition characterized by the presence of benign hamartomas and a predisposition to the development of malignancies including breast, endometrial, and thyroid cancers.^9,10 There is no such association with desmoplastic trichilemmomas.¹¹

Pilar sheath acanthoma is a benign neoplasm that clinically presents as a solitary flesh-colored nodule with a central pore containing keratin.¹² Histologically, pilar sheath acanthoma is similar to a dilated pore of Winer with the addition of acanthotic epidermal projections (Figure 3).

Warty dyskeratoma (WD) is a benign endophytic neoplasm traditionally seen as a solitary lesion histologically similar to Darier disease. Warty dyskeratomas are known to occur both on the skin and oral mucosa.¹³ Histologically, WD is characterized as a cup-shaped lesion with numerous villi at the base of the lesion along with acantholysis and dyskeratosis (Figure 4). The dyskeratotic cells in WD consist of corps ronds, which are cells with abundant pink cytoplasm, and small nuclei along with grains, which are flattened basophilic cells. These dyskeratotic cells help differentiate WD from IFK. Although they are endophytic neoplasms, WDs are well circumscribed and should not be confused with SCC. Despite this entity's name and histologic similarity to verrucae, no relationship with HPV has been established.¹⁴

The Diagnosis: Inverted Follicular Keratosis

The differential diagnosis for endophytic squamous neoplasms encompasses benign and malignant entities. The histologic findings of our patient's lesion were compatible with the diagnosis of inverted follicular keratosis (IFK), a benign neoplasm that usually presents as a keratotic papule on the head or neck. Histologically, IFK is characterized by an endophytic growth pattern with squamous eddies (quiz images). Inverted follicular keratosis may represent an irritated seborrheic keratosis or a distinct neoplasm derived from the infundibular portion of the hair follicle; the exact etiology is uncertain.^1,2 No relationship between IFK and human papillomavirus (HPV) has been established.³ Inverted follicular keratosis can mimic squamous cell carcinoma (SCC). Important clues to the diagnosis of IFK are the presence of squamous eddies and the lack of squamous pearls or cytologic atypia.⁴ Squamous eddies consist of whorled keratinocytes without keratinization or atypia. Superficial shave biopsies may fail to demonstrate the characteristic well-circumscribed architecture and may lead to an erroneous diagnosis.

Acantholytic SCC is characterized by atypical keratinocytes that have lost cohesive properties, resulting in acantholysis (Figure 1).⁵ This histologic variant was once categorized as an aggressive variant of SCC, but studies have failed to support this assertion.^5,6 Acantholytic SCC has a discohesive nature producing a pseudoglandular appearance sometimes mistaken for adenosquamous carcinoma or metastatic carcinoma. Recent literature has suggested that acantholytic SCCs, similar to IFKs, are derived from the follicular infundibulum.^5,6 Also similar to IFKs, acantholytic SCCs often are located on the face. The invasive architecture and atypical cytology of acantholytic SCCs can differentiate them from IFKs. Acantholytic SCCs can contain keratin pearls with concentric keratinocytes showing incomplete keratinization centrally, often with retained nuclei, but rare to no squamous eddies unless irritated.

Trichilemmoma is an endophytic benign neoplasm derived from the outer sheath of the pilosebaceous follicle characterized by lobules of clear cells hanging from the epidermis.⁷ A study investigating the relationship between HPV and trichilemmomas failed to definitively detect HPV in trichilemmomas and this relationship remains unclear.⁸ Desmoplastic trichilemmoma is a subtype histologically characterized by jagged islands of epithelial cells separated by dense pink stroma and encased in a glassy basement membrane (Figure 2). The presence of desmoplasia and a jagged growth pattern can mimic invasive SCC, but the absence of cytologic atypia and the surrounding basement membrane differs from SCC.^4,7 Trichilemmomas typically are solitary, but multiple lesions are associated with Cowden syndrome. Cowden syndrome is a rare autosomal-dominant condition characterized by the presence of benign hamartomas and a predisposition to the development of malignancies including breast, endometrial, and thyroid cancers.^9,10 There is no such association with desmoplastic trichilemmomas.¹¹

Pilar sheath acanthoma is a benign neoplasm that clinically presents as a solitary flesh-colored nodule with a central pore containing keratin.¹² Histologically, pilar sheath acanthoma is similar to a dilated pore of Winer with the addition of acanthotic epidermal projections (Figure 3).

Warty dyskeratoma (WD) is a benign endophytic neoplasm traditionally seen as a solitary lesion histologically similar to Darier disease. Warty dyskeratomas are known to occur both on the skin and oral mucosa.¹³ Histologically, WD is characterized as a cup-shaped lesion with numerous villi at the base of the lesion along with acantholysis and dyskeratosis (Figure 4). The dyskeratotic cells in WD consist of corps ronds, which are cells with abundant pink cytoplasm, and small nuclei along with grains, which are flattened basophilic cells. These dyskeratotic cells help differentiate WD from IFK. Although they are endophytic neoplasms, WDs are well circumscribed and should not be confused with SCC. Despite this entity's name and histologic similarity to verrucae, no relationship with HPV has been established.¹⁴

The Diagnosis: Inverted Follicular Keratosis

The differential diagnosis for endophytic squamous neoplasms encompasses benign and malignant entities. The histologic findings of our patient's lesion were compatible with the diagnosis of inverted follicular keratosis (IFK), a benign neoplasm that usually presents as a keratotic papule on the head or neck. Histologically, IFK is characterized by an endophytic growth pattern with squamous eddies (quiz images). Inverted follicular keratosis may represent an irritated seborrheic keratosis or a distinct neoplasm derived from the infundibular portion of the hair follicle; the exact etiology is uncertain.^1,2 No relationship between IFK and human papillomavirus (HPV) has been established.³ Inverted follicular keratosis can mimic squamous cell carcinoma (SCC). Important clues to the diagnosis of IFK are the presence of squamous eddies and the lack of squamous pearls or cytologic atypia.⁴ Squamous eddies consist of whorled keratinocytes without keratinization or atypia. Superficial shave biopsies may fail to demonstrate the characteristic well-circumscribed architecture and may lead to an erroneous diagnosis.

Acantholytic SCC is characterized by atypical keratinocytes that have lost cohesive properties, resulting in acantholysis (Figure 1).⁵ This histologic variant was once categorized as an aggressive variant of SCC, but studies have failed to support this assertion.^5,6 Acantholytic SCC has a discohesive nature producing a pseudoglandular appearance sometimes mistaken for adenosquamous carcinoma or metastatic carcinoma. Recent literature has suggested that acantholytic SCCs, similar to IFKs, are derived from the follicular infundibulum.^5,6 Also similar to IFKs, acantholytic SCCs often are located on the face. The invasive architecture and atypical cytology of acantholytic SCCs can differentiate them from IFKs. Acantholytic SCCs can contain keratin pearls with concentric keratinocytes showing incomplete keratinization centrally, often with retained nuclei, but rare to no squamous eddies unless irritated.

Trichilemmoma is an endophytic benign neoplasm derived from the outer sheath of the pilosebaceous follicle characterized by lobules of clear cells hanging from the epidermis.⁷ A study investigating the relationship between HPV and trichilemmomas failed to definitively detect HPV in trichilemmomas and this relationship remains unclear.⁸ Desmoplastic trichilemmoma is a subtype histologically characterized by jagged islands of epithelial cells separated by dense pink stroma and encased in a glassy basement membrane (Figure 2). The presence of desmoplasia and a jagged growth pattern can mimic invasive SCC, but the absence of cytologic atypia and the surrounding basement membrane differs from SCC.^4,7 Trichilemmomas typically are solitary, but multiple lesions are associated with Cowden syndrome. Cowden syndrome is a rare autosomal-dominant condition characterized by the presence of benign hamartomas and a predisposition to the development of malignancies including breast, endometrial, and thyroid cancers.^9,10 There is no such association with desmoplastic trichilemmomas.¹¹

Pilar sheath acanthoma is a benign neoplasm that clinically presents as a solitary flesh-colored nodule with a central pore containing keratin.¹² Histologically, pilar sheath acanthoma is similar to a dilated pore of Winer with the addition of acanthotic epidermal projections (Figure 3).

Warty dyskeratoma (WD) is a benign endophytic neoplasm traditionally seen as a solitary lesion histologically similar to Darier disease. Warty dyskeratomas are known to occur both on the skin and oral mucosa.¹³ Histologically, WD is characterized as a cup-shaped lesion with numerous villi at the base of the lesion along with acantholysis and dyskeratosis (Figure 4). The dyskeratotic cells in WD consist of corps ronds, which are cells with abundant pink cytoplasm, and small nuclei along with grains, which are flattened basophilic cells. These dyskeratotic cells help differentiate WD from IFK. Although they are endophytic neoplasms, WDs are well circumscribed and should not be confused with SCC. Despite this entity's name and histologic similarity to verrucae, no relationship with HPV has been established.¹⁴

The Diagnosis: Antiphospholipid Antibody Syndrome

A  biopsy demonstrated scattered intravascular thrombi in the dermis and subcutis, intact vascular walls, and scant lymphocytic inflammation in a background of stasis (Figure 1). A periodic acid-Schiff stain was negative for fungal elements and highlighted the intravascular thrombi. Histologic findings were consistent with thrombotic vasculopathy. On further laboratory workup, lupus anticoagulant studies, including a mixing study, diluted Russell viper venom test, and hexagonal phase phospholipid neutralization test, were abnormal. Titers of anticardiolipin and β₂-glycoprotein I antibodies were elevated (anticardiolipin IgG, 137.7 calculated units [normal, <15 calculated units]; β₂-glycoprotein I IgG, 256.4 calculated units [normal, <20 calculated units]). Tissue cultures showed no growth of microorganisms and studies for cryoglobulinemia were negative.

The patient was diagnosed with primary antiphospholipid syndrome (APS). He remained on anticoagulation therapy with fondaparinux as an inpatient and was treated with pulse-dose intravenous (IV) corticosteroids followed by a slow oral taper, daily plasmapheresis for 1 week, IV immunoglobulin (0.5 g/kg) for 3 doses, and 4 weekly doses of rituximab (375 mg/m²). His cutaneous findings slowly improved over the next several weeks (Figure 2).

Antiphospholipid syndrome is an autoimmune disorder characterized by thrombotic events and the presence of autoantibodies. The syndrome is defined by 2 major criteria: (1) the occurrence of at least 1 clinical feature of either an episode of vascular thrombosis or pregnancy morbidity such as unexplained fetal death beyond 10 weeks of gestation or recurrent unexplained pregnancy losses; and (2) the presence of at least 1 type of autoantibody, including lupus anticoagulant, anticardiolipin, or β₂-glycoprotein antibodies, on 2 separate occasions at least 12 weeks apart.¹ Antiphospholipid syndrome can either be primary with no identifiable associated rheumatologic disease or secondary to another autoimmune disease such as systemic lupus erythematosus. Cutaneous manifestations are common and frequently are the first sign of disease in 30% to 40% of patients.² The most common skin finding is persistent livedo reticularis, which can be seen in 20% to 25% of patients. Patients also may develop skin necrosis, ulcerations, digital gangrene, splinter hemorrhages, and livedoid vasculopathy.² Systemic manifestations of APS include thrombocytopenia, nephropathy, cognitive dysfunction, and cardiac valve abnormalities. 

The exact pathogenesis of APS remains unknown. It is thought to be due to the combination of an inflammatory stimulus that has yet to be characterized in conjunction with autoantibodies that affect multiple target cells including monocytes, platelets, and endothelial cells, which results in activation of the complement system and clotting cascade.³ In rare cases, the disorder can progress to catastrophic antiphospholipid syndrome (CAPS), which requires fulfillment of 4 criteria: (1) evidence of involvement of 3 organs, tissues, or systems; (2) development of manifestations simultaneously or in less than 1 week; (3) laboratory confirmation of the presence of antiphospholipid antibodies; and (4) confirmation by histopathology of small vessel occlusion.⁴ Probable CAPS is diagnosed when 3 of 4 criteria are present. Our patient met criteria for probable CAPS, as his antibody titers remained elevated 15 weeks after initial presentation. Precipitating factors that can lead to CAPS are thought to include infection, surgical procedures, medications, or discontinuation of anticoagulation drugs.² Although the mainstay of management of APS is anticoagulation therapy with warfarin and antiplatelet agents such as aspirin, first-line treatment of CAPS involves high-dose systemic glucocorticoids and plasma exchange. Intravenous immunoglobulin also may be employed in treatment. Data from the CAPS registry demonstrate a role for rituximab, an anti-CD20 antibody, at 375 mg/m² weekly for 4 weeks (the regimen described in our case) or 1 g every 14 days for 2 sessions.⁵ A majority of the registry patients treated with rituximab recovered (75% [15/20]) and had no recurrent thrombosis (87% [13/15]) at follow-up.⁵ Data also are emerging on the role of eculizumab, an anti-C5 antibody that inhibits the terminal complement cascade, as a therapy in difficult-to-treat or refractory CAPS.^6-8 The prognosis for CAPS patients without treatment is poor, and mortality has been reported in up to 44% of patients. However, with intervention mortality is reduced by more than 2-fold.^9,10

It is important to recognize that acral cyanosis with persistent livedo reticularis and digital gangrene can be a presenting manifestation of APS. These cutaneous manifestations should prompt histologic evaluation for thrombotic vasculopathy in addition to serologic tests for APS autoantibodies. Although APS may be treated with anticoagulants and antiplatelet agents, CAPS may require more aggressive therapy with systemic steroids, plasma exchange, IV immunoglobulin, rituximab, and/or eculizumab.

The Diagnosis: Antiphospholipid Antibody Syndrome

A  biopsy demonstrated scattered intravascular thrombi in the dermis and subcutis, intact vascular walls, and scant lymphocytic inflammation in a background of stasis (Figure 1). A periodic acid-Schiff stain was negative for fungal elements and highlighted the intravascular thrombi. Histologic findings were consistent with thrombotic vasculopathy. On further laboratory workup, lupus anticoagulant studies, including a mixing study, diluted Russell viper venom test, and hexagonal phase phospholipid neutralization test, were abnormal. Titers of anticardiolipin and β₂-glycoprotein I antibodies were elevated (anticardiolipin IgG, 137.7 calculated units [normal, <15 calculated units]; β₂-glycoprotein I IgG, 256.4 calculated units [normal, <20 calculated units]). Tissue cultures showed no growth of microorganisms and studies for cryoglobulinemia were negative.

The patient was diagnosed with primary antiphospholipid syndrome (APS). He remained on anticoagulation therapy with fondaparinux as an inpatient and was treated with pulse-dose intravenous (IV) corticosteroids followed by a slow oral taper, daily plasmapheresis for 1 week, IV immunoglobulin (0.5 g/kg) for 3 doses, and 4 weekly doses of rituximab (375 mg/m²). His cutaneous findings slowly improved over the next several weeks (Figure 2).

Antiphospholipid syndrome is an autoimmune disorder characterized by thrombotic events and the presence of autoantibodies. The syndrome is defined by 2 major criteria: (1) the occurrence of at least 1 clinical feature of either an episode of vascular thrombosis or pregnancy morbidity such as unexplained fetal death beyond 10 weeks of gestation or recurrent unexplained pregnancy losses; and (2) the presence of at least 1 type of autoantibody, including lupus anticoagulant, anticardiolipin, or β₂-glycoprotein antibodies, on 2 separate occasions at least 12 weeks apart.¹ Antiphospholipid syndrome can either be primary with no identifiable associated rheumatologic disease or secondary to another autoimmune disease such as systemic lupus erythematosus. Cutaneous manifestations are common and frequently are the first sign of disease in 30% to 40% of patients.² The most common skin finding is persistent livedo reticularis, which can be seen in 20% to 25% of patients. Patients also may develop skin necrosis, ulcerations, digital gangrene, splinter hemorrhages, and livedoid vasculopathy.² Systemic manifestations of APS include thrombocytopenia, nephropathy, cognitive dysfunction, and cardiac valve abnormalities. 

The exact pathogenesis of APS remains unknown. It is thought to be due to the combination of an inflammatory stimulus that has yet to be characterized in conjunction with autoantibodies that affect multiple target cells including monocytes, platelets, and endothelial cells, which results in activation of the complement system and clotting cascade.³ In rare cases, the disorder can progress to catastrophic antiphospholipid syndrome (CAPS), which requires fulfillment of 4 criteria: (1) evidence of involvement of 3 organs, tissues, or systems; (2) development of manifestations simultaneously or in less than 1 week; (3) laboratory confirmation of the presence of antiphospholipid antibodies; and (4) confirmation by histopathology of small vessel occlusion.⁴ Probable CAPS is diagnosed when 3 of 4 criteria are present. Our patient met criteria for probable CAPS, as his antibody titers remained elevated 15 weeks after initial presentation. Precipitating factors that can lead to CAPS are thought to include infection, surgical procedures, medications, or discontinuation of anticoagulation drugs.² Although the mainstay of management of APS is anticoagulation therapy with warfarin and antiplatelet agents such as aspirin, first-line treatment of CAPS involves high-dose systemic glucocorticoids and plasma exchange. Intravenous immunoglobulin also may be employed in treatment. Data from the CAPS registry demonstrate a role for rituximab, an anti-CD20 antibody, at 375 mg/m² weekly for 4 weeks (the regimen described in our case) or 1 g every 14 days for 2 sessions.⁵ A majority of the registry patients treated with rituximab recovered (75% [15/20]) and had no recurrent thrombosis (87% [13/15]) at follow-up.⁵ Data also are emerging on the role of eculizumab, an anti-C5 antibody that inhibits the terminal complement cascade, as a therapy in difficult-to-treat or refractory CAPS.^6-8 The prognosis for CAPS patients without treatment is poor, and mortality has been reported in up to 44% of patients. However, with intervention mortality is reduced by more than 2-fold.^9,10

It is important to recognize that acral cyanosis with persistent livedo reticularis and digital gangrene can be a presenting manifestation of APS. These cutaneous manifestations should prompt histologic evaluation for thrombotic vasculopathy in addition to serologic tests for APS autoantibodies. Although APS may be treated with anticoagulants and antiplatelet agents, CAPS may require more aggressive therapy with systemic steroids, plasma exchange, IV immunoglobulin, rituximab, and/or eculizumab.

The Diagnosis: Antiphospholipid Antibody Syndrome

A  biopsy demonstrated scattered intravascular thrombi in the dermis and subcutis, intact vascular walls, and scant lymphocytic inflammation in a background of stasis (Figure 1). A periodic acid-Schiff stain was negative for fungal elements and highlighted the intravascular thrombi. Histologic findings were consistent with thrombotic vasculopathy. On further laboratory workup, lupus anticoagulant studies, including a mixing study, diluted Russell viper venom test, and hexagonal phase phospholipid neutralization test, were abnormal. Titers of anticardiolipin and β₂-glycoprotein I antibodies were elevated (anticardiolipin IgG, 137.7 calculated units [normal, <15 calculated units]; β₂-glycoprotein I IgG, 256.4 calculated units [normal, <20 calculated units]). Tissue cultures showed no growth of microorganisms and studies for cryoglobulinemia were negative.

The patient was diagnosed with primary antiphospholipid syndrome (APS). He remained on anticoagulation therapy with fondaparinux as an inpatient and was treated with pulse-dose intravenous (IV) corticosteroids followed by a slow oral taper, daily plasmapheresis for 1 week, IV immunoglobulin (0.5 g/kg) for 3 doses, and 4 weekly doses of rituximab (375 mg/m²). His cutaneous findings slowly improved over the next several weeks (Figure 2).

Antiphospholipid syndrome is an autoimmune disorder characterized by thrombotic events and the presence of autoantibodies. The syndrome is defined by 2 major criteria: (1) the occurrence of at least 1 clinical feature of either an episode of vascular thrombosis or pregnancy morbidity such as unexplained fetal death beyond 10 weeks of gestation or recurrent unexplained pregnancy losses; and (2) the presence of at least 1 type of autoantibody, including lupus anticoagulant, anticardiolipin, or β₂-glycoprotein antibodies, on 2 separate occasions at least 12 weeks apart.¹ Antiphospholipid syndrome can either be primary with no identifiable associated rheumatologic disease or secondary to another autoimmune disease such as systemic lupus erythematosus. Cutaneous manifestations are common and frequently are the first sign of disease in 30% to 40% of patients.² The most common skin finding is persistent livedo reticularis, which can be seen in 20% to 25% of patients. Patients also may develop skin necrosis, ulcerations, digital gangrene, splinter hemorrhages, and livedoid vasculopathy.² Systemic manifestations of APS include thrombocytopenia, nephropathy, cognitive dysfunction, and cardiac valve abnormalities. 

The exact pathogenesis of APS remains unknown. It is thought to be due to the combination of an inflammatory stimulus that has yet to be characterized in conjunction with autoantibodies that affect multiple target cells including monocytes, platelets, and endothelial cells, which results in activation of the complement system and clotting cascade.³ In rare cases, the disorder can progress to catastrophic antiphospholipid syndrome (CAPS), which requires fulfillment of 4 criteria: (1) evidence of involvement of 3 organs, tissues, or systems; (2) development of manifestations simultaneously or in less than 1 week; (3) laboratory confirmation of the presence of antiphospholipid antibodies; and (4) confirmation by histopathology of small vessel occlusion.⁴ Probable CAPS is diagnosed when 3 of 4 criteria are present. Our patient met criteria for probable CAPS, as his antibody titers remained elevated 15 weeks after initial presentation. Precipitating factors that can lead to CAPS are thought to include infection, surgical procedures, medications, or discontinuation of anticoagulation drugs.² Although the mainstay of management of APS is anticoagulation therapy with warfarin and antiplatelet agents such as aspirin, first-line treatment of CAPS involves high-dose systemic glucocorticoids and plasma exchange. Intravenous immunoglobulin also may be employed in treatment. Data from the CAPS registry demonstrate a role for rituximab, an anti-CD20 antibody, at 375 mg/m² weekly for 4 weeks (the regimen described in our case) or 1 g every 14 days for 2 sessions.⁵ A majority of the registry patients treated with rituximab recovered (75% [15/20]) and had no recurrent thrombosis (87% [13/15]) at follow-up.⁵ Data also are emerging on the role of eculizumab, an anti-C5 antibody that inhibits the terminal complement cascade, as a therapy in difficult-to-treat or refractory CAPS.^6-8 The prognosis for CAPS patients without treatment is poor, and mortality has been reported in up to 44% of patients. However, with intervention mortality is reduced by more than 2-fold.^9,10

It is important to recognize that acral cyanosis with persistent livedo reticularis and digital gangrene can be a presenting manifestation of APS. These cutaneous manifestations should prompt histologic evaluation for thrombotic vasculopathy in addition to serologic tests for APS autoantibodies. Although APS may be treated with anticoagulants and antiplatelet agents, CAPS may require more aggressive therapy with systemic steroids, plasma exchange, IV immunoglobulin, rituximab, and/or eculizumab.

In 1964, Sweet¹ described 8 women with acute onset of fever and erythematous plaques associated with a nonspecific infection of the respiratory or gastrointestinal tract. The lesions were histologically characterized by a neutrophilic infiltrate, and the author named the constellation of findings acute febrile neutrophilic dermatosis.¹ In 1968, Whittle et al² reported on similar cases and coined the term Sweet syndrome (SS).

Although the etiology and pathogenesis of SS remain unknown, several theories have been proposed. Because SS often is preceded by a respiratory or gastrointestinal tract infection, it has been postulated that it may represent a hypersensitivity reaction or may be related to local or systemic dysregulation of cytokine secretion.^3,4 In addition to respiratory or gastrointestinal tract infections, SS has been reported in association with malignancies, autoimmune diseases, drugs, vaccines, pregnancy, inflammatory bowel disease, and chemotherapy. It also may be idiopathic.⁵

The eruption of SS manifests as erythematous, indurated, and sharply demarcated plaques or nodules that typically favor the head, neck, and arms, with a particularly strong predilection for the dorsal aspects of the hands.⁶ Plaques and nodules are histologically characterized by a diffuse dermal neutrophilic infiltrate, papillary dermal edema, neutrophilic spongiosis, subcorneal pustules, and leukocytoclasia. Vasculitic features are not seen.⁷ The eruption typically resolves spontaneously in 5 to 12 weeks but recurs in approximately 30% of cases.⁸ Relatively common extracutaneous findings include ocular involvement, arthralgia, myalgia, and arthritis.^4,9 Both cutaneous and extracutaneous findings typically are responsive to prednisone at a dosage of 0.5 to 1 mg/kg daily for 4 to 6 weeks. Prolonged low-dose prednisone for 2 to 3 additional months may be necessary to suppress recurrence.⁸ Potassium iodide at 900 mg daily may be used as an alternative regimen.^3,8

Sweet syndrome is divided into 5 subcategories based on the underlying etiology: (1) classic or idiopathic, (2) paraneoplastic, (3) inflammatory and/or autoimmune disease related, (4) pregnancy related, and (5) drug induced.³ Although drug-induced SS comprises the minority of total cases (<5%), its reported incidence has been rising in recent years and has been associated with an escalating number of medications.¹⁰ We report a rare case of SS induced by administration of oral acetaminophen-codeine.

Case Report

A 32-year-old man with a history of diabetes mellitus underwent postoperative repair of a facial fracture. The patient was administered an oral acetaminophen-codeine suspension for postoperative pain control. One week later, he developed a painful eruption on the forehead and presented to the emergency department. He was prescribed acetaminophen-codeine 300/30-mg tablets every 6 hours in addition to hydrocortisone cream 1% applied every 6 hours. After this reintroduction of oral acetaminophen-codeine, he experienced intermittent fevers and an exacerbation of the initial cutaneous eruption. The patient presented for a second time 2 days after being seen in the emergency department and a dermatology consultation was obtained.

At the time of consultation, the patient was noted to have injected conjunctiva and erythematous, well-demarcated, and indurated plaques on the forehead with associated pain and burning (Figures 1A and 1B). Additional erythematous annular plaques were found on the palms, arms, and right knee. Laboratory workup revealed only mild anemia on complete blood cell count with a white blood cell count of 10.1×10⁹/L (reference range, 4.5–11.0×10⁹/L), hemoglobin of 12.9 g/dL (reference range, 14.0–17.4 g/dL), and hematocrit of 37.3% (reference range, 41%–50%). The platelet count was 284×10³/µL (reference range, 150–350×10³/µL). Basic metabolic panel was notable for an elevated glucose level of 418 mg/dL (reference range, 70–110 mg/dL). The most recent hemoglobin A_1C (several months prior) was notable at 14.7% of total hemoglobin (reference range, 4%–7% of total hemoglobin). A 4-mm punch biopsy of the right side of the forehead demonstrated minimal to mild papillary dermal edema and a diffuse dermal neutrophilic infiltrate spanning the upper, middle, and lower dermis with evidence of mild leukocytoclasia and no evidence of leukocytoclastic vasculitis (Figure 2). These histologic features together with the clinical presentation were consistent with a diagnosis of SS.

After an initial dose of intravenous methylprednisolone sodium succinate 125 mg in the emergency department, the patient was admitted for additional intravenous steroid administration in the context of uncontrolled hyperglycemia and history of poor glucose control. Upon admission, acetaminophen-codeine was discontinued and the patient was transitioned to intravenous methylprednisolone sodium succinate 60 mg every 8 hours. The patient also was given intravenous diphenhydramine 25 mg every 6 hours and desonide ointment 0.05% was applied to facial lesions. The inpatient medication regimen resulted in notable improvement of symptoms within 48 hours. Due to rapid improvement with steroids, no special stains for infectious etiologies were performed. The patient was discharged after 3 days in the hospital with triamcinolone ointment 0.1% to be applied to affected areas twice daily. The patient experienced no recurrence 2 months after treatment (Figure 1C).

Comment

Although SS itself is relatively rare, there has been an increasing incidence of the drug-induced subtype, most often in association with use of granulocyte colony-stimulating factor and granulocyte monocyte-stimulating factor. There also have been reported associations with a growing number of medications that include antibiotics, antiepileptic drugs, furosemide, hydralazine, and all-trans retinoic acid.^11-19 Moghimi et al¹¹ also reported an association with antivirals, cancer biotherapies, nonsteroidal anti-inflammatory drugs, psychotropes, azathioprine, oral contraceptives, and propylthiouracil.^10,20-26 Moghimi et al¹¹ further reported an association with several vaccines.

Several therapies for advanced melanoma also have been reviewed in the literature, including ipilimumab and vemurafenib,^27-30 as have several medications for the treatment of myelodysplastic syndrome including azacitidine.^31,32 A severe episode of drug-induced SS, predominantly on the legs, has been reported in association with lenalidomide, an immunomodulatory agent used in the treatment of myelodysplastic syndrome.³³

Additional medications more recently involved in the pathogenesis of drug-induced SS include the chemotherapeutic agents topetecan, mitoxantrone, gemcitabine, and vorinostat.^34-37 The antimalarial medication chloroquine also has been implicated, as have selective cyclooxygenase-2 inhibitors, hypomethylating agents, the tumor necrosis factor inhibitor adalimumab, IL-2 therapies, aripiprazole, and several other medications.^38-49

Despite drug-induced SS being reported in association with an increasing number of medications, there had been a lack of appropriate diagnostic criteria. To that end, Walker and Cohen⁵⁰ proposed 5 specific diagnostic criteria in 1996, including abrupt onset of painful erythematous plaques or nodules, histopathologic evidence of a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis, pyrexia (temperature >38°C), temporal relationship between drug ingestion and clinical presentation or temporally related recurrence after oral rechallenge, and temporally related resolution of lesions after drug withdrawal or treatment with systemic corticosteroids.^50,51 Our patient met all of these criteria.

Conclusion

The number of cases of drug-induced SS in the literature continues to climb; however, the association with acetaminophen-codeine is unique. The importance of this case lies in educating both physicians and pharmacists alike regarding a newly recognized adverse effect of acetaminophen-codeine. Because acetaminophen-codeine often is used for its analgesic properties, and the predominant symptom of the cutaneous eruption of SS is pain, the therapeutic value of acetaminophen-codeine is substantially diminished in acetaminophen-codeine–induced SS. Accordingly, in these cases, the medication may be discontinued or substituted upon recognition of this adverse reaction to reduce patient morbidity.

In 1964, Sweet¹ described 8 women with acute onset of fever and erythematous plaques associated with a nonspecific infection of the respiratory or gastrointestinal tract. The lesions were histologically characterized by a neutrophilic infiltrate, and the author named the constellation of findings acute febrile neutrophilic dermatosis.¹ In 1968, Whittle et al² reported on similar cases and coined the term Sweet syndrome (SS).

Although the etiology and pathogenesis of SS remain unknown, several theories have been proposed. Because SS often is preceded by a respiratory or gastrointestinal tract infection, it has been postulated that it may represent a hypersensitivity reaction or may be related to local or systemic dysregulation of cytokine secretion.^3,4 In addition to respiratory or gastrointestinal tract infections, SS has been reported in association with malignancies, autoimmune diseases, drugs, vaccines, pregnancy, inflammatory bowel disease, and chemotherapy. It also may be idiopathic.⁵

The eruption of SS manifests as erythematous, indurated, and sharply demarcated plaques or nodules that typically favor the head, neck, and arms, with a particularly strong predilection for the dorsal aspects of the hands.⁶ Plaques and nodules are histologically characterized by a diffuse dermal neutrophilic infiltrate, papillary dermal edema, neutrophilic spongiosis, subcorneal pustules, and leukocytoclasia. Vasculitic features are not seen.⁷ The eruption typically resolves spontaneously in 5 to 12 weeks but recurs in approximately 30% of cases.⁸ Relatively common extracutaneous findings include ocular involvement, arthralgia, myalgia, and arthritis.^4,9 Both cutaneous and extracutaneous findings typically are responsive to prednisone at a dosage of 0.5 to 1 mg/kg daily for 4 to 6 weeks. Prolonged low-dose prednisone for 2 to 3 additional months may be necessary to suppress recurrence.⁸ Potassium iodide at 900 mg daily may be used as an alternative regimen.^3,8

Sweet syndrome is divided into 5 subcategories based on the underlying etiology: (1) classic or idiopathic, (2) paraneoplastic, (3) inflammatory and/or autoimmune disease related, (4) pregnancy related, and (5) drug induced.³ Although drug-induced SS comprises the minority of total cases (<5%), its reported incidence has been rising in recent years and has been associated with an escalating number of medications.¹⁰ We report a rare case of SS induced by administration of oral acetaminophen-codeine.

Case Report

A 32-year-old man with a history of diabetes mellitus underwent postoperative repair of a facial fracture. The patient was administered an oral acetaminophen-codeine suspension for postoperative pain control. One week later, he developed a painful eruption on the forehead and presented to the emergency department. He was prescribed acetaminophen-codeine 300/30-mg tablets every 6 hours in addition to hydrocortisone cream 1% applied every 6 hours. After this reintroduction of oral acetaminophen-codeine, he experienced intermittent fevers and an exacerbation of the initial cutaneous eruption. The patient presented for a second time 2 days after being seen in the emergency department and a dermatology consultation was obtained.

At the time of consultation, the patient was noted to have injected conjunctiva and erythematous, well-demarcated, and indurated plaques on the forehead with associated pain and burning (Figures 1A and 1B). Additional erythematous annular plaques were found on the palms, arms, and right knee. Laboratory workup revealed only mild anemia on complete blood cell count with a white blood cell count of 10.1×10⁹/L (reference range, 4.5–11.0×10⁹/L), hemoglobin of 12.9 g/dL (reference range, 14.0–17.4 g/dL), and hematocrit of 37.3% (reference range, 41%–50%). The platelet count was 284×10³/µL (reference range, 150–350×10³/µL). Basic metabolic panel was notable for an elevated glucose level of 418 mg/dL (reference range, 70–110 mg/dL). The most recent hemoglobin A_1C (several months prior) was notable at 14.7% of total hemoglobin (reference range, 4%–7% of total hemoglobin). A 4-mm punch biopsy of the right side of the forehead demonstrated minimal to mild papillary dermal edema and a diffuse dermal neutrophilic infiltrate spanning the upper, middle, and lower dermis with evidence of mild leukocytoclasia and no evidence of leukocytoclastic vasculitis (Figure 2). These histologic features together with the clinical presentation were consistent with a diagnosis of SS.

After an initial dose of intravenous methylprednisolone sodium succinate 125 mg in the emergency department, the patient was admitted for additional intravenous steroid administration in the context of uncontrolled hyperglycemia and history of poor glucose control. Upon admission, acetaminophen-codeine was discontinued and the patient was transitioned to intravenous methylprednisolone sodium succinate 60 mg every 8 hours. The patient also was given intravenous diphenhydramine 25 mg every 6 hours and desonide ointment 0.05% was applied to facial lesions. The inpatient medication regimen resulted in notable improvement of symptoms within 48 hours. Due to rapid improvement with steroids, no special stains for infectious etiologies were performed. The patient was discharged after 3 days in the hospital with triamcinolone ointment 0.1% to be applied to affected areas twice daily. The patient experienced no recurrence 2 months after treatment (Figure 1C).

Comment

Although SS itself is relatively rare, there has been an increasing incidence of the drug-induced subtype, most often in association with use of granulocyte colony-stimulating factor and granulocyte monocyte-stimulating factor. There also have been reported associations with a growing number of medications that include antibiotics, antiepileptic drugs, furosemide, hydralazine, and all-trans retinoic acid.^11-19 Moghimi et al¹¹ also reported an association with antivirals, cancer biotherapies, nonsteroidal anti-inflammatory drugs, psychotropes, azathioprine, oral contraceptives, and propylthiouracil.^10,20-26 Moghimi et al¹¹ further reported an association with several vaccines.

Several therapies for advanced melanoma also have been reviewed in the literature, including ipilimumab and vemurafenib,^27-30 as have several medications for the treatment of myelodysplastic syndrome including azacitidine.^31,32 A severe episode of drug-induced SS, predominantly on the legs, has been reported in association with lenalidomide, an immunomodulatory agent used in the treatment of myelodysplastic syndrome.³³

Additional medications more recently involved in the pathogenesis of drug-induced SS include the chemotherapeutic agents topetecan, mitoxantrone, gemcitabine, and vorinostat.^34-37 The antimalarial medication chloroquine also has been implicated, as have selective cyclooxygenase-2 inhibitors, hypomethylating agents, the tumor necrosis factor inhibitor adalimumab, IL-2 therapies, aripiprazole, and several other medications.^38-49

Despite drug-induced SS being reported in association with an increasing number of medications, there had been a lack of appropriate diagnostic criteria. To that end, Walker and Cohen⁵⁰ proposed 5 specific diagnostic criteria in 1996, including abrupt onset of painful erythematous plaques or nodules, histopathologic evidence of a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis, pyrexia (temperature >38°C), temporal relationship between drug ingestion and clinical presentation or temporally related recurrence after oral rechallenge, and temporally related resolution of lesions after drug withdrawal or treatment with systemic corticosteroids.^50,51 Our patient met all of these criteria.

Conclusion

The number of cases of drug-induced SS in the literature continues to climb; however, the association with acetaminophen-codeine is unique. The importance of this case lies in educating both physicians and pharmacists alike regarding a newly recognized adverse effect of acetaminophen-codeine. Because acetaminophen-codeine often is used for its analgesic properties, and the predominant symptom of the cutaneous eruption of SS is pain, the therapeutic value of acetaminophen-codeine is substantially diminished in acetaminophen-codeine–induced SS. Accordingly, in these cases, the medication may be discontinued or substituted upon recognition of this adverse reaction to reduce patient morbidity.

In 1964, Sweet¹ described 8 women with acute onset of fever and erythematous plaques associated with a nonspecific infection of the respiratory or gastrointestinal tract. The lesions were histologically characterized by a neutrophilic infiltrate, and the author named the constellation of findings acute febrile neutrophilic dermatosis.¹ In 1968, Whittle et al² reported on similar cases and coined the term Sweet syndrome (SS).

Although the etiology and pathogenesis of SS remain unknown, several theories have been proposed. Because SS often is preceded by a respiratory or gastrointestinal tract infection, it has been postulated that it may represent a hypersensitivity reaction or may be related to local or systemic dysregulation of cytokine secretion.^3,4 In addition to respiratory or gastrointestinal tract infections, SS has been reported in association with malignancies, autoimmune diseases, drugs, vaccines, pregnancy, inflammatory bowel disease, and chemotherapy. It also may be idiopathic.⁵

The eruption of SS manifests as erythematous, indurated, and sharply demarcated plaques or nodules that typically favor the head, neck, and arms, with a particularly strong predilection for the dorsal aspects of the hands.⁶ Plaques and nodules are histologically characterized by a diffuse dermal neutrophilic infiltrate, papillary dermal edema, neutrophilic spongiosis, subcorneal pustules, and leukocytoclasia. Vasculitic features are not seen.⁷ The eruption typically resolves spontaneously in 5 to 12 weeks but recurs in approximately 30% of cases.⁸ Relatively common extracutaneous findings include ocular involvement, arthralgia, myalgia, and arthritis.^4,9 Both cutaneous and extracutaneous findings typically are responsive to prednisone at a dosage of 0.5 to 1 mg/kg daily for 4 to 6 weeks. Prolonged low-dose prednisone for 2 to 3 additional months may be necessary to suppress recurrence.⁸ Potassium iodide at 900 mg daily may be used as an alternative regimen.^3,8

Sweet syndrome is divided into 5 subcategories based on the underlying etiology: (1) classic or idiopathic, (2) paraneoplastic, (3) inflammatory and/or autoimmune disease related, (4) pregnancy related, and (5) drug induced.³ Although drug-induced SS comprises the minority of total cases (<5%), its reported incidence has been rising in recent years and has been associated with an escalating number of medications.¹⁰ We report a rare case of SS induced by administration of oral acetaminophen-codeine.

Case Report

A 32-year-old man with a history of diabetes mellitus underwent postoperative repair of a facial fracture. The patient was administered an oral acetaminophen-codeine suspension for postoperative pain control. One week later, he developed a painful eruption on the forehead and presented to the emergency department. He was prescribed acetaminophen-codeine 300/30-mg tablets every 6 hours in addition to hydrocortisone cream 1% applied every 6 hours. After this reintroduction of oral acetaminophen-codeine, he experienced intermittent fevers and an exacerbation of the initial cutaneous eruption. The patient presented for a second time 2 days after being seen in the emergency department and a dermatology consultation was obtained.

At the time of consultation, the patient was noted to have injected conjunctiva and erythematous, well-demarcated, and indurated plaques on the forehead with associated pain and burning (Figures 1A and 1B). Additional erythematous annular plaques were found on the palms, arms, and right knee. Laboratory workup revealed only mild anemia on complete blood cell count with a white blood cell count of 10.1×10⁹/L (reference range, 4.5–11.0×10⁹/L), hemoglobin of 12.9 g/dL (reference range, 14.0–17.4 g/dL), and hematocrit of 37.3% (reference range, 41%–50%). The platelet count was 284×10³/µL (reference range, 150–350×10³/µL). Basic metabolic panel was notable for an elevated glucose level of 418 mg/dL (reference range, 70–110 mg/dL). The most recent hemoglobin A_1C (several months prior) was notable at 14.7% of total hemoglobin (reference range, 4%–7% of total hemoglobin). A 4-mm punch biopsy of the right side of the forehead demonstrated minimal to mild papillary dermal edema and a diffuse dermal neutrophilic infiltrate spanning the upper, middle, and lower dermis with evidence of mild leukocytoclasia and no evidence of leukocytoclastic vasculitis (Figure 2). These histologic features together with the clinical presentation were consistent with a diagnosis of SS.

After an initial dose of intravenous methylprednisolone sodium succinate 125 mg in the emergency department, the patient was admitted for additional intravenous steroid administration in the context of uncontrolled hyperglycemia and history of poor glucose control. Upon admission, acetaminophen-codeine was discontinued and the patient was transitioned to intravenous methylprednisolone sodium succinate 60 mg every 8 hours. The patient also was given intravenous diphenhydramine 25 mg every 6 hours and desonide ointment 0.05% was applied to facial lesions. The inpatient medication regimen resulted in notable improvement of symptoms within 48 hours. Due to rapid improvement with steroids, no special stains for infectious etiologies were performed. The patient was discharged after 3 days in the hospital with triamcinolone ointment 0.1% to be applied to affected areas twice daily. The patient experienced no recurrence 2 months after treatment (Figure 1C).

Comment

Although SS itself is relatively rare, there has been an increasing incidence of the drug-induced subtype, most often in association with use of granulocyte colony-stimulating factor and granulocyte monocyte-stimulating factor. There also have been reported associations with a growing number of medications that include antibiotics, antiepileptic drugs, furosemide, hydralazine, and all-trans retinoic acid.^11-19 Moghimi et al¹¹ also reported an association with antivirals, cancer biotherapies, nonsteroidal anti-inflammatory drugs, psychotropes, azathioprine, oral contraceptives, and propylthiouracil.^10,20-26 Moghimi et al¹¹ further reported an association with several vaccines.

Several therapies for advanced melanoma also have been reviewed in the literature, including ipilimumab and vemurafenib,^27-30 as have several medications for the treatment of myelodysplastic syndrome including azacitidine.^31,32 A severe episode of drug-induced SS, predominantly on the legs, has been reported in association with lenalidomide, an immunomodulatory agent used in the treatment of myelodysplastic syndrome.³³

Additional medications more recently involved in the pathogenesis of drug-induced SS include the chemotherapeutic agents topetecan, mitoxantrone, gemcitabine, and vorinostat.^34-37 The antimalarial medication chloroquine also has been implicated, as have selective cyclooxygenase-2 inhibitors, hypomethylating agents, the tumor necrosis factor inhibitor adalimumab, IL-2 therapies, aripiprazole, and several other medications.^38-49

Despite drug-induced SS being reported in association with an increasing number of medications, there had been a lack of appropriate diagnostic criteria. To that end, Walker and Cohen⁵⁰ proposed 5 specific diagnostic criteria in 1996, including abrupt onset of painful erythematous plaques or nodules, histopathologic evidence of a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis, pyrexia (temperature >38°C), temporal relationship between drug ingestion and clinical presentation or temporally related recurrence after oral rechallenge, and temporally related resolution of lesions after drug withdrawal or treatment with systemic corticosteroids.^50,51 Our patient met all of these criteria.

Conclusion

The number of cases of drug-induced SS in the literature continues to climb; however, the association with acetaminophen-codeine is unique. The importance of this case lies in educating both physicians and pharmacists alike regarding a newly recognized adverse effect of acetaminophen-codeine. Because acetaminophen-codeine often is used for its analgesic properties, and the predominant symptom of the cutaneous eruption of SS is pain, the therapeutic value of acetaminophen-codeine is substantially diminished in acetaminophen-codeine–induced SS. Accordingly, in these cases, the medication may be discontinued or substituted upon recognition of this adverse reaction to reduce patient morbidity.

Trichoblastomas are rare cutaneous tumors that recapitulate the germinative hair bulb and the surrounding mesenchyme. Although benign, they can present diagnostic difficulties for both the clinician and pathologist because of their rarity and overlap both clinically and microscopically with other follicular neoplasms as well as basal cell carcinoma (BCC). Several classification schemes for hair follicle neoplasms have been established based on the relative proportions of epithelial and mesenchymal components as well as stromal inductive change, but nomenclature continues to be problematic, as individual neoplasms show varying degrees of differentiation that do not always uniformly fit within these categories.^1,2 One of these established categories is a pigmented trichoblastoma.³ An exceedingly rare variant of a pigmented trichoblastoma referred to as melanotrichoblastoma was first described in 2002⁴ and has only been documented in 3 cases, according to a PubMed search of articles indexed for MEDLINE using the term melanotrichoblastoma.^4-6 We report another case of this rare tumor and review the literature on this unique group of tumors.

Case Report

A 25-year-old white woman with a medical history of chronic migraines, myofascial syndrome, and Arnold-Chiari malformation type I presented to dermatology with a 1.5-cm, pedunculated, well-circumscribed tumor on the left side of the scalp (Figure 1). The tumor was grossly flesh colored with heterogeneous areas of dark pigmentation. Microscopic examination demonstrated that within the superficial and deep dermis were variable-sized nests of basaloid cells. Some of the nests had large central cystic spaces with brown pigment within some of these spaces and focal pigmentation of the basaloid cells (Figure 2A). Focal areas of keratinization were present. Mitotic figures were easily identified; however, no atypical mitotic figures were present. Areas of peripheral palisading were present but there was no retraction artifact. Connection to the overlying epidermis was not identified. Surrounding the basaloid nodules was a mildly cellular proliferation of cytologically bland spindle cells. Occasional pigment-laden macrophages were present in the dermis. Focal areas suggestive of papillary mesenchymal body formation were present (Figure 2B). Immunohistochemical staining for Melan-A was performed and demonstrated the presence of a prominent number of melanocytes in some of the nests (Figure 3) and minimal to no melanocytes in other nests. There was no evidence of a melanocytic lesion involving the overlying epidermis. Features of nevus sebaceus were not present. Immunohistochemical staining for cytokeratin (CK) 20 was performed and demonstrated no notable number of Merkel cells within the lesion.

Comment

Overview of Trichoblastomas
Trichoblastomas most often present as solitary, flesh-colored, well-circumscribed, slow-growing tumors that usually progress in size over months to years. Although they may be present at any age, they most commonly occur in adults in the fifth to seventh decades of life and are equally distributed between males and females.^7,8 They most often occur on the head and neck with a predilection for the scalp. Although they behave in a benign fashion, cases of malignant trichoblastomas have been reported.⁹

Histopathology
Histologically, these tumors are well circumscribed but unencapsulated and usually located within the deep dermis, often with extension into the subcutaneous tissue. An epidermal connection is not identified. The tumor typically is composed of variable-sized nests of basaloid cells surrounded by a variable cellular stromal component. Although peripheral palisading is present in the basaloid component, retraction artifact is not present. Several histologic variants of trichoblastomas have been reported including cribriform, racemiform, retiform, pigmented, giant, subcutaneous, rippled pattern, and clear cell.⁵ Pigmented trichoblastomas are histologically similar to typical trichoblastomas, except for the presence of large amounts of melanin deposited within and around the tumor nests.⁶ A melanotrichoblastoma is a rare variant of a pigmented trichoblastoma; pigment is present in the lesion and melanocytes are identified within the basaloid nests.

The stromal component of trichoblastomas may show areas of condensation associated with some of the basaloid cells, resembling an attempt at hair bulb formation. Staining for CD10 will be positive in these areas of papillary mesenchymal bodies.¹⁰

In an immunohistochemical study of 13 cases of trichoblastomas, there was diffuse positive staining for CK14 and CK17 in all cases (similar to BCC) and positive staining for CK19 in 70% (9/13) of cases compared to 21% (4/19) of BCC cases. Staining for CK8 and CK20 demonstrated the presence of numerous Merkel cells in all trichoblastomas but in none of the 19 cases of BCC tested.¹¹ However, other studies have reported the presence of Merkel cells in only 42% to 70% of trichoblastomas.^12,13 Despite the lack of Merkel cells in our case, the lesion was interpreted as a melanotrichoblastoma based on the histologic features in conjunction with the presence of the melanocytes.

Differential Diagnosis
The clinical and histologic differential diagnosis of trichoblastomas includes both trichoepithelioma and BCC. Clinically, all 3 lesions often are slow growing, dome shaped, and small in size (several millimeters), and are observed in the same anatomic distribution of the head and neck region. Furthermore, they often affect middle-aged to older individuals and those of Caucasian descent, though other ethnicities can be affected. Histologic evaluation often is necessary to differentiate between these 3 entities.

Histologically, trichoepitheliomas are composed of nodules of basaloid cells encircled by stromal spindle cells. Although there can be histologic overlap between trichoepitheliomas and trichoblastoma, trichoepitheliomas typically will display obvious features of hair follicle differentiation with the presence of small keratinous cysts and hair bulb structures, while trichoblastomas tend to display minimal changes suggestive of its hair follicle origin. Similar to trichoblastomas, BCC is composed of nests of basaloid cells; however, BCCs often demonstrate retraction artifact and connection to the overlying epidermis. In addition, BCCs typically demonstrate a fibromucinous stromal component that is distinct from the cellular stroma of trichoblastic tumors. Immunoperoxidase staining for androgen receptors has been reported to be positive in 78% (25/32) of BCCs and negative in trichoblastic tumors.¹⁴

Melanotrichoblastoma Differentiating Characteristics
An exceedingly rare variant of pigmented trichoblastoma is the melanotrichoblastoma. There are clinical and histologic similarities and differences between the reported cases. The first case, described by Kanitakis et al,⁴ reported a 32-year-old black woman with a 2-cm scalp mass that slowly enlarged over the course of 2 years. The second case, presented by Kim et al,⁵ described a 51-year-old Korean man with a subcutaneous 6-cm mass on the back that had been present and slowly enlarging over the course of 5 years. The third case, reported by Hung et al,⁶ described a 34-year-old Taiwanese man with a 1-cm, left-sided, temporal scalp mass present for 3 years, arising from a nevus sebaceous. Comparing these clinical findings with our case of a 25-year-old white woman with a 1.5-cm mass on the left side of the scalp, melanotrichoblastomas demonstrate a relatively similar age of onset in the early to middle-aged adult years. All 4 tumors were slow growing. Additionally, 3 of 4 cases demonstrated a predilection for the head, particularly the scalp, and grossly showed well-circumscribed lesions with notable pigmentation. Although age, size, location, and gross appearance were similar, a comparable ethnic and gender demographic was not identified.

Microscopic similarities between the 4 cases were present. Each case was characterized by a large, well-circumscribed, unencapsulated, basaloid tumor present in the lower dermis, with only 1 case having tumor cells occasionally reaching the undersurface of the epidermis. The tumor cells were monomorphic round-ovoid in appearance with scant cytoplasm. There was melanin pigment in the basaloid nests. The basaloid nests were surrounded by a proliferation of stromal cells. The mitotic rate was sparse in 2 cases, brisk in 1 case, and not discussed in 1 case. Melanocytes were identified in the basaloid nests in all 4 cases; however, in the current case, the melanocytes were seen in only some of the nests. None of the cases exhibited an overlying junctional melanocytic lesion, which would argue against a possible collision tumor or colonization of an epithelial lesion by a melanocytic lesion.

Although the histologic features of our cases are consistent with prior reports of melanotrichoblastoma, there is some question as to whether it represents a true variant of a pigmented trichoblastoma. There are relatively few articles in the literature that describe pigmented trichoblastomas, and of those, immunohistochemistry staining for melanocytes is uncommon. In one of the earliest descriptions of a pigmented trichoblastoma, dendritic melanocytes were present within the tumor lobules; however, the lesion was reported as a pigmented trichoblastoma and not a melanotrichoblastoma.³ It is possible that all pigmented trichoblastomas may contain some number of dendritic melanocytes, thus negating the existence of a melanotrichoblastoma as a true subtype of pigmented trichoblastomas. Additional study looking at multiple examples of pigmented trichoblastomas would be required to more definitively classify melanotrichoblastomas. It is important to appreciate that at least some cases of pigmented trichoblastomas may contain melanocytes and not to confuse the lesion as representing an example of colonization or collision tumor. A rare case of melanoma possibly arising from these dendritic melanocytes has been reported.¹⁵

Conclusion

Trichoblastomas are uncommon tumors of germinative hair bulb origin that can have several histologic variants. A well-documented subtype of trichoblastoma characterized by melanin deposits within and around tumor nests has been identified and classified as a pigmented trichoblastoma. Four cases of melanotrichoblastoma have been reported and represent a variant of a pigmented trichoblastoma characterized by the presence of melanocytes within the lesion. Whether they represent a true variant is of some debate and additional study is required. Although these tumors are exceedingly rare, it is important for the clinician and pathologist to be aware of this entity to prevent confusion with other similarly appearing follicular lesions, most notably BCCs, because of the difference in treatment and follow-up.

Trichoblastomas are rare cutaneous tumors that recapitulate the germinative hair bulb and the surrounding mesenchyme. Although benign, they can present diagnostic difficulties for both the clinician and pathologist because of their rarity and overlap both clinically and microscopically with other follicular neoplasms as well as basal cell carcinoma (BCC). Several classification schemes for hair follicle neoplasms have been established based on the relative proportions of epithelial and mesenchymal components as well as stromal inductive change, but nomenclature continues to be problematic, as individual neoplasms show varying degrees of differentiation that do not always uniformly fit within these categories.^1,2 One of these established categories is a pigmented trichoblastoma.³ An exceedingly rare variant of a pigmented trichoblastoma referred to as melanotrichoblastoma was first described in 2002⁴ and has only been documented in 3 cases, according to a PubMed search of articles indexed for MEDLINE using the term melanotrichoblastoma.^4-6 We report another case of this rare tumor and review the literature on this unique group of tumors.

Case Report

A 25-year-old white woman with a medical history of chronic migraines, myofascial syndrome, and Arnold-Chiari malformation type I presented to dermatology with a 1.5-cm, pedunculated, well-circumscribed tumor on the left side of the scalp (Figure 1). The tumor was grossly flesh colored with heterogeneous areas of dark pigmentation. Microscopic examination demonstrated that within the superficial and deep dermis were variable-sized nests of basaloid cells. Some of the nests had large central cystic spaces with brown pigment within some of these spaces and focal pigmentation of the basaloid cells (Figure 2A). Focal areas of keratinization were present. Mitotic figures were easily identified; however, no atypical mitotic figures were present. Areas of peripheral palisading were present but there was no retraction artifact. Connection to the overlying epidermis was not identified. Surrounding the basaloid nodules was a mildly cellular proliferation of cytologically bland spindle cells. Occasional pigment-laden macrophages were present in the dermis. Focal areas suggestive of papillary mesenchymal body formation were present (Figure 2B). Immunohistochemical staining for Melan-A was performed and demonstrated the presence of a prominent number of melanocytes in some of the nests (Figure 3) and minimal to no melanocytes in other nests. There was no evidence of a melanocytic lesion involving the overlying epidermis. Features of nevus sebaceus were not present. Immunohistochemical staining for cytokeratin (CK) 20 was performed and demonstrated no notable number of Merkel cells within the lesion.

Comment

Overview of Trichoblastomas
Trichoblastomas most often present as solitary, flesh-colored, well-circumscribed, slow-growing tumors that usually progress in size over months to years. Although they may be present at any age, they most commonly occur in adults in the fifth to seventh decades of life and are equally distributed between males and females.^7,8 They most often occur on the head and neck with a predilection for the scalp. Although they behave in a benign fashion, cases of malignant trichoblastomas have been reported.⁹

Histopathology
Histologically, these tumors are well circumscribed but unencapsulated and usually located within the deep dermis, often with extension into the subcutaneous tissue. An epidermal connection is not identified. The tumor typically is composed of variable-sized nests of basaloid cells surrounded by a variable cellular stromal component. Although peripheral palisading is present in the basaloid component, retraction artifact is not present. Several histologic variants of trichoblastomas have been reported including cribriform, racemiform, retiform, pigmented, giant, subcutaneous, rippled pattern, and clear cell.⁵ Pigmented trichoblastomas are histologically similar to typical trichoblastomas, except for the presence of large amounts of melanin deposited within and around the tumor nests.⁶ A melanotrichoblastoma is a rare variant of a pigmented trichoblastoma; pigment is present in the lesion and melanocytes are identified within the basaloid nests.

The stromal component of trichoblastomas may show areas of condensation associated with some of the basaloid cells, resembling an attempt at hair bulb formation. Staining for CD10 will be positive in these areas of papillary mesenchymal bodies.¹⁰

In an immunohistochemical study of 13 cases of trichoblastomas, there was diffuse positive staining for CK14 and CK17 in all cases (similar to BCC) and positive staining for CK19 in 70% (9/13) of cases compared to 21% (4/19) of BCC cases. Staining for CK8 and CK20 demonstrated the presence of numerous Merkel cells in all trichoblastomas but in none of the 19 cases of BCC tested.¹¹ However, other studies have reported the presence of Merkel cells in only 42% to 70% of trichoblastomas.^12,13 Despite the lack of Merkel cells in our case, the lesion was interpreted as a melanotrichoblastoma based on the histologic features in conjunction with the presence of the melanocytes.

Differential Diagnosis
The clinical and histologic differential diagnosis of trichoblastomas includes both trichoepithelioma and BCC. Clinically, all 3 lesions often are slow growing, dome shaped, and small in size (several millimeters), and are observed in the same anatomic distribution of the head and neck region. Furthermore, they often affect middle-aged to older individuals and those of Caucasian descent, though other ethnicities can be affected. Histologic evaluation often is necessary to differentiate between these 3 entities.

Histologically, trichoepitheliomas are composed of nodules of basaloid cells encircled by stromal spindle cells. Although there can be histologic overlap between trichoepitheliomas and trichoblastoma, trichoepitheliomas typically will display obvious features of hair follicle differentiation with the presence of small keratinous cysts and hair bulb structures, while trichoblastomas tend to display minimal changes suggestive of its hair follicle origin. Similar to trichoblastomas, BCC is composed of nests of basaloid cells; however, BCCs often demonstrate retraction artifact and connection to the overlying epidermis. In addition, BCCs typically demonstrate a fibromucinous stromal component that is distinct from the cellular stroma of trichoblastic tumors. Immunoperoxidase staining for androgen receptors has been reported to be positive in 78% (25/32) of BCCs and negative in trichoblastic tumors.¹⁴

Melanotrichoblastoma Differentiating Characteristics
An exceedingly rare variant of pigmented trichoblastoma is the melanotrichoblastoma. There are clinical and histologic similarities and differences between the reported cases. The first case, described by Kanitakis et al,⁴ reported a 32-year-old black woman with a 2-cm scalp mass that slowly enlarged over the course of 2 years. The second case, presented by Kim et al,⁵ described a 51-year-old Korean man with a subcutaneous 6-cm mass on the back that had been present and slowly enlarging over the course of 5 years. The third case, reported by Hung et al,⁶ described a 34-year-old Taiwanese man with a 1-cm, left-sided, temporal scalp mass present for 3 years, arising from a nevus sebaceous. Comparing these clinical findings with our case of a 25-year-old white woman with a 1.5-cm mass on the left side of the scalp, melanotrichoblastomas demonstrate a relatively similar age of onset in the early to middle-aged adult years. All 4 tumors were slow growing. Additionally, 3 of 4 cases demonstrated a predilection for the head, particularly the scalp, and grossly showed well-circumscribed lesions with notable pigmentation. Although age, size, location, and gross appearance were similar, a comparable ethnic and gender demographic was not identified.

Microscopic similarities between the 4 cases were present. Each case was characterized by a large, well-circumscribed, unencapsulated, basaloid tumor present in the lower dermis, with only 1 case having tumor cells occasionally reaching the undersurface of the epidermis. The tumor cells were monomorphic round-ovoid in appearance with scant cytoplasm. There was melanin pigment in the basaloid nests. The basaloid nests were surrounded by a proliferation of stromal cells. The mitotic rate was sparse in 2 cases, brisk in 1 case, and not discussed in 1 case. Melanocytes were identified in the basaloid nests in all 4 cases; however, in the current case, the melanocytes were seen in only some of the nests. None of the cases exhibited an overlying junctional melanocytic lesion, which would argue against a possible collision tumor or colonization of an epithelial lesion by a melanocytic lesion.

Although the histologic features of our cases are consistent with prior reports of melanotrichoblastoma, there is some question as to whether it represents a true variant of a pigmented trichoblastoma. There are relatively few articles in the literature that describe pigmented trichoblastomas, and of those, immunohistochemistry staining for melanocytes is uncommon. In one of the earliest descriptions of a pigmented trichoblastoma, dendritic melanocytes were present within the tumor lobules; however, the lesion was reported as a pigmented trichoblastoma and not a melanotrichoblastoma.³ It is possible that all pigmented trichoblastomas may contain some number of dendritic melanocytes, thus negating the existence of a melanotrichoblastoma as a true subtype of pigmented trichoblastomas. Additional study looking at multiple examples of pigmented trichoblastomas would be required to more definitively classify melanotrichoblastomas. It is important to appreciate that at least some cases of pigmented trichoblastomas may contain melanocytes and not to confuse the lesion as representing an example of colonization or collision tumor. A rare case of melanoma possibly arising from these dendritic melanocytes has been reported.¹⁵

Conclusion

Trichoblastomas are uncommon tumors of germinative hair bulb origin that can have several histologic variants. A well-documented subtype of trichoblastoma characterized by melanin deposits within and around tumor nests has been identified and classified as a pigmented trichoblastoma. Four cases of melanotrichoblastoma have been reported and represent a variant of a pigmented trichoblastoma characterized by the presence of melanocytes within the lesion. Whether they represent a true variant is of some debate and additional study is required. Although these tumors are exceedingly rare, it is important for the clinician and pathologist to be aware of this entity to prevent confusion with other similarly appearing follicular lesions, most notably BCCs, because of the difference in treatment and follow-up.

Trichoblastomas are rare cutaneous tumors that recapitulate the germinative hair bulb and the surrounding mesenchyme. Although benign, they can present diagnostic difficulties for both the clinician and pathologist because of their rarity and overlap both clinically and microscopically with other follicular neoplasms as well as basal cell carcinoma (BCC). Several classification schemes for hair follicle neoplasms have been established based on the relative proportions of epithelial and mesenchymal components as well as stromal inductive change, but nomenclature continues to be problematic, as individual neoplasms show varying degrees of differentiation that do not always uniformly fit within these categories.^1,2 One of these established categories is a pigmented trichoblastoma.³ An exceedingly rare variant of a pigmented trichoblastoma referred to as melanotrichoblastoma was first described in 2002⁴ and has only been documented in 3 cases, according to a PubMed search of articles indexed for MEDLINE using the term melanotrichoblastoma.^4-6 We report another case of this rare tumor and review the literature on this unique group of tumors.

Case Report

A 25-year-old white woman with a medical history of chronic migraines, myofascial syndrome, and Arnold-Chiari malformation type I presented to dermatology with a 1.5-cm, pedunculated, well-circumscribed tumor on the left side of the scalp (Figure 1). The tumor was grossly flesh colored with heterogeneous areas of dark pigmentation. Microscopic examination demonstrated that within the superficial and deep dermis were variable-sized nests of basaloid cells. Some of the nests had large central cystic spaces with brown pigment within some of these spaces and focal pigmentation of the basaloid cells (Figure 2A). Focal areas of keratinization were present. Mitotic figures were easily identified; however, no atypical mitotic figures were present. Areas of peripheral palisading were present but there was no retraction artifact. Connection to the overlying epidermis was not identified. Surrounding the basaloid nodules was a mildly cellular proliferation of cytologically bland spindle cells. Occasional pigment-laden macrophages were present in the dermis. Focal areas suggestive of papillary mesenchymal body formation were present (Figure 2B). Immunohistochemical staining for Melan-A was performed and demonstrated the presence of a prominent number of melanocytes in some of the nests (Figure 3) and minimal to no melanocytes in other nests. There was no evidence of a melanocytic lesion involving the overlying epidermis. Features of nevus sebaceus were not present. Immunohistochemical staining for cytokeratin (CK) 20 was performed and demonstrated no notable number of Merkel cells within the lesion.

Comment

Overview of Trichoblastomas
Trichoblastomas most often present as solitary, flesh-colored, well-circumscribed, slow-growing tumors that usually progress in size over months to years. Although they may be present at any age, they most commonly occur in adults in the fifth to seventh decades of life and are equally distributed between males and females.^7,8 They most often occur on the head and neck with a predilection for the scalp. Although they behave in a benign fashion, cases of malignant trichoblastomas have been reported.⁹

Histopathology
Histologically, these tumors are well circumscribed but unencapsulated and usually located within the deep dermis, often with extension into the subcutaneous tissue. An epidermal connection is not identified. The tumor typically is composed of variable-sized nests of basaloid cells surrounded by a variable cellular stromal component. Although peripheral palisading is present in the basaloid component, retraction artifact is not present. Several histologic variants of trichoblastomas have been reported including cribriform, racemiform, retiform, pigmented, giant, subcutaneous, rippled pattern, and clear cell.⁵ Pigmented trichoblastomas are histologically similar to typical trichoblastomas, except for the presence of large amounts of melanin deposited within and around the tumor nests.⁶ A melanotrichoblastoma is a rare variant of a pigmented trichoblastoma; pigment is present in the lesion and melanocytes are identified within the basaloid nests.

The stromal component of trichoblastomas may show areas of condensation associated with some of the basaloid cells, resembling an attempt at hair bulb formation. Staining for CD10 will be positive in these areas of papillary mesenchymal bodies.¹⁰

In an immunohistochemical study of 13 cases of trichoblastomas, there was diffuse positive staining for CK14 and CK17 in all cases (similar to BCC) and positive staining for CK19 in 70% (9/13) of cases compared to 21% (4/19) of BCC cases. Staining for CK8 and CK20 demonstrated the presence of numerous Merkel cells in all trichoblastomas but in none of the 19 cases of BCC tested.¹¹ However, other studies have reported the presence of Merkel cells in only 42% to 70% of trichoblastomas.^12,13 Despite the lack of Merkel cells in our case, the lesion was interpreted as a melanotrichoblastoma based on the histologic features in conjunction with the presence of the melanocytes.

Differential Diagnosis
The clinical and histologic differential diagnosis of trichoblastomas includes both trichoepithelioma and BCC. Clinically, all 3 lesions often are slow growing, dome shaped, and small in size (several millimeters), and are observed in the same anatomic distribution of the head and neck region. Furthermore, they often affect middle-aged to older individuals and those of Caucasian descent, though other ethnicities can be affected. Histologic evaluation often is necessary to differentiate between these 3 entities.

Histologically, trichoepitheliomas are composed of nodules of basaloid cells encircled by stromal spindle cells. Although there can be histologic overlap between trichoepitheliomas and trichoblastoma, trichoepitheliomas typically will display obvious features of hair follicle differentiation with the presence of small keratinous cysts and hair bulb structures, while trichoblastomas tend to display minimal changes suggestive of its hair follicle origin. Similar to trichoblastomas, BCC is composed of nests of basaloid cells; however, BCCs often demonstrate retraction artifact and connection to the overlying epidermis. In addition, BCCs typically demonstrate a fibromucinous stromal component that is distinct from the cellular stroma of trichoblastic tumors. Immunoperoxidase staining for androgen receptors has been reported to be positive in 78% (25/32) of BCCs and negative in trichoblastic tumors.¹⁴

Melanotrichoblastoma Differentiating Characteristics
An exceedingly rare variant of pigmented trichoblastoma is the melanotrichoblastoma. There are clinical and histologic similarities and differences between the reported cases. The first case, described by Kanitakis et al,⁴ reported a 32-year-old black woman with a 2-cm scalp mass that slowly enlarged over the course of 2 years. The second case, presented by Kim et al,⁵ described a 51-year-old Korean man with a subcutaneous 6-cm mass on the back that had been present and slowly enlarging over the course of 5 years. The third case, reported by Hung et al,⁶ described a 34-year-old Taiwanese man with a 1-cm, left-sided, temporal scalp mass present for 3 years, arising from a nevus sebaceous. Comparing these clinical findings with our case of a 25-year-old white woman with a 1.5-cm mass on the left side of the scalp, melanotrichoblastomas demonstrate a relatively similar age of onset in the early to middle-aged adult years. All 4 tumors were slow growing. Additionally, 3 of 4 cases demonstrated a predilection for the head, particularly the scalp, and grossly showed well-circumscribed lesions with notable pigmentation. Although age, size, location, and gross appearance were similar, a comparable ethnic and gender demographic was not identified.

Microscopic similarities between the 4 cases were present. Each case was characterized by a large, well-circumscribed, unencapsulated, basaloid tumor present in the lower dermis, with only 1 case having tumor cells occasionally reaching the undersurface of the epidermis. The tumor cells were monomorphic round-ovoid in appearance with scant cytoplasm. There was melanin pigment in the basaloid nests. The basaloid nests were surrounded by a proliferation of stromal cells. The mitotic rate was sparse in 2 cases, brisk in 1 case, and not discussed in 1 case. Melanocytes were identified in the basaloid nests in all 4 cases; however, in the current case, the melanocytes were seen in only some of the nests. None of the cases exhibited an overlying junctional melanocytic lesion, which would argue against a possible collision tumor or colonization of an epithelial lesion by a melanocytic lesion.

Although the histologic features of our cases are consistent with prior reports of melanotrichoblastoma, there is some question as to whether it represents a true variant of a pigmented trichoblastoma. There are relatively few articles in the literature that describe pigmented trichoblastomas, and of those, immunohistochemistry staining for melanocytes is uncommon. In one of the earliest descriptions of a pigmented trichoblastoma, dendritic melanocytes were present within the tumor lobules; however, the lesion was reported as a pigmented trichoblastoma and not a melanotrichoblastoma.³ It is possible that all pigmented trichoblastomas may contain some number of dendritic melanocytes, thus negating the existence of a melanotrichoblastoma as a true subtype of pigmented trichoblastomas. Additional study looking at multiple examples of pigmented trichoblastomas would be required to more definitively classify melanotrichoblastomas. It is important to appreciate that at least some cases of pigmented trichoblastomas may contain melanocytes and not to confuse the lesion as representing an example of colonization or collision tumor. A rare case of melanoma possibly arising from these dendritic melanocytes has been reported.¹⁵

Conclusion

Trichoblastomas are uncommon tumors of germinative hair bulb origin that can have several histologic variants. A well-documented subtype of trichoblastoma characterized by melanin deposits within and around tumor nests has been identified and classified as a pigmented trichoblastoma. Four cases of melanotrichoblastoma have been reported and represent a variant of a pigmented trichoblastoma characterized by the presence of melanocytes within the lesion. Whether they represent a true variant is of some debate and additional study is required. Although these tumors are exceedingly rare, it is important for the clinician and pathologist to be aware of this entity to prevent confusion with other similarly appearing follicular lesions, most notably BCCs, because of the difference in treatment and follow-up.

Atypical fibroxanthoma (AFX) is a low-grade dermal malignancy comprised of atypical spindle cells.¹ Classified as a superficial fibrohistiocytic tumor with intermediate malignant potential, AFX has an incidence of approximately 0.24% worldwide.² The tumor appears mainly on the head and neck in sun-exposed areas but can occur less frequently on the trunk and limbs in non–sun-exposed areas. There is a 70% to 80% predominance in men aged 69 to 77 years, with lesions primarily occurring in sun-exposed areas of the head and neck.³ A median period of 4 months between time of onset and time of diagnosis has been previously established.⁴

When AFX does occur in non–sun-exposed areas, it tends to be in a younger patient population. Clinically, it presents as a rather nondescript, firm, erythematous papule or nodule less than 2 cm in diameter. Atypical fibroxanthoma most often presents asymptomatically, but the tumor may ulcerate and bleed, though pain and pruritus are uncommon.5 Findings are nonspecific, and the diagnosis must be confirmed with biopsy, as it can resemble other common dermatological lesions. The pathogenesis of AFX has been controversial. Two different studies looked at AFX using electron microscopy and concluded that the tumor most closely resembled a myofibroblast,^6,7 which is consistent with current thinking today.

Atypical fibroxanthoma is believed to be associated with p53 mutation and is closely linked with exposure to UV radiation due to its predominance in sun-exposed areas. Other predisposing factors may include prior exposure to UV radiation, history of organ transplantation, immunosuppression, advanced age in men, and xeroderma pigmentosum. The differential diagnosis for AFX encompasses basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, adnexal tumor, and pyogenic granuloma.

Case Report

A 93-year-old man was referred to our clinic for treatment of erosive pustular dermatosis of the scalp with photodynamic therapy (PDT). He had a more than 20-year history of multiple skin lesions including basal cell carcinoma, squamous cell carcinoma, and actinic keratoses (AKs). For one year prior to the current presentation the patient had concerns of pustules, scaling, itching, and scabbing on the scalp. The patient admitted that the pruritus caused him to pick at the scabs on the scalp. He had previously been treated with lactic acid 12% neutralized with ammonium hydroxide, tacrolimus, and halobetasol, all to no avail.

On physical examination, the lesions appeared erosive with crusting and granulation tissue (Figure 1A). The presentation was consistent with erosive pustular dermatosis of the scalp. Biopsy revealed granulation tissue. The patient underwent PDT and prednisone treatment with improvement. Additional biopsies revealed AKs. His condition improved with 2 PDT sessions but never fully cleared. During the PDT sessions, the patient reported intense unilateral headaches without visual changes. The headaches were intermittent and not apparently related to the treatments. He was referred for a temporal artery biopsy and rebiopsy of the remaining lesion on the scalp. The temporal artery biopsy was negative. The lesion that remained was a large nodule on the vertex scalp, and biopsy revealed AFX.

Immunohistochemical marker studies for S-100 and cytokeratin were negative. Invasion into subcutaneous fat was encountered (Figure 2A). Highly atypical spindle cells and mitoses were present (Figure 2B). Neoplastic cells were noted adjacent to nerve (Figure 2C). Excision of the lesion was curative, and his symptoms of pain and erosive pustular dermatosis resolved weeks thereafter (Figure 1B). The area of erosive pustular dermatosis was not excised, but symptoms resolved weeks following excision of the AFX.

Comment

Our case of AFX is unique due to the patient’s atypical presentation of severe pain. Because AFX usually presents asymptomatically, pain is an uncommon symptom. Based on the histologic findings in our case, we suspected that neural involvement of the tumor most likely explained the intense pain that our patient experienced.

The presence of erosive pustular dermatosis of the scalp also is interesting in our case. This elderly man had an extensive history of actinic damage and had reported pustules, scaling, itching, and scabbing of the scalp. It is possible that erosive pustular dermatosis was superimposed over the tumor and could have been the reason that multiple biopsies were needed to eventually arrive at a diagnosis. The coexistence of the 2 entities suggests that the chronic actinic damage played a role in the etiology of both.

Classification
There is a question regarding nomenclature when discussing AFX. Atypical fibroxanthoma has been referred to as a variant of undifferentiated pleomorphic sarcoma, which is a type of soft tissue sarcoma. Atypical fibroxanthoma can be referred to as undifferentiated pleomorphic sarcoma if it is more than 2 cm in diameter, if it involves the fascia or subcutaneous tissue, or if there is evidence of necrosis.³ Atypical fibroxanthoma generally is confined to the head and neck region and usually is less than 2 cm in diameter. In this patient, the presentation was consistent with AFX, as there was evidence of necrosis and invasion into the subcutaneous fat. The fact that the lesion also appeared on the scalp further supported the diagnosis of AFX.

Pathology
Biopsy of AFX typically reveals a spindle cell proliferation that usually arises in the setting of profound actinic damage. The epidermis may or may not be ulcerated, and in most cases, it is seen in close proximity to the overlying epidermis but not arising from it.8 Classic AFX is composed of highly atypical histiocytelike (epithelioid) cells admixed with pleomorphic spindle cells and giant cells, all showing frequent mitoses including atypical ones.9 Several histologic subtypes of AFX have been described, including clear cell, granular cell, pigmented cell, chondroid, osteoid, osteoclastic, and the most common spindle cell subtype.9 Features that indicate potential aggressive behavior include infiltration into the subcutaneous tissue, vascular invasion, and presence of necrosis. A diagnosis of AFX is made by exclusion of other malignant neoplasms with similar morphology, namely spindle cell squamous cell carcinoma, spindle cell melanoma, and leiomyoscarcoma.9 As such, immunohistochemistry plays a critical role in distinguishing these lesions, as they arise as part of the differential diagnosis. A panel of immunohistochemical stains is helpful for diagnosis and commonly includes but is not limited to S-100, Melan-A, smooth muscle actin, desmin, and cytokeratin.

Sampling error is an inherent flaw in any biopsy specimen. The eventual diagnosis of AFX in our case supports the argument for multiple biopsies of an unknown lesion, seeing as the affected area was interpreted as both granulation tissue and AK prior to the eventual diagnosis. Repeat biopsies, especially if a lesion is nonhealing, often can help clinicians arrive at a definitive diagnosis.

Treatment
Different treatment options have been used to manage AFX. Mohs micrographic surgery is most often used because of its tissue-sparing potential, often giving the most cosmetically appealing result. Wide local excision is another surgical technique utilized, generally with fixed margins of at least 1 cm.¹⁰ Radiation at the tumor site is used as a treatment method but most often during cases of reoccurrence. Cryotherapy as well as electrodesiccation and curettage are possible treatment options but are not the standard of care.

Atypical fibroxanthoma (AFX) is a low-grade dermal malignancy comprised of atypical spindle cells.¹ Classified as a superficial fibrohistiocytic tumor with intermediate malignant potential, AFX has an incidence of approximately 0.24% worldwide.² The tumor appears mainly on the head and neck in sun-exposed areas but can occur less frequently on the trunk and limbs in non–sun-exposed areas. There is a 70% to 80% predominance in men aged 69 to 77 years, with lesions primarily occurring in sun-exposed areas of the head and neck.³ A median period of 4 months between time of onset and time of diagnosis has been previously established.⁴

When AFX does occur in non–sun-exposed areas, it tends to be in a younger patient population. Clinically, it presents as a rather nondescript, firm, erythematous papule or nodule less than 2 cm in diameter. Atypical fibroxanthoma most often presents asymptomatically, but the tumor may ulcerate and bleed, though pain and pruritus are uncommon.5 Findings are nonspecific, and the diagnosis must be confirmed with biopsy, as it can resemble other common dermatological lesions. The pathogenesis of AFX has been controversial. Two different studies looked at AFX using electron microscopy and concluded that the tumor most closely resembled a myofibroblast,^6,7 which is consistent with current thinking today.

Atypical fibroxanthoma is believed to be associated with p53 mutation and is closely linked with exposure to UV radiation due to its predominance in sun-exposed areas. Other predisposing factors may include prior exposure to UV radiation, history of organ transplantation, immunosuppression, advanced age in men, and xeroderma pigmentosum. The differential diagnosis for AFX encompasses basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, adnexal tumor, and pyogenic granuloma.

Case Report

A 93-year-old man was referred to our clinic for treatment of erosive pustular dermatosis of the scalp with photodynamic therapy (PDT). He had a more than 20-year history of multiple skin lesions including basal cell carcinoma, squamous cell carcinoma, and actinic keratoses (AKs). For one year prior to the current presentation the patient had concerns of pustules, scaling, itching, and scabbing on the scalp. The patient admitted that the pruritus caused him to pick at the scabs on the scalp. He had previously been treated with lactic acid 12% neutralized with ammonium hydroxide, tacrolimus, and halobetasol, all to no avail.

On physical examination, the lesions appeared erosive with crusting and granulation tissue (Figure 1A). The presentation was consistent with erosive pustular dermatosis of the scalp. Biopsy revealed granulation tissue. The patient underwent PDT and prednisone treatment with improvement. Additional biopsies revealed AKs. His condition improved with 2 PDT sessions but never fully cleared. During the PDT sessions, the patient reported intense unilateral headaches without visual changes. The headaches were intermittent and not apparently related to the treatments. He was referred for a temporal artery biopsy and rebiopsy of the remaining lesion on the scalp. The temporal artery biopsy was negative. The lesion that remained was a large nodule on the vertex scalp, and biopsy revealed AFX.

Immunohistochemical marker studies for S-100 and cytokeratin were negative. Invasion into subcutaneous fat was encountered (Figure 2A). Highly atypical spindle cells and mitoses were present (Figure 2B). Neoplastic cells were noted adjacent to nerve (Figure 2C). Excision of the lesion was curative, and his symptoms of pain and erosive pustular dermatosis resolved weeks thereafter (Figure 1B). The area of erosive pustular dermatosis was not excised, but symptoms resolved weeks following excision of the AFX.

Comment

Our case of AFX is unique due to the patient’s atypical presentation of severe pain. Because AFX usually presents asymptomatically, pain is an uncommon symptom. Based on the histologic findings in our case, we suspected that neural involvement of the tumor most likely explained the intense pain that our patient experienced.

The presence of erosive pustular dermatosis of the scalp also is interesting in our case. This elderly man had an extensive history of actinic damage and had reported pustules, scaling, itching, and scabbing of the scalp. It is possible that erosive pustular dermatosis was superimposed over the tumor and could have been the reason that multiple biopsies were needed to eventually arrive at a diagnosis. The coexistence of the 2 entities suggests that the chronic actinic damage played a role in the etiology of both.

Classification
There is a question regarding nomenclature when discussing AFX. Atypical fibroxanthoma has been referred to as a variant of undifferentiated pleomorphic sarcoma, which is a type of soft tissue sarcoma. Atypical fibroxanthoma can be referred to as undifferentiated pleomorphic sarcoma if it is more than 2 cm in diameter, if it involves the fascia or subcutaneous tissue, or if there is evidence of necrosis.³ Atypical fibroxanthoma generally is confined to the head and neck region and usually is less than 2 cm in diameter. In this patient, the presentation was consistent with AFX, as there was evidence of necrosis and invasion into the subcutaneous fat. The fact that the lesion also appeared on the scalp further supported the diagnosis of AFX.

Pathology
Biopsy of AFX typically reveals a spindle cell proliferation that usually arises in the setting of profound actinic damage. The epidermis may or may not be ulcerated, and in most cases, it is seen in close proximity to the overlying epidermis but not arising from it.8 Classic AFX is composed of highly atypical histiocytelike (epithelioid) cells admixed with pleomorphic spindle cells and giant cells, all showing frequent mitoses including atypical ones.9 Several histologic subtypes of AFX have been described, including clear cell, granular cell, pigmented cell, chondroid, osteoid, osteoclastic, and the most common spindle cell subtype.9 Features that indicate potential aggressive behavior include infiltration into the subcutaneous tissue, vascular invasion, and presence of necrosis. A diagnosis of AFX is made by exclusion of other malignant neoplasms with similar morphology, namely spindle cell squamous cell carcinoma, spindle cell melanoma, and leiomyoscarcoma.9 As such, immunohistochemistry plays a critical role in distinguishing these lesions, as they arise as part of the differential diagnosis. A panel of immunohistochemical stains is helpful for diagnosis and commonly includes but is not limited to S-100, Melan-A, smooth muscle actin, desmin, and cytokeratin.

Sampling error is an inherent flaw in any biopsy specimen. The eventual diagnosis of AFX in our case supports the argument for multiple biopsies of an unknown lesion, seeing as the affected area was interpreted as both granulation tissue and AK prior to the eventual diagnosis. Repeat biopsies, especially if a lesion is nonhealing, often can help clinicians arrive at a definitive diagnosis.

Treatment
Different treatment options have been used to manage AFX. Mohs micrographic surgery is most often used because of its tissue-sparing potential, often giving the most cosmetically appealing result. Wide local excision is another surgical technique utilized, generally with fixed margins of at least 1 cm.¹⁰ Radiation at the tumor site is used as a treatment method but most often during cases of reoccurrence. Cryotherapy as well as electrodesiccation and curettage are possible treatment options but are not the standard of care.

Atypical fibroxanthoma (AFX) is a low-grade dermal malignancy comprised of atypical spindle cells.¹ Classified as a superficial fibrohistiocytic tumor with intermediate malignant potential, AFX has an incidence of approximately 0.24% worldwide.² The tumor appears mainly on the head and neck in sun-exposed areas but can occur less frequently on the trunk and limbs in non–sun-exposed areas. There is a 70% to 80% predominance in men aged 69 to 77 years, with lesions primarily occurring in sun-exposed areas of the head and neck.³ A median period of 4 months between time of onset and time of diagnosis has been previously established.⁴

When AFX does occur in non–sun-exposed areas, it tends to be in a younger patient population. Clinically, it presents as a rather nondescript, firm, erythematous papule or nodule less than 2 cm in diameter. Atypical fibroxanthoma most often presents asymptomatically, but the tumor may ulcerate and bleed, though pain and pruritus are uncommon.5 Findings are nonspecific, and the diagnosis must be confirmed with biopsy, as it can resemble other common dermatological lesions. The pathogenesis of AFX has been controversial. Two different studies looked at AFX using electron microscopy and concluded that the tumor most closely resembled a myofibroblast,^6,7 which is consistent with current thinking today.

Atypical fibroxanthoma is believed to be associated with p53 mutation and is closely linked with exposure to UV radiation due to its predominance in sun-exposed areas. Other predisposing factors may include prior exposure to UV radiation, history of organ transplantation, immunosuppression, advanced age in men, and xeroderma pigmentosum. The differential diagnosis for AFX encompasses basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, adnexal tumor, and pyogenic granuloma.

Case Report

A 93-year-old man was referred to our clinic for treatment of erosive pustular dermatosis of the scalp with photodynamic therapy (PDT). He had a more than 20-year history of multiple skin lesions including basal cell carcinoma, squamous cell carcinoma, and actinic keratoses (AKs). For one year prior to the current presentation the patient had concerns of pustules, scaling, itching, and scabbing on the scalp. The patient admitted that the pruritus caused him to pick at the scabs on the scalp. He had previously been treated with lactic acid 12% neutralized with ammonium hydroxide, tacrolimus, and halobetasol, all to no avail.

On physical examination, the lesions appeared erosive with crusting and granulation tissue (Figure 1A). The presentation was consistent with erosive pustular dermatosis of the scalp. Biopsy revealed granulation tissue. The patient underwent PDT and prednisone treatment with improvement. Additional biopsies revealed AKs. His condition improved with 2 PDT sessions but never fully cleared. During the PDT sessions, the patient reported intense unilateral headaches without visual changes. The headaches were intermittent and not apparently related to the treatments. He was referred for a temporal artery biopsy and rebiopsy of the remaining lesion on the scalp. The temporal artery biopsy was negative. The lesion that remained was a large nodule on the vertex scalp, and biopsy revealed AFX.

Immunohistochemical marker studies for S-100 and cytokeratin were negative. Invasion into subcutaneous fat was encountered (Figure 2A). Highly atypical spindle cells and mitoses were present (Figure 2B). Neoplastic cells were noted adjacent to nerve (Figure 2C). Excision of the lesion was curative, and his symptoms of pain and erosive pustular dermatosis resolved weeks thereafter (Figure 1B). The area of erosive pustular dermatosis was not excised, but symptoms resolved weeks following excision of the AFX.

Comment

Our case of AFX is unique due to the patient’s atypical presentation of severe pain. Because AFX usually presents asymptomatically, pain is an uncommon symptom. Based on the histologic findings in our case, we suspected that neural involvement of the tumor most likely explained the intense pain that our patient experienced.

The presence of erosive pustular dermatosis of the scalp also is interesting in our case. This elderly man had an extensive history of actinic damage and had reported pustules, scaling, itching, and scabbing of the scalp. It is possible that erosive pustular dermatosis was superimposed over the tumor and could have been the reason that multiple biopsies were needed to eventually arrive at a diagnosis. The coexistence of the 2 entities suggests that the chronic actinic damage played a role in the etiology of both.

Classification
There is a question regarding nomenclature when discussing AFX. Atypical fibroxanthoma has been referred to as a variant of undifferentiated pleomorphic sarcoma, which is a type of soft tissue sarcoma. Atypical fibroxanthoma can be referred to as undifferentiated pleomorphic sarcoma if it is more than 2 cm in diameter, if it involves the fascia or subcutaneous tissue, or if there is evidence of necrosis.³ Atypical fibroxanthoma generally is confined to the head and neck region and usually is less than 2 cm in diameter. In this patient, the presentation was consistent with AFX, as there was evidence of necrosis and invasion into the subcutaneous fat. The fact that the lesion also appeared on the scalp further supported the diagnosis of AFX.

Pathology
Biopsy of AFX typically reveals a spindle cell proliferation that usually arises in the setting of profound actinic damage. The epidermis may or may not be ulcerated, and in most cases, it is seen in close proximity to the overlying epidermis but not arising from it.8 Classic AFX is composed of highly atypical histiocytelike (epithelioid) cells admixed with pleomorphic spindle cells and giant cells, all showing frequent mitoses including atypical ones.9 Several histologic subtypes of AFX have been described, including clear cell, granular cell, pigmented cell, chondroid, osteoid, osteoclastic, and the most common spindle cell subtype.9 Features that indicate potential aggressive behavior include infiltration into the subcutaneous tissue, vascular invasion, and presence of necrosis. A diagnosis of AFX is made by exclusion of other malignant neoplasms with similar morphology, namely spindle cell squamous cell carcinoma, spindle cell melanoma, and leiomyoscarcoma.9 As such, immunohistochemistry plays a critical role in distinguishing these lesions, as they arise as part of the differential diagnosis. A panel of immunohistochemical stains is helpful for diagnosis and commonly includes but is not limited to S-100, Melan-A, smooth muscle actin, desmin, and cytokeratin.

Sampling error is an inherent flaw in any biopsy specimen. The eventual diagnosis of AFX in our case supports the argument for multiple biopsies of an unknown lesion, seeing as the affected area was interpreted as both granulation tissue and AK prior to the eventual diagnosis. Repeat biopsies, especially if a lesion is nonhealing, often can help clinicians arrive at a definitive diagnosis.

Treatment
Different treatment options have been used to manage AFX. Mohs micrographic surgery is most often used because of its tissue-sparing potential, often giving the most cosmetically appealing result. Wide local excision is another surgical technique utilized, generally with fixed margins of at least 1 cm.¹⁰ Radiation at the tumor site is used as a treatment method but most often during cases of reoccurrence. Cryotherapy as well as electrodesiccation and curettage are possible treatment options but are not the standard of care.

NEW YORK – We share more than affection with our dogs and cats. We also share diseases – about which our four-legged furry friends can teach us plenty.

That was the conclusion of speakers at a session on “cases at the intersection of human and veterinary dermatology,” presented at the summer meeting of the American Academy of Dermatology.

“Human health is intimately connected to animal health,” said Jennifer Gardner, MD, of the division of dermatology, University of Washington, Seattle, and a collaborating member of the school’s Center for One Health Research. The One Health framework looks at factors involved in the human, environmental, and animal sectors from the molecular level to the individual level and even to the planetary level.

Dr. Gardner challenged her audience to think beyond their individual areas of expertise. “How does the work you’re doing with a patient or test tube connect up the line and make an impact to levels higher up?” she asked.

The One Health framework also challenges practitioners to look horizontally, at how work done in the human world connects to what’s going on in the veterinary world – that is, how treatments for dermatologic conditions in dogs may one day affect how dermatologists treat the same or similar disorders in humans.

Learning from the mighty mite

For example, the study of mites that live on the skin of animals could eventually shed light on how dermatologists treat mite-related conditions in humans.

Dirk M. Elston, MD, professor and chair of the department of dermatology at the Medical University of South Carolina, Charleston, noted that Demodex mites occur in humans and in pets.

Eriklam/Thinkstock

Atopic dermatitis

Atopic dermatitis (AD) tends to be similar in people and dogs, according to Charles W. Bradley, DVM, of the University of Pennsylvania School of Veterinary Medicine, Philadelphia. About 10%-30% of children and up to 10% of adults have the disorder, the prevalence of which has more than doubled in recent years, he said.

In dogs, the prevalence is 10%-20%, making it “an extraordinarily common disorder,” he said. Lesions tend to be located on the feet, face, pinnae, ventrum, and axilla/inguinum. Additional sites vary by breed, with Dalmatians tending to get AD on the lips, French Bulldogs on the eyelids, German Shepherds on the elbows, Shar-Peis on the thorax, and Boxers on the ears.

In humans, Staphylococcus aureus is the chief microorganism of concern, said Elizabeth Grice, PhD, of the department of dermatology at the University of Pennsylvania, Philadelphia, who copresented the topic with Dr. Bradley.

A rash of itches

Among dermatology patients – man or beast – itch can outweigh rash as a key focus of concern, according to Brian Kim, MD, of the division of dermatology at Washington University in St. Louis, and codirector for the University’s Center for the Study of Itch. “The problem is my patients don’t complain about their rash; they complain about their itch,” he said. “But we don’t understand the basic question of itch.” In fact, the FDA has not approved any drugs for the treatment of chronic itch, he said.

‘The perfect culture plate’

Lessons can be learned from studying canine AD, which “is immunophysiologically homologous to human AD,” said Daniel O. Morris, DVM, MPH, professor of dermatology, at the University of Pennsylvania School of Veterinary Medicine, Philadelphia. “The main difference: My patients are covered in dense hair coats.” Because of that, systemic treatment is necessary, he said.

Canine AD primarily affects areas where hair is sparse or where the surface microclimate is moist, he said. A dog’s ear canal, which can be 10 times longer than a human’s, harbors plenty of moisture and heat, he said. “It’s the perfect culture plate.”

But, he added, the owners of his patients tend to resist using topical therapies “that could be potentially smeared on the babies and grandma’s diabetic foot ulcer.” So he has long relied on systemic treatments, initially steroids and cyclosporine. But they can have major side effects, and cyclosporine can take 60-90 days before it exerts maximum effect.

A faster-acting compound called oclacitinib has shown promise based on its high affinity for inhibiting JAK-1 enzyme-mediated activation of cytokine expression, including interleukin (IL)-31, he said. “Clinical trials demonstrate an antipruritic efficacy equivalent to both prednisolone and cyclosporine,” he noted. Contraindications include a history of neoplasia, the presence of severe infection, and age under 1 year.

Monoclonal antibody targets IL-31

The latest promising arrival is lokivetmab, a monoclonal antibody that targets canine IL-31, according to Dr. Morris. It acts rapidly (within 1 day for many dogs) and prevents binding of IL-31 to its neuronal receptor for at least a month, thereby interrupting neurotransmission of itch.

But side effects can be serious and common. Equal efficacy with a reduced side effect is the holy grail, he said.

Some doctors are not waiting. “People are throwing these two products at anything that itches,” he said. Unfortunately, they tend to “work miserably” for causes other than AD, he added.

Dr. Gardner, Dr. Elston, Dr. Rook, Dr. Bradley, and Dr. Morris reported no financial conflicts. Dr. Grice’s disclosures include having served as a speaker for GlaxoSmithKline and for L’Oreal France, and having received grants/research funding from Janssen Research & Development. Dr. Kim has served as a consultant to biotechnology and pharmaceutical companies.

NEW YORK – We share more than affection with our dogs and cats. We also share diseases – about which our four-legged furry friends can teach us plenty.

That was the conclusion of speakers at a session on “cases at the intersection of human and veterinary dermatology,” presented at the summer meeting of the American Academy of Dermatology.

“Human health is intimately connected to animal health,” said Jennifer Gardner, MD, of the division of dermatology, University of Washington, Seattle, and a collaborating member of the school’s Center for One Health Research. The One Health framework looks at factors involved in the human, environmental, and animal sectors from the molecular level to the individual level and even to the planetary level.

Dr. Gardner challenged her audience to think beyond their individual areas of expertise. “How does the work you’re doing with a patient or test tube connect up the line and make an impact to levels higher up?” she asked.

The One Health framework also challenges practitioners to look horizontally, at how work done in the human world connects to what’s going on in the veterinary world – that is, how treatments for dermatologic conditions in dogs may one day affect how dermatologists treat the same or similar disorders in humans.

Learning from the mighty mite

For example, the study of mites that live on the skin of animals could eventually shed light on how dermatologists treat mite-related conditions in humans.

Dirk M. Elston, MD, professor and chair of the department of dermatology at the Medical University of South Carolina, Charleston, noted that Demodex mites occur in humans and in pets.

Eriklam/Thinkstock

Atopic dermatitis

Atopic dermatitis (AD) tends to be similar in people and dogs, according to Charles W. Bradley, DVM, of the University of Pennsylvania School of Veterinary Medicine, Philadelphia. About 10%-30% of children and up to 10% of adults have the disorder, the prevalence of which has more than doubled in recent years, he said.

In dogs, the prevalence is 10%-20%, making it “an extraordinarily common disorder,” he said. Lesions tend to be located on the feet, face, pinnae, ventrum, and axilla/inguinum. Additional sites vary by breed, with Dalmatians tending to get AD on the lips, French Bulldogs on the eyelids, German Shepherds on the elbows, Shar-Peis on the thorax, and Boxers on the ears.

In humans, Staphylococcus aureus is the chief microorganism of concern, said Elizabeth Grice, PhD, of the department of dermatology at the University of Pennsylvania, Philadelphia, who copresented the topic with Dr. Bradley.

A rash of itches

Among dermatology patients – man or beast – itch can outweigh rash as a key focus of concern, according to Brian Kim, MD, of the division of dermatology at Washington University in St. Louis, and codirector for the University’s Center for the Study of Itch. “The problem is my patients don’t complain about their rash; they complain about their itch,” he said. “But we don’t understand the basic question of itch.” In fact, the FDA has not approved any drugs for the treatment of chronic itch, he said.

‘The perfect culture plate’

Lessons can be learned from studying canine AD, which “is immunophysiologically homologous to human AD,” said Daniel O. Morris, DVM, MPH, professor of dermatology, at the University of Pennsylvania School of Veterinary Medicine, Philadelphia. “The main difference: My patients are covered in dense hair coats.” Because of that, systemic treatment is necessary, he said.

Canine AD primarily affects areas where hair is sparse or where the surface microclimate is moist, he said. A dog’s ear canal, which can be 10 times longer than a human’s, harbors plenty of moisture and heat, he said. “It’s the perfect culture plate.”

But, he added, the owners of his patients tend to resist using topical therapies “that could be potentially smeared on the babies and grandma’s diabetic foot ulcer.” So he has long relied on systemic treatments, initially steroids and cyclosporine. But they can have major side effects, and cyclosporine can take 60-90 days before it exerts maximum effect.

A faster-acting compound called oclacitinib has shown promise based on its high affinity for inhibiting JAK-1 enzyme-mediated activation of cytokine expression, including interleukin (IL)-31, he said. “Clinical trials demonstrate an antipruritic efficacy equivalent to both prednisolone and cyclosporine,” he noted. Contraindications include a history of neoplasia, the presence of severe infection, and age under 1 year.

Monoclonal antibody targets IL-31

The latest promising arrival is lokivetmab, a monoclonal antibody that targets canine IL-31, according to Dr. Morris. It acts rapidly (within 1 day for many dogs) and prevents binding of IL-31 to its neuronal receptor for at least a month, thereby interrupting neurotransmission of itch.

But side effects can be serious and common. Equal efficacy with a reduced side effect is the holy grail, he said.

Some doctors are not waiting. “People are throwing these two products at anything that itches,” he said. Unfortunately, they tend to “work miserably” for causes other than AD, he added.

Dr. Gardner, Dr. Elston, Dr. Rook, Dr. Bradley, and Dr. Morris reported no financial conflicts. Dr. Grice’s disclosures include having served as a speaker for GlaxoSmithKline and for L’Oreal France, and having received grants/research funding from Janssen Research & Development. Dr. Kim has served as a consultant to biotechnology and pharmaceutical companies.

NEW YORK – We share more than affection with our dogs and cats. We also share diseases – about which our four-legged furry friends can teach us plenty.

That was the conclusion of speakers at a session on “cases at the intersection of human and veterinary dermatology,” presented at the summer meeting of the American Academy of Dermatology.

“Human health is intimately connected to animal health,” said Jennifer Gardner, MD, of the division of dermatology, University of Washington, Seattle, and a collaborating member of the school’s Center for One Health Research. The One Health framework looks at factors involved in the human, environmental, and animal sectors from the molecular level to the individual level and even to the planetary level.

Dr. Gardner challenged her audience to think beyond their individual areas of expertise. “How does the work you’re doing with a patient or test tube connect up the line and make an impact to levels higher up?” she asked.

The One Health framework also challenges practitioners to look horizontally, at how work done in the human world connects to what’s going on in the veterinary world – that is, how treatments for dermatologic conditions in dogs may one day affect how dermatologists treat the same or similar disorders in humans.

Learning from the mighty mite

For example, the study of mites that live on the skin of animals could eventually shed light on how dermatologists treat mite-related conditions in humans.

Dirk M. Elston, MD, professor and chair of the department of dermatology at the Medical University of South Carolina, Charleston, noted that Demodex mites occur in humans and in pets.

Eriklam/Thinkstock

Atopic dermatitis

Atopic dermatitis (AD) tends to be similar in people and dogs, according to Charles W. Bradley, DVM, of the University of Pennsylvania School of Veterinary Medicine, Philadelphia. About 10%-30% of children and up to 10% of adults have the disorder, the prevalence of which has more than doubled in recent years, he said.

In dogs, the prevalence is 10%-20%, making it “an extraordinarily common disorder,” he said. Lesions tend to be located on the feet, face, pinnae, ventrum, and axilla/inguinum. Additional sites vary by breed, with Dalmatians tending to get AD on the lips, French Bulldogs on the eyelids, German Shepherds on the elbows, Shar-Peis on the thorax, and Boxers on the ears.

In humans, Staphylococcus aureus is the chief microorganism of concern, said Elizabeth Grice, PhD, of the department of dermatology at the University of Pennsylvania, Philadelphia, who copresented the topic with Dr. Bradley.

A rash of itches

Among dermatology patients – man or beast – itch can outweigh rash as a key focus of concern, according to Brian Kim, MD, of the division of dermatology at Washington University in St. Louis, and codirector for the University’s Center for the Study of Itch. “The problem is my patients don’t complain about their rash; they complain about their itch,” he said. “But we don’t understand the basic question of itch.” In fact, the FDA has not approved any drugs for the treatment of chronic itch, he said.

‘The perfect culture plate’

Lessons can be learned from studying canine AD, which “is immunophysiologically homologous to human AD,” said Daniel O. Morris, DVM, MPH, professor of dermatology, at the University of Pennsylvania School of Veterinary Medicine, Philadelphia. “The main difference: My patients are covered in dense hair coats.” Because of that, systemic treatment is necessary, he said.

Canine AD primarily affects areas where hair is sparse or where the surface microclimate is moist, he said. A dog’s ear canal, which can be 10 times longer than a human’s, harbors plenty of moisture and heat, he said. “It’s the perfect culture plate.”

But, he added, the owners of his patients tend to resist using topical therapies “that could be potentially smeared on the babies and grandma’s diabetic foot ulcer.” So he has long relied on systemic treatments, initially steroids and cyclosporine. But they can have major side effects, and cyclosporine can take 60-90 days before it exerts maximum effect.

A faster-acting compound called oclacitinib has shown promise based on its high affinity for inhibiting JAK-1 enzyme-mediated activation of cytokine expression, including interleukin (IL)-31, he said. “Clinical trials demonstrate an antipruritic efficacy equivalent to both prednisolone and cyclosporine,” he noted. Contraindications include a history of neoplasia, the presence of severe infection, and age under 1 year.

Monoclonal antibody targets IL-31

The latest promising arrival is lokivetmab, a monoclonal antibody that targets canine IL-31, according to Dr. Morris. It acts rapidly (within 1 day for many dogs) and prevents binding of IL-31 to its neuronal receptor for at least a month, thereby interrupting neurotransmission of itch.

But side effects can be serious and common. Equal efficacy with a reduced side effect is the holy grail, he said.

Some doctors are not waiting. “People are throwing these two products at anything that itches,” he said. Unfortunately, they tend to “work miserably” for causes other than AD, he added.

Dr. Gardner, Dr. Elston, Dr. Rook, Dr. Bradley, and Dr. Morris reported no financial conflicts. Dr. Grice’s disclosures include having served as a speaker for GlaxoSmithKline and for L’Oreal France, and having received grants/research funding from Janssen Research & Development. Dr. Kim has served as a consultant to biotechnology and pharmaceutical companies.

The Diagnosis: Nonuremic Calciphylaxis

Histopathologic findings revealed ischemic necrosis and a subepidermal blister (Figure 1) with arteriosclerotic changes and fat necrosis. Foci of calcification were noted within the fat lobules. Arterioles within the deeper dermis and subcutis showed thickened hyalinized walls, narrowed lumina, and medial calcification (Figure 2). Multiple sections did not reveal any granulomatous inflammation. Periodic acid-Schiff and Gram stains were negative for fungal and bacterial elements, respectively. No dense neutrophilic infiltrate was seen. Multifocal calcific deposits within fat lobules and vessel walls (endothelium highlighted by the CD31 stain) suggested calciphylaxis.

Laboratory test results revealed a normal white blood cell count, international normalized ratio level of 4 (on warfarin), and an elevated sedimentation rate at 72 mm/h (reference range, 0-20 mm/h). Serum creatinine was 1.1 mg/dL (reference range, 0.6-1.2 mg/dL) and the calcium-phosphorous product was 40.8 mg²/dL (reference range, <55 mg²/dL). Hemoglobin A_1C (glycated hemoglobin) was 8.2% (reference range, 4%-7%). Wound cultures grew Proteus mirabilis sensitive to cefazolin. Acid-fast bacilli and fungal cultures were negative. Computed tomography of the left lower leg without contrast showed no evidence of osteomyelitis. Of note, the popliteal arteries and distal vessels showed moderate vascular calcification.

Histopathology findings as well as a clinical picture of painful ulceration on the distal extremities and uncontrolled diabetes with normal renal function favored a diagnosis of nonuremic calciphylaxis (NUC). The patient was treated with intravenous infusions of sodium thiosulfate 25 mg 3 times weekly and oral cefazolin for superadded bacterial infection. Local wound care included collagenase dressings with light compression. Warfarin was discontinued, as it can worsen calciphylaxis. Complete reepithelialization of the ulcer along with substantial reduction in pain was noted within 4 weeks.

Ulceration of the lower legs is a relatively common condition in the Western world, the prevalence of which increases up to 5% in patients older than 65 years.¹ Of the myriad of causes that lead to ulceration of the distal aspect of the leg, NUC is a rare but known phenomenon. The pathogenesis of NUC is complicated based on theories of derangement of receptor activator of nuclear factor κβ, receptor activator of nuclear factor κβ ligand, and osteoprotegerin, leading to calcium deposits in the media of the arteries.² This deposition precipitates vascular occlusion coupled with ischemic necrosis of the subcutaneous tissue and skin.³ Some of the more common causes of NUC are primary hyperparathyroidism, malignancy, and rheumatoid arthritis. Type 2 diabetes mellitus is a less common cause but often is found in association with NUC, as noted by Nigwekar et al.² According to their study, the laboratory parameters commonly found in NUC included a calcium-phosphorous product greater than 50 mg²/dL and serum creatinine of 1.2 mg/dL or less.²

Our patient displayed these laboratory findings. However, distinguishing NUC from other atypical lower extremity ulcers such as Martorell hypertensive ischemic ulcer, pyoderma gangrenosum, and warfarin necrosis can pose a challenge to the dermatologist. Martorell hypertensive ischemic ulcer is excruciatingly painful and occurs more frequently near the Achilles tendon, responding well to surgical debridement. Histopathologically, medial calcinosis and arteriosclerosis are seen.⁴

Pyoderma gangrenosum is a neutrophilic dermatosis wherein the classical ulcerative variant is painful. It occurs mostly on the pretibial area and worsens after debridement.⁵ Clinically and histopathologically, it is a diagnosis of exclusion in which a dense neutrophilic to mixed lymphocytic infiltrate is seen with necrosis of dermal vessels.⁶ 

Warfarin necrosis is extremely rare, affecting 0.01% to 0.1% of patients on warfarin-derived anticoagulant therapy.⁷ Necrosis occurs mostly on fat-bearing areas such as the breasts, abdomen, and thighs 3 to 5 days after initiating treatment. Histologically, fibrin deposits occlude dermal vessels without perivascular inflammation.⁸

Necrobiosis lipoidica is a rare cutaneous entity seen in 0.3% of diabetic patients.⁹ The exact pathogenesis is unknown; however, microangiopathy in collaboration with cross-linking of abnormal collagen fibers play a role. These lesions appear as erythematous plaques with a slightly depressed to atrophic center, ultimately taking on a waxy porcelain appearance. Although most of these lesions either resolve or become chronically persistent, approximately 15% undergo ulceration, which can be painful. Histologically, with hematoxylin and eosin staining, areas of necrobiosis are seen surrounded by an inflammatory infiltrate comprised mainly of histiocytes along with lymphocytes and plasma cells.⁹

Nonuremic calciphylaxis can mimic the aforementioned conditions to a greater extent in female patients with obesity, diabetes mellitus, and hypertension. However, microscopic calcium deposition in the media of dermal arterioles, extravascular calcification within fat lobules, and cutaneous necrosis, along with remarkable response to intravenous sodium thiosulfate, confirmed a diagnosis of NUC in our patient. Sodium thiosulfate scavenges reactive oxygen species and promotes nitric oxygen generation, thereby reducing endothelial damage.¹⁰ Although there are no randomized controlled trials to support its use, sodium thiosulfate has been successfully used to treat established cases of NUC.¹¹

The Diagnosis: Nonuremic Calciphylaxis

Histopathologic findings revealed ischemic necrosis and a subepidermal blister (Figure 1) with arteriosclerotic changes and fat necrosis. Foci of calcification were noted within the fat lobules. Arterioles within the deeper dermis and subcutis showed thickened hyalinized walls, narrowed lumina, and medial calcification (Figure 2). Multiple sections did not reveal any granulomatous inflammation. Periodic acid-Schiff and Gram stains were negative for fungal and bacterial elements, respectively. No dense neutrophilic infiltrate was seen. Multifocal calcific deposits within fat lobules and vessel walls (endothelium highlighted by the CD31 stain) suggested calciphylaxis.

Laboratory test results revealed a normal white blood cell count, international normalized ratio level of 4 (on warfarin), and an elevated sedimentation rate at 72 mm/h (reference range, 0-20 mm/h). Serum creatinine was 1.1 mg/dL (reference range, 0.6-1.2 mg/dL) and the calcium-phosphorous product was 40.8 mg²/dL (reference range, <55 mg²/dL). Hemoglobin A_1C (glycated hemoglobin) was 8.2% (reference range, 4%-7%). Wound cultures grew Proteus mirabilis sensitive to cefazolin. Acid-fast bacilli and fungal cultures were negative. Computed tomography of the left lower leg without contrast showed no evidence of osteomyelitis. Of note, the popliteal arteries and distal vessels showed moderate vascular calcification.

Histopathology findings as well as a clinical picture of painful ulceration on the distal extremities and uncontrolled diabetes with normal renal function favored a diagnosis of nonuremic calciphylaxis (NUC). The patient was treated with intravenous infusions of sodium thiosulfate 25 mg 3 times weekly and oral cefazolin for superadded bacterial infection. Local wound care included collagenase dressings with light compression. Warfarin was discontinued, as it can worsen calciphylaxis. Complete reepithelialization of the ulcer along with substantial reduction in pain was noted within 4 weeks.

Ulceration of the lower legs is a relatively common condition in the Western world, the prevalence of which increases up to 5% in patients older than 65 years.¹ Of the myriad of causes that lead to ulceration of the distal aspect of the leg, NUC is a rare but known phenomenon. The pathogenesis of NUC is complicated based on theories of derangement of receptor activator of nuclear factor κβ, receptor activator of nuclear factor κβ ligand, and osteoprotegerin, leading to calcium deposits in the media of the arteries.² This deposition precipitates vascular occlusion coupled with ischemic necrosis of the subcutaneous tissue and skin.³ Some of the more common causes of NUC are primary hyperparathyroidism, malignancy, and rheumatoid arthritis. Type 2 diabetes mellitus is a less common cause but often is found in association with NUC, as noted by Nigwekar et al.² According to their study, the laboratory parameters commonly found in NUC included a calcium-phosphorous product greater than 50 mg²/dL and serum creatinine of 1.2 mg/dL or less.²

Our patient displayed these laboratory findings. However, distinguishing NUC from other atypical lower extremity ulcers such as Martorell hypertensive ischemic ulcer, pyoderma gangrenosum, and warfarin necrosis can pose a challenge to the dermatologist. Martorell hypertensive ischemic ulcer is excruciatingly painful and occurs more frequently near the Achilles tendon, responding well to surgical debridement. Histopathologically, medial calcinosis and arteriosclerosis are seen.⁴

Pyoderma gangrenosum is a neutrophilic dermatosis wherein the classical ulcerative variant is painful. It occurs mostly on the pretibial area and worsens after debridement.⁵ Clinically and histopathologically, it is a diagnosis of exclusion in which a dense neutrophilic to mixed lymphocytic infiltrate is seen with necrosis of dermal vessels.⁶ 

Warfarin necrosis is extremely rare, affecting 0.01% to 0.1% of patients on warfarin-derived anticoagulant therapy.⁷ Necrosis occurs mostly on fat-bearing areas such as the breasts, abdomen, and thighs 3 to 5 days after initiating treatment. Histologically, fibrin deposits occlude dermal vessels without perivascular inflammation.⁸

Necrobiosis lipoidica is a rare cutaneous entity seen in 0.3% of diabetic patients.⁹ The exact pathogenesis is unknown; however, microangiopathy in collaboration with cross-linking of abnormal collagen fibers play a role. These lesions appear as erythematous plaques with a slightly depressed to atrophic center, ultimately taking on a waxy porcelain appearance. Although most of these lesions either resolve or become chronically persistent, approximately 15% undergo ulceration, which can be painful. Histologically, with hematoxylin and eosin staining, areas of necrobiosis are seen surrounded by an inflammatory infiltrate comprised mainly of histiocytes along with lymphocytes and plasma cells.⁹

Nonuremic calciphylaxis can mimic the aforementioned conditions to a greater extent in female patients with obesity, diabetes mellitus, and hypertension. However, microscopic calcium deposition in the media of dermal arterioles, extravascular calcification within fat lobules, and cutaneous necrosis, along with remarkable response to intravenous sodium thiosulfate, confirmed a diagnosis of NUC in our patient. Sodium thiosulfate scavenges reactive oxygen species and promotes nitric oxygen generation, thereby reducing endothelial damage.¹⁰ Although there are no randomized controlled trials to support its use, sodium thiosulfate has been successfully used to treat established cases of NUC.¹¹

The Diagnosis: Nonuremic Calciphylaxis

Histopathologic findings revealed ischemic necrosis and a subepidermal blister (Figure 1) with arteriosclerotic changes and fat necrosis. Foci of calcification were noted within the fat lobules. Arterioles within the deeper dermis and subcutis showed thickened hyalinized walls, narrowed lumina, and medial calcification (Figure 2). Multiple sections did not reveal any granulomatous inflammation. Periodic acid-Schiff and Gram stains were negative for fungal and bacterial elements, respectively. No dense neutrophilic infiltrate was seen. Multifocal calcific deposits within fat lobules and vessel walls (endothelium highlighted by the CD31 stain) suggested calciphylaxis.

Laboratory test results revealed a normal white blood cell count, international normalized ratio level of 4 (on warfarin), and an elevated sedimentation rate at 72 mm/h (reference range, 0-20 mm/h). Serum creatinine was 1.1 mg/dL (reference range, 0.6-1.2 mg/dL) and the calcium-phosphorous product was 40.8 mg²/dL (reference range, <55 mg²/dL). Hemoglobin A_1C (glycated hemoglobin) was 8.2% (reference range, 4%-7%). Wound cultures grew Proteus mirabilis sensitive to cefazolin. Acid-fast bacilli and fungal cultures were negative. Computed tomography of the left lower leg without contrast showed no evidence of osteomyelitis. Of note, the popliteal arteries and distal vessels showed moderate vascular calcification.

Histopathology findings as well as a clinical picture of painful ulceration on the distal extremities and uncontrolled diabetes with normal renal function favored a diagnosis of nonuremic calciphylaxis (NUC). The patient was treated with intravenous infusions of sodium thiosulfate 25 mg 3 times weekly and oral cefazolin for superadded bacterial infection. Local wound care included collagenase dressings with light compression. Warfarin was discontinued, as it can worsen calciphylaxis. Complete reepithelialization of the ulcer along with substantial reduction in pain was noted within 4 weeks.

Ulceration of the lower legs is a relatively common condition in the Western world, the prevalence of which increases up to 5% in patients older than 65 years.¹ Of the myriad of causes that lead to ulceration of the distal aspect of the leg, NUC is a rare but known phenomenon. The pathogenesis of NUC is complicated based on theories of derangement of receptor activator of nuclear factor κβ, receptor activator of nuclear factor κβ ligand, and osteoprotegerin, leading to calcium deposits in the media of the arteries.² This deposition precipitates vascular occlusion coupled with ischemic necrosis of the subcutaneous tissue and skin.³ Some of the more common causes of NUC are primary hyperparathyroidism, malignancy, and rheumatoid arthritis. Type 2 diabetes mellitus is a less common cause but often is found in association with NUC, as noted by Nigwekar et al.² According to their study, the laboratory parameters commonly found in NUC included a calcium-phosphorous product greater than 50 mg²/dL and serum creatinine of 1.2 mg/dL or less.²

Our patient displayed these laboratory findings. However, distinguishing NUC from other atypical lower extremity ulcers such as Martorell hypertensive ischemic ulcer, pyoderma gangrenosum, and warfarin necrosis can pose a challenge to the dermatologist. Martorell hypertensive ischemic ulcer is excruciatingly painful and occurs more frequently near the Achilles tendon, responding well to surgical debridement. Histopathologically, medial calcinosis and arteriosclerosis are seen.⁴

Pyoderma gangrenosum is a neutrophilic dermatosis wherein the classical ulcerative variant is painful. It occurs mostly on the pretibial area and worsens after debridement.⁵ Clinically and histopathologically, it is a diagnosis of exclusion in which a dense neutrophilic to mixed lymphocytic infiltrate is seen with necrosis of dermal vessels.⁶ 

Warfarin necrosis is extremely rare, affecting 0.01% to 0.1% of patients on warfarin-derived anticoagulant therapy.⁷ Necrosis occurs mostly on fat-bearing areas such as the breasts, abdomen, and thighs 3 to 5 days after initiating treatment. Histologically, fibrin deposits occlude dermal vessels without perivascular inflammation.⁸

Necrobiosis lipoidica is a rare cutaneous entity seen in 0.3% of diabetic patients.⁹ The exact pathogenesis is unknown; however, microangiopathy in collaboration with cross-linking of abnormal collagen fibers play a role. These lesions appear as erythematous plaques with a slightly depressed to atrophic center, ultimately taking on a waxy porcelain appearance. Although most of these lesions either resolve or become chronically persistent, approximately 15% undergo ulceration, which can be painful. Histologically, with hematoxylin and eosin staining, areas of necrobiosis are seen surrounded by an inflammatory infiltrate comprised mainly of histiocytes along with lymphocytes and plasma cells.⁹

Nonuremic calciphylaxis can mimic the aforementioned conditions to a greater extent in female patients with obesity, diabetes mellitus, and hypertension. However, microscopic calcium deposition in the media of dermal arterioles, extravascular calcification within fat lobules, and cutaneous necrosis, along with remarkable response to intravenous sodium thiosulfate, confirmed a diagnosis of NUC in our patient. Sodium thiosulfate scavenges reactive oxygen species and promotes nitric oxygen generation, thereby reducing endothelial damage.¹⁰ Although there are no randomized controlled trials to support its use, sodium thiosulfate has been successfully used to treat established cases of NUC.¹¹

The Diagnosis: Rosai-Dorfman Disease

Rosai-Dorfman disease is a rare histiocytic proliferative disorder of unknown etiology. It has 2 forms: limited cutaneous and systemic. The systemic form, also known as sinus histiocytosis with massive lym­phadenopathy, affects the lymph nodes and other organs at times. The disease is characterized by a proliferation of histiocytes in the lymph nodes, most commonly in the cervical basin¹; however, the inguinal, axillary, mediastinal, or para-aortic nodes also may be affected.^1,2 The skin is the most common site of extranodal disease, seen in approximately 10% of cases.¹ Cutaneous involvement often is in the facial area but also can be found on the trunk, ears, neck, arms, legs, and genitals. Clinically, skin lesions appear as papules, plaques, and/or nodules.²

Histopathologic examination of Rosai-Dorfman disease generally shows a dense sheetlike dermal infiltrate of large polygonal histiocytes (Figure 1). Histiocytes may display pale pink or clear cytoplasm. The pathognomonic finding is emperipolesis, which consists of histiocytes with engulfed lymphocytes, erythrocytes, plasma cells, and/or granulocytes surrounded by a clear halo. Immunohistochemical staining also is characteristic, with lesional histiocytes showing expression of S-100 protein (Figure 1, inset) and CD68. The associated inflammatory infiltrate is mixed, containing primarily plasma cells but also lymphocytes, neutrophils, and eosinophils.

Blastomycosis (Figure 2) is a systemic infection due to inhalation of Blastomyces dermatitidis conidia. Primary infection occurs in the lungs, and with dissemination the skin is the most common subsequently involved organ.³ Cutaneous blastomycosis shows pseudoepitheliomatous hyperplasia with neutrophilic microabscesses and a dense dermal infiltrate containing suppurative granulomatous inflammation. The nonpigmented yeast phase typically is 8 to 15 µm in length with a refractile cell wall and characteristic single, broad-based budding.³

Granuloma faciale (Figure 3) is a rare disease with unknown etiology characterized by reddish brown plaques or nodules most commonly occurring on the face.^4,5 Histology shows a dense nodular dermal infiltrate with a grenz zone. The infiltrate is mixed, containing mostly neutrophils with leukocytoclasis and eosinophils. Leukocytoclastic vasculitis is present with associated extravasated erythrocytes. In chronic fibrosing granuloma faciale, lesions can demonstrate fibrosis and hemosiderin deposition, similar to erythema elevatum diutinum.

Juvenile xanthogranuloma (Figure 4) is a common histiocytic disease of early childhood, though adult cases have been reported.⁶ Tumors are found on the head and trunk and are typically firm, reddish yellow papules or nodules.^6,7 Histologic examination shows a nodular infiltrate of foamy histiocytes in the superficial dermis. Touton-type multinucleated giant cells with a peripheral rim of xanthomatized foamy cytoplasm and a wreathlike arrangement of nuclei are characteristic. Associated eosinophils are seen. No emperipolesis is present.

Reticulohistiocytoma (Figure 5) is a benign dermal lesion that presents as solitary or less commonly multiple red-brown papules or nodules.⁸ Lesions consist of well-delineated nodular aggregates of histiocytes containing a finely granular eosinophilic ground glass cytoplasm. Few, if any, eosinophils are found. The lack of Touton multinucleated giant cells or emperipolesis and lack of expression of S-100 protein helps to distinguish reticulohistiocytoma from other entities in the differential diagnosis.

The Diagnosis: Rosai-Dorfman Disease

Rosai-Dorfman disease is a rare histiocytic proliferative disorder of unknown etiology. It has 2 forms: limited cutaneous and systemic. The systemic form, also known as sinus histiocytosis with massive lym­phadenopathy, affects the lymph nodes and other organs at times. The disease is characterized by a proliferation of histiocytes in the lymph nodes, most commonly in the cervical basin¹; however, the inguinal, axillary, mediastinal, or para-aortic nodes also may be affected.^1,2 The skin is the most common site of extranodal disease, seen in approximately 10% of cases.¹ Cutaneous involvement often is in the facial area but also can be found on the trunk, ears, neck, arms, legs, and genitals. Clinically, skin lesions appear as papules, plaques, and/or nodules.²

Histopathologic examination of Rosai-Dorfman disease generally shows a dense sheetlike dermal infiltrate of large polygonal histiocytes (Figure 1). Histiocytes may display pale pink or clear cytoplasm. The pathognomonic finding is emperipolesis, which consists of histiocytes with engulfed lymphocytes, erythrocytes, plasma cells, and/or granulocytes surrounded by a clear halo. Immunohistochemical staining also is characteristic, with lesional histiocytes showing expression of S-100 protein (Figure 1, inset) and CD68. The associated inflammatory infiltrate is mixed, containing primarily plasma cells but also lymphocytes, neutrophils, and eosinophils.

Blastomycosis (Figure 2) is a systemic infection due to inhalation of Blastomyces dermatitidis conidia. Primary infection occurs in the lungs, and with dissemination the skin is the most common subsequently involved organ.³ Cutaneous blastomycosis shows pseudoepitheliomatous hyperplasia with neutrophilic microabscesses and a dense dermal infiltrate containing suppurative granulomatous inflammation. The nonpigmented yeast phase typically is 8 to 15 µm in length with a refractile cell wall and characteristic single, broad-based budding.³

Granuloma faciale (Figure 3) is a rare disease with unknown etiology characterized by reddish brown plaques or nodules most commonly occurring on the face.^4,5 Histology shows a dense nodular dermal infiltrate with a grenz zone. The infiltrate is mixed, containing mostly neutrophils with leukocytoclasis and eosinophils. Leukocytoclastic vasculitis is present with associated extravasated erythrocytes. In chronic fibrosing granuloma faciale, lesions can demonstrate fibrosis and hemosiderin deposition, similar to erythema elevatum diutinum.

Juvenile xanthogranuloma (Figure 4) is a common histiocytic disease of early childhood, though adult cases have been reported.⁶ Tumors are found on the head and trunk and are typically firm, reddish yellow papules or nodules.^6,7 Histologic examination shows a nodular infiltrate of foamy histiocytes in the superficial dermis. Touton-type multinucleated giant cells with a peripheral rim of xanthomatized foamy cytoplasm and a wreathlike arrangement of nuclei are characteristic. Associated eosinophils are seen. No emperipolesis is present.

Reticulohistiocytoma (Figure 5) is a benign dermal lesion that presents as solitary or less commonly multiple red-brown papules or nodules.⁸ Lesions consist of well-delineated nodular aggregates of histiocytes containing a finely granular eosinophilic ground glass cytoplasm. Few, if any, eosinophils are found. The lack of Touton multinucleated giant cells or emperipolesis and lack of expression of S-100 protein helps to distinguish reticulohistiocytoma from other entities in the differential diagnosis.

The Diagnosis: Rosai-Dorfman Disease

Rosai-Dorfman disease is a rare histiocytic proliferative disorder of unknown etiology. It has 2 forms: limited cutaneous and systemic. The systemic form, also known as sinus histiocytosis with massive lym­phadenopathy, affects the lymph nodes and other organs at times. The disease is characterized by a proliferation of histiocytes in the lymph nodes, most commonly in the cervical basin¹; however, the inguinal, axillary, mediastinal, or para-aortic nodes also may be affected.^1,2 The skin is the most common site of extranodal disease, seen in approximately 10% of cases.¹ Cutaneous involvement often is in the facial area but also can be found on the trunk, ears, neck, arms, legs, and genitals. Clinically, skin lesions appear as papules, plaques, and/or nodules.²

Histopathologic examination of Rosai-Dorfman disease generally shows a dense sheetlike dermal infiltrate of large polygonal histiocytes (Figure 1). Histiocytes may display pale pink or clear cytoplasm. The pathognomonic finding is emperipolesis, which consists of histiocytes with engulfed lymphocytes, erythrocytes, plasma cells, and/or granulocytes surrounded by a clear halo. Immunohistochemical staining also is characteristic, with lesional histiocytes showing expression of S-100 protein (Figure 1, inset) and CD68. The associated inflammatory infiltrate is mixed, containing primarily plasma cells but also lymphocytes, neutrophils, and eosinophils.

Blastomycosis (Figure 2) is a systemic infection due to inhalation of Blastomyces dermatitidis conidia. Primary infection occurs in the lungs, and with dissemination the skin is the most common subsequently involved organ.³ Cutaneous blastomycosis shows pseudoepitheliomatous hyperplasia with neutrophilic microabscesses and a dense dermal infiltrate containing suppurative granulomatous inflammation. The nonpigmented yeast phase typically is 8 to 15 µm in length with a refractile cell wall and characteristic single, broad-based budding.³

Granuloma faciale (Figure 3) is a rare disease with unknown etiology characterized by reddish brown plaques or nodules most commonly occurring on the face.^4,5 Histology shows a dense nodular dermal infiltrate with a grenz zone. The infiltrate is mixed, containing mostly neutrophils with leukocytoclasis and eosinophils. Leukocytoclastic vasculitis is present with associated extravasated erythrocytes. In chronic fibrosing granuloma faciale, lesions can demonstrate fibrosis and hemosiderin deposition, similar to erythema elevatum diutinum.

Juvenile xanthogranuloma (Figure 4) is a common histiocytic disease of early childhood, though adult cases have been reported.⁶ Tumors are found on the head and trunk and are typically firm, reddish yellow papules or nodules.^6,7 Histologic examination shows a nodular infiltrate of foamy histiocytes in the superficial dermis. Touton-type multinucleated giant cells with a peripheral rim of xanthomatized foamy cytoplasm and a wreathlike arrangement of nuclei are characteristic. Associated eosinophils are seen. No emperipolesis is present.

Reticulohistiocytoma (Figure 5) is a benign dermal lesion that presents as solitary or less commonly multiple red-brown papules or nodules.⁸ Lesions consist of well-delineated nodular aggregates of histiocytes containing a finely granular eosinophilic ground glass cytoplasm. Few, if any, eosinophils are found. The lack of Touton multinucleated giant cells or emperipolesis and lack of expression of S-100 protein helps to distinguish reticulohistiocytoma from other entities in the differential diagnosis.

The Diagnosis: Lichen Aureus

The clinicopathological findings were diagnostic of lichen aureus (LA). Microscopic examination revealed a relatively sparse, superficial, perivascular and interstitial lymphohistiocytic infiltrate with scattered siderophages in the upper dermis. Extravasation of red blood cells also was noted (Figure 1). An immunohistochemical stain for Melan-A highlighted a normal number and distribution of single melanocytes at the dermoepidermal junction with no evidence of pagetoid scatter. A Perls Prussian blue stain for iron demonstrated abundant hemosiderin in the dermis (Figure 2).

Pigmented purpuric dermatosis (PPD) describes a group of cutaneous lesions that are characterized by petechiae and pigmentary changes. These lesions most commonly present on the lower limbs; however, other sites have been reported.1 This group includes several major clinical forms such as Schamberg disease, LA, purpura annularis telangiectodes of Majocchi, eczematidlike purpura of Doucas and Kapetanakis, and lichenoid PPD of Gougerot and Blum. Lesions typically demonstrate a striking golden brown color clinically and by definition occur in the absence of platelet defects or vasculitis.¹

Factors implicated in the pathogenesis of pigmented purpura include gravitational dependency, venous stasis, infection, and drugs.² It is suggested that cellular immunity may play a role in the development of the disease based on the presence of CD4⁺ T lymphocytes in the infiltrate and the expression of HLA-DR by these lymphocytes and the keratinocytes.³ Lichen aureus differs in that it relates to increased intravascular pressure from an incompetent valve in an underlying perforating vein.⁴

Lichen aureus, also referred to as lichen purpuricus, is one major variant of PPD. The name reflects both the characteristic golden brown color and the histopathologic pattern of inflammation.¹ Lichen aureus usually presents as a unilateral, asymptomatic, confined single lesion located mainly on the leg,¹ though it can develop at other sites or as a localized group of lesions. Extensive lesions have been reported⁵ and cases with a segmental distribution have been described.⁶ In contrast, Schamberg disease demonstrates pinhead-sized reddish lesions giving the characteristic cayenne pepper pigmentation. These lesions coalesce to form thumbprint patches that progress proximally.¹ Majocchi purpura is annular and telangiectatic, while lichenoid purpura of Gougerot and Blum presents with flat-topped, polygonal, violaceous papules that turn brown over time.

Some authors have championed a role for dermoscopy in diagnosis of LA.⁷ By dermoscopy, LA demonstrates a diffuse copper background reflecting the lymphohistiocytic dermal infiltrate, red dots and globules representing the extravasated red blood cells and the dilated swollen vessels, and grey dots that reflect the hemosiderin present in the dermis.⁸

Histologically, LA demonstrates a superficial perivascular infiltrate composed mainly of CD4⁺ lymphocytes surrounding the superficial capillaries. Over time, red cell extravasation leads to the formation of hemosiderin-laden macrophages, which can be highlighted with Perls Prussian blue stain. A bandlike infiltrate with thin strands of collagen separating it from the epidermis also may be noted.⁹

An important consideration in the differential diagnosis of PPD is mycosis fungoides (MF). Mycosis fungoides is a cutaneous T-cell lymphoma that clinically presents as a single or multiple hypopigmented or hyperpigmented patches or as erythematous scaly lesions in the patch or plaque stage. These lesions eventually may evolve into tumor stage.¹⁰ Mycosis fungoides may mimic PPD clinically and/or histopathologically, and rarely PPD also may precede MF.¹¹ Involvement of the trunk, especially the lower abdomen and buttock region, favors a diagnosis of MF. Typically, histopathologic examination of MF demonstrates an epidermotropic lymphocytic infiltrate composed of atypical cerebriform lymphocytes overlying papillary dermal fibrosis. Although classic MF would be difficult to confuse with PPD, the atrophic lichenoid pattern of MF may show remarkable overlap with PPD.¹² Such cases require clinicopathologic correlation, immunophenotyping of the epidermotropic lymphocytes, and occasionally T-cell clonality studies.

Lichen aureus is a chronic persistent disease unless the underlying incompetent perforator vessel is ligated. Various treatments have been used for other forms of pigmented purpura including topical corticosteroids, topical tacrolimus, systemic vasodilators such as prostacyclin and pentoxifylline, and phototherapy.¹ Clinical follow-up is recommended for lesions that show some clinical or histopathological overlap with MF. Additional biopsies also may prove useful in establishing a definitive diagnosis in ambiguous cases.

The Diagnosis: Lichen Aureus

The clinicopathological findings were diagnostic of lichen aureus (LA). Microscopic examination revealed a relatively sparse, superficial, perivascular and interstitial lymphohistiocytic infiltrate with scattered siderophages in the upper dermis. Extravasation of red blood cells also was noted (Figure 1). An immunohistochemical stain for Melan-A highlighted a normal number and distribution of single melanocytes at the dermoepidermal junction with no evidence of pagetoid scatter. A Perls Prussian blue stain for iron demonstrated abundant hemosiderin in the dermis (Figure 2).

Pigmented purpuric dermatosis (PPD) describes a group of cutaneous lesions that are characterized by petechiae and pigmentary changes. These lesions most commonly present on the lower limbs; however, other sites have been reported.1 This group includes several major clinical forms such as Schamberg disease, LA, purpura annularis telangiectodes of Majocchi, eczematidlike purpura of Doucas and Kapetanakis, and lichenoid PPD of Gougerot and Blum. Lesions typically demonstrate a striking golden brown color clinically and by definition occur in the absence of platelet defects or vasculitis.¹

Factors implicated in the pathogenesis of pigmented purpura include gravitational dependency, venous stasis, infection, and drugs.² It is suggested that cellular immunity may play a role in the development of the disease based on the presence of CD4⁺ T lymphocytes in the infiltrate and the expression of HLA-DR by these lymphocytes and the keratinocytes.³ Lichen aureus differs in that it relates to increased intravascular pressure from an incompetent valve in an underlying perforating vein.⁴

Lichen aureus, also referred to as lichen purpuricus, is one major variant of PPD. The name reflects both the characteristic golden brown color and the histopathologic pattern of inflammation.¹ Lichen aureus usually presents as a unilateral, asymptomatic, confined single lesion located mainly on the leg,¹ though it can develop at other sites or as a localized group of lesions. Extensive lesions have been reported⁵ and cases with a segmental distribution have been described.⁶ In contrast, Schamberg disease demonstrates pinhead-sized reddish lesions giving the characteristic cayenne pepper pigmentation. These lesions coalesce to form thumbprint patches that progress proximally.¹ Majocchi purpura is annular and telangiectatic, while lichenoid purpura of Gougerot and Blum presents with flat-topped, polygonal, violaceous papules that turn brown over time.

Some authors have championed a role for dermoscopy in diagnosis of LA.⁷ By dermoscopy, LA demonstrates a diffuse copper background reflecting the lymphohistiocytic dermal infiltrate, red dots and globules representing the extravasated red blood cells and the dilated swollen vessels, and grey dots that reflect the hemosiderin present in the dermis.⁸

Histologically, LA demonstrates a superficial perivascular infiltrate composed mainly of CD4⁺ lymphocytes surrounding the superficial capillaries. Over time, red cell extravasation leads to the formation of hemosiderin-laden macrophages, which can be highlighted with Perls Prussian blue stain. A bandlike infiltrate with thin strands of collagen separating it from the epidermis also may be noted.⁹

An important consideration in the differential diagnosis of PPD is mycosis fungoides (MF). Mycosis fungoides is a cutaneous T-cell lymphoma that clinically presents as a single or multiple hypopigmented or hyperpigmented patches or as erythematous scaly lesions in the patch or plaque stage. These lesions eventually may evolve into tumor stage.¹⁰ Mycosis fungoides may mimic PPD clinically and/or histopathologically, and rarely PPD also may precede MF.¹¹ Involvement of the trunk, especially the lower abdomen and buttock region, favors a diagnosis of MF. Typically, histopathologic examination of MF demonstrates an epidermotropic lymphocytic infiltrate composed of atypical cerebriform lymphocytes overlying papillary dermal fibrosis. Although classic MF would be difficult to confuse with PPD, the atrophic lichenoid pattern of MF may show remarkable overlap with PPD.¹² Such cases require clinicopathologic correlation, immunophenotyping of the epidermotropic lymphocytes, and occasionally T-cell clonality studies.

Lichen aureus is a chronic persistent disease unless the underlying incompetent perforator vessel is ligated. Various treatments have been used for other forms of pigmented purpura including topical corticosteroids, topical tacrolimus, systemic vasodilators such as prostacyclin and pentoxifylline, and phototherapy.¹ Clinical follow-up is recommended for lesions that show some clinical or histopathological overlap with MF. Additional biopsies also may prove useful in establishing a definitive diagnosis in ambiguous cases.

The Diagnosis: Lichen Aureus

The clinicopathological findings were diagnostic of lichen aureus (LA). Microscopic examination revealed a relatively sparse, superficial, perivascular and interstitial lymphohistiocytic infiltrate with scattered siderophages in the upper dermis. Extravasation of red blood cells also was noted (Figure 1). An immunohistochemical stain for Melan-A highlighted a normal number and distribution of single melanocytes at the dermoepidermal junction with no evidence of pagetoid scatter. A Perls Prussian blue stain for iron demonstrated abundant hemosiderin in the dermis (Figure 2).

Pigmented purpuric dermatosis (PPD) describes a group of cutaneous lesions that are characterized by petechiae and pigmentary changes. These lesions most commonly present on the lower limbs; however, other sites have been reported.1 This group includes several major clinical forms such as Schamberg disease, LA, purpura annularis telangiectodes of Majocchi, eczematidlike purpura of Doucas and Kapetanakis, and lichenoid PPD of Gougerot and Blum. Lesions typically demonstrate a striking golden brown color clinically and by definition occur in the absence of platelet defects or vasculitis.¹

Factors implicated in the pathogenesis of pigmented purpura include gravitational dependency, venous stasis, infection, and drugs.² It is suggested that cellular immunity may play a role in the development of the disease based on the presence of CD4⁺ T lymphocytes in the infiltrate and the expression of HLA-DR by these lymphocytes and the keratinocytes.³ Lichen aureus differs in that it relates to increased intravascular pressure from an incompetent valve in an underlying perforating vein.⁴

Lichen aureus, also referred to as lichen purpuricus, is one major variant of PPD. The name reflects both the characteristic golden brown color and the histopathologic pattern of inflammation.¹ Lichen aureus usually presents as a unilateral, asymptomatic, confined single lesion located mainly on the leg,¹ though it can develop at other sites or as a localized group of lesions. Extensive lesions have been reported⁵ and cases with a segmental distribution have been described.⁶ In contrast, Schamberg disease demonstrates pinhead-sized reddish lesions giving the characteristic cayenne pepper pigmentation. These lesions coalesce to form thumbprint patches that progress proximally.¹ Majocchi purpura is annular and telangiectatic, while lichenoid purpura of Gougerot and Blum presents with flat-topped, polygonal, violaceous papules that turn brown over time.

Some authors have championed a role for dermoscopy in diagnosis of LA.⁷ By dermoscopy, LA demonstrates a diffuse copper background reflecting the lymphohistiocytic dermal infiltrate, red dots and globules representing the extravasated red blood cells and the dilated swollen vessels, and grey dots that reflect the hemosiderin present in the dermis.⁸

Histologically, LA demonstrates a superficial perivascular infiltrate composed mainly of CD4⁺ lymphocytes surrounding the superficial capillaries. Over time, red cell extravasation leads to the formation of hemosiderin-laden macrophages, which can be highlighted with Perls Prussian blue stain. A bandlike infiltrate with thin strands of collagen separating it from the epidermis also may be noted.⁹

An important consideration in the differential diagnosis of PPD is mycosis fungoides (MF). Mycosis fungoides is a cutaneous T-cell lymphoma that clinically presents as a single or multiple hypopigmented or hyperpigmented patches or as erythematous scaly lesions in the patch or plaque stage. These lesions eventually may evolve into tumor stage.¹⁰ Mycosis fungoides may mimic PPD clinically and/or histopathologically, and rarely PPD also may precede MF.¹¹ Involvement of the trunk, especially the lower abdomen and buttock region, favors a diagnosis of MF. Typically, histopathologic examination of MF demonstrates an epidermotropic lymphocytic infiltrate composed of atypical cerebriform lymphocytes overlying papillary dermal fibrosis. Although classic MF would be difficult to confuse with PPD, the atrophic lichenoid pattern of MF may show remarkable overlap with PPD.¹² Such cases require clinicopathologic correlation, immunophenotyping of the epidermotropic lymphocytes, and occasionally T-cell clonality studies.

Lichen aureus is a chronic persistent disease unless the underlying incompetent perforator vessel is ligated. Various treatments have been used for other forms of pigmented purpura including topical corticosteroids, topical tacrolimus, systemic vasodilators such as prostacyclin and pentoxifylline, and phototherapy.¹ Clinical follow-up is recommended for lesions that show some clinical or histopathological overlap with MF. Additional biopsies also may prove useful in establishing a definitive diagnosis in ambiguous cases.

Traumatic ulcerative granuloma with stromal eosinophilia (TUGSE) is an uncommon, benign, self-limited condition that is restricted to the oral mucosa, most commonly seen in the fifth to seventh decades of life.^1-3 The pathogenesis of TUGSE is unknown, but current theory suggests trauma is the instigating factor. The presence of CD30⁺ mononuclear cells within TUGSE raises the possibility of a CD30⁺ lymphoproliferative disorder in some cases.⁴ However, because CD30⁺ cells are not uncommon in other benign reactive processes, they may simply represent a reactive phenomenon.³

Traumatic ulcerative granuloma with stromal eosinophilia traverses multiple disciplines, including dermatology, oral surgery, dentistry, and pathology, resulting in a diverse nomenclature including traumatic granuloma of the tongue, traumatic eosinophilic granuloma of the oral mucosa, ulcerated granuloma eosinophilicum diutinum, and eosinophilic ulcer of the oral mucosa.^1,4-6 It is important to differentiate eosinophilic granuloma of the oral mucosa from the eosinophilic granuloma that is associated with Langerhans cell histiocytosis. Although both may present with oral ulceration, Langerhans cell–associated eosinophilic granuloma typically develops from underlying bone, whereas eosinophilic granuloma of the oral mucosa (TUGSE) is described as nonosseous.^7,8 Furthermore, the gingiva is the most common oral site in Langerhans cell–associated eosinophilic granuloma, whereas the tongue is most commonly involved in TUGSE.⁸ Shapiro and Juhlin⁹ clearly distinguished TUGSE from Langerhans cell–associated eosinophilic granuloma in 1970. Histologically, the 2 conditions are completely different.

When ulcerative granulomas develop in the pediatric population, usually in children younger than 2 years, it is termed Riga-Fede disease.¹⁰ These children were typically breastfeeding, suckling, or teething, suggesting trauma as a triggering event. In 1961, Hjorting-Hansen and Schmidt⁵ described 3 separate lesions similar to Riga-Fede disease in an adult patient. Subsequently, Riga-Fede disease was grouped under TUGSE.³

Histologically, TUGSE shows an ulcerated epithelium with a polymorphic inflammatory cell infiltrate that has a large predominance of eosinophils. The infiltrate affects the superficial and deep layers of the muscle tissue and penetrates into the salivary glands. Large atypical mononuclear cells with an ovoid and pale-appearing nucleus often are present. These cells may be mitotically active and stain positively for CD30.^1,4,11 CD68⁺ macrophages, T lymphocytes, and factor XIIIa–positive dendritic cells commonly are present.¹²

Given the presence of large atypical CD30⁺ cells in many lesions, the possibility of a CD30⁺ lymphoproliferative disorder has been postulated by some authors. Indeed, lymphomatoid papulosis (LyP) has been documented to involve the oral mucosa.^2,4

Case Report

An 81-year-old man presented with a rapidly enlarging, 1.7×1.3-cm, vascular-appearing nodule with a collarette of mucosal epithelium on the left side of the dorsal surface of the tongue of 2 weeks’ duration (Figure 1). He denied any history of trauma, tobacco chewing, weight change, fever, or fatigue; however, he did report a 30 pack-year smoking history. There was no other pertinent medical history to include medications or allergies.

The differential diagnosis included pyogenic granuloma, granular cell tumor, squamous cell carcinoma, other neoplasms (eg, oral lymphoma, salivary gland tumors), and a traumatic blood blister from tongue biting. The patient was referred to the oral maxillofacial surgery department for an excisional biopsy, which showed a solitary ulcerated nodule with associated granulation tissue, thrombus, and fibrinoid debris (Figure 2). A surrounding dense mixed inflammatory cell infiltrate composed of lymphocytes, histiocytes, and numerous eosinophils was noted extending through the submucosal tissue and underlying striated muscle fibers (Figure 3). The adjacent mucosal epithelium appeared normal. CD30 staining showed only rare positive cells. These findings were consistent with TUGSE.

Due to the benign nature of TUGSE, the patient was released with symptomatic care and instructed to return for any new growth. The growth spontaneously resolved over 1 month and no recurrence or new lesions were reported 1 year later.

Comment

Despite encompassing multiple disciplines of medicine, TUGSE has minimal exposure in the dermatologic literature. It is an important clinical and histologic diagnosis that will provide reassurance to the patient when accurately identified and reduce potentially harmful treatments.

Clinical Presentation
Typically, TUGSE presents as a painful solitary nodule with a central ulcer and yellow fibrinous base. The margins of the ulcer typically have an indurated and rolled appearance.^1,4 More than 50% of the lesions develop on the tongue, specifically the dorsal or lateral surfaces, but they may present anywhere in the oral mucosa.⁷ Traumatic ulcerative granuloma with stromal eosinophilia is a fast-growing lesion, typically developing in days to weeks. Although it spontaneously regresses, the lesion may take weeks or months to resolve. In one case, it resolved 1 year later.¹ Traumatic ulcerative granuloma with stromal eosinophilia has a bimodal age distribution, generally appearing in the first 2 years of life and later in the fifth through seventh decades. The male-to-female predominance is equal.^1,7,11 Reoccurrence is rare, but some reports have shown patients with multiple episodes of TUGSE.^13,14

Differential Diagnosis
The clinical differential diagnosis for TUGSE includes squamous cell carcinoma, pyogenic granuloma, lymphoproliferative disorder, traumatic neuroma, Langerhans cell histiocytosis, granulomatous disorders, and oral lymphoma. Inflammatory disorders such as syphilis, Behçet’s disease, herpes, histoplasmosis, Wegener granulomatosis, and others also should be considered.

Immunohistochemistry
Immunohistochemical analysis of TUGSE lesions recently has revealed the presence of CD30⁺ cells. These cells are associated with cutaneous lymphoproliferative disorders including LyP, anaplastic large cell lymphoma (ALCL), and borderline CD30⁺ lesions, among others. Systemic diseases with CD30⁺ cells include mycosis fungoides, other T-cell lymphomas, and Hodgkin lymphoma.^15,16 Once CD30⁺ cells were recognized, multiple authors began speculating there was a correlation between TUGSE and the CD30⁺ lymphoproliferative disorders.^1,2,13 Anaplastic large cell lymphoma and LyP of the oral mucosa have been reported in several cases.^17-20 One report described 2 cases of ulcerated CD30⁺ T-cell non-Hodgkin lymphoma of the oral mucosa, one of which showed eosinophilic infiltrates and was initially thought to be TUGSE. Based on these overlapping clinical and histologic features, the authors hypothesized there was a correlation between oral ALCL, LyP, and TUGSE.¹⁷ In one report, a patient developed multiple TUGSE lesions throughout his life, suggesting a pathologic process similar to LyP. The lesion biopsied showed that 70% of the T cells expressed CD30 (Ki-1) antigen.¹³

Underlying Causes
In support of an underlying immunologic process that augments the growth of these lesions, 2 separate case reports of TUGSE in the presence of human T-lymphotropic virus 1 (HTLV-1) and Epstein-Barr virus have been documented.^2,21 Concurrent presentation of TUGSE and HTLV-1 in one report demonstrated eosinophilia in both the oral lesion and peripheral blood, suggesting an immunologic relationship. Furthermore, the authors postulated that local trauma initiated the development of TUGSE, providing the catalyst for the HTLV-1 carrier to develop peripheral eosinophilia.²¹

In the second case, a 12-year-old boy developed TUGSE in the presence of Epstein-Barr virus.² Immunologically, this virus can be reactivated from its latent stage during immunosuppression. Epstein-Barr virus has been implicated in lymphoproliferative diseases of both B- and T-cell origin, including CD30⁺ ALCL and LyP.^22,23 The authors in this report again hypothesized there was a correlation between lymphoproliferative disorders and TUGSE lesions.^2,24

Alternatively, TUGSE may simply be a reactive process to trauma or another underlying trigger. It has been speculated that the presence of eosinophils correlates with antigen insertion into the oral mucosa, whereas other ulcers of the oral mucosa are devoid of eosinophils.¹ These antigens may include microorganisms, endogenous degradation products, or foreign proteins.^7,25 Additionally, the presence of CD30⁺ lymphocytes is not isolated to lymphoproliferative disorders. CD30⁺ cells have been documented in arthropod bite reactions, atopic dermatitis, drug reactions, molluscum contagiosum, and scabies, among others.^1,26

Healing and Management
The length of healing in TUGSE ulcers has substantial variability, from days to up to 1 year in an isolated case.^1,24 Sequential expression of transforming growth factor (TGF) α and TGF-β expressed by tissue eosinophils may be underlying factors associated with a quicker healing response as demonstrated by similar ulcers in hamsters.²⁷ Chronic nonhealing oral ulcers, particularly TUGSE lesions that demonstrated the typical increase in eosinophils in 11 of 12 cases, showed minimal TGF-α or TGF-β expression by eosinophils, perhaps indicating a possible mechanism leading to delayed wound healing in some cases. Interestingly, incisional biopsies often led to rapid wound healing, suggesting that the biopsy itself allowed for a transition back to the regular wound-healing processes.²⁸

Traumatic ulcerative granuloma with stromal eosinophilia spontaneously resolves on its own in most cases; however, because of the concern for malignancy, it has the potential to be overtreated.²⁶ Symptomatic treatment only is the mainstay of therapy. The patient should be instructed to avoid trauma, and referral to a dental professional is indicated when associated with dentures or other periprosthetic devices. Diet should consist of soft foods while avoiding spicy foods. Topical or oral analgesics may be necessary if substantial pain is associated with the lesion.² Oral prednisolone was used in a patient with concurrent HTLV-1 and TUGSE to treat peripheral eosinophilia.²¹ The patient’s peripheral eosinophils dropped to 1% in 1 day, and the patient’s oral lesion began to improve at day 3 and disappeared by day 10. Although TUGSE may spontaneously resolve within a 10-day period without steroids, it may be a reasonable treatment to improve healing time in an otherwise healthy individual.^21,26 If there is concern for malignancy, the patient should have the lesion biopsied to provide reassurance and for the added benefit of a transition to normal healing response and decreased healing time.²⁸

Clinical Recognition
The clinician should be aware of the possibility of a CD30⁺ lymphoproliferative disorder, which has been associated with TUGSE in some cases, or may simulate TUGSE both clinically and histologically. Further studies are needed to clarify the relationship between these 2 entities. Whether it is a true relationship, simple coincidence, or simply overlapping clinical and histologic features remains to be determined.

Traumatic ulcerative granuloma with stromal eosinophilia (TUGSE) is an uncommon, benign, self-limited condition that is restricted to the oral mucosa, most commonly seen in the fifth to seventh decades of life.^1-3 The pathogenesis of TUGSE is unknown, but current theory suggests trauma is the instigating factor. The presence of CD30⁺ mononuclear cells within TUGSE raises the possibility of a CD30⁺ lymphoproliferative disorder in some cases.⁴ However, because CD30⁺ cells are not uncommon in other benign reactive processes, they may simply represent a reactive phenomenon.³

Traumatic ulcerative granuloma with stromal eosinophilia traverses multiple disciplines, including dermatology, oral surgery, dentistry, and pathology, resulting in a diverse nomenclature including traumatic granuloma of the tongue, traumatic eosinophilic granuloma of the oral mucosa, ulcerated granuloma eosinophilicum diutinum, and eosinophilic ulcer of the oral mucosa.^1,4-6 It is important to differentiate eosinophilic granuloma of the oral mucosa from the eosinophilic granuloma that is associated with Langerhans cell histiocytosis. Although both may present with oral ulceration, Langerhans cell–associated eosinophilic granuloma typically develops from underlying bone, whereas eosinophilic granuloma of the oral mucosa (TUGSE) is described as nonosseous.^7,8 Furthermore, the gingiva is the most common oral site in Langerhans cell–associated eosinophilic granuloma, whereas the tongue is most commonly involved in TUGSE.⁸ Shapiro and Juhlin⁹ clearly distinguished TUGSE from Langerhans cell–associated eosinophilic granuloma in 1970. Histologically, the 2 conditions are completely different.

When ulcerative granulomas develop in the pediatric population, usually in children younger than 2 years, it is termed Riga-Fede disease.¹⁰ These children were typically breastfeeding, suckling, or teething, suggesting trauma as a triggering event. In 1961, Hjorting-Hansen and Schmidt⁵ described 3 separate lesions similar to Riga-Fede disease in an adult patient. Subsequently, Riga-Fede disease was grouped under TUGSE.³

Histologically, TUGSE shows an ulcerated epithelium with a polymorphic inflammatory cell infiltrate that has a large predominance of eosinophils. The infiltrate affects the superficial and deep layers of the muscle tissue and penetrates into the salivary glands. Large atypical mononuclear cells with an ovoid and pale-appearing nucleus often are present. These cells may be mitotically active and stain positively for CD30.^1,4,11 CD68⁺ macrophages, T lymphocytes, and factor XIIIa–positive dendritic cells commonly are present.¹²

Given the presence of large atypical CD30⁺ cells in many lesions, the possibility of a CD30⁺ lymphoproliferative disorder has been postulated by some authors. Indeed, lymphomatoid papulosis (LyP) has been documented to involve the oral mucosa.^2,4

Case Report

An 81-year-old man presented with a rapidly enlarging, 1.7×1.3-cm, vascular-appearing nodule with a collarette of mucosal epithelium on the left side of the dorsal surface of the tongue of 2 weeks’ duration (Figure 1). He denied any history of trauma, tobacco chewing, weight change, fever, or fatigue; however, he did report a 30 pack-year smoking history. There was no other pertinent medical history to include medications or allergies.

The differential diagnosis included pyogenic granuloma, granular cell tumor, squamous cell carcinoma, other neoplasms (eg, oral lymphoma, salivary gland tumors), and a traumatic blood blister from tongue biting. The patient was referred to the oral maxillofacial surgery department for an excisional biopsy, which showed a solitary ulcerated nodule with associated granulation tissue, thrombus, and fibrinoid debris (Figure 2). A surrounding dense mixed inflammatory cell infiltrate composed of lymphocytes, histiocytes, and numerous eosinophils was noted extending through the submucosal tissue and underlying striated muscle fibers (Figure 3). The adjacent mucosal epithelium appeared normal. CD30 staining showed only rare positive cells. These findings were consistent with TUGSE.

Due to the benign nature of TUGSE, the patient was released with symptomatic care and instructed to return for any new growth. The growth spontaneously resolved over 1 month and no recurrence or new lesions were reported 1 year later.

Comment

Despite encompassing multiple disciplines of medicine, TUGSE has minimal exposure in the dermatologic literature. It is an important clinical and histologic diagnosis that will provide reassurance to the patient when accurately identified and reduce potentially harmful treatments.

Clinical Presentation
Typically, TUGSE presents as a painful solitary nodule with a central ulcer and yellow fibrinous base. The margins of the ulcer typically have an indurated and rolled appearance.^1,4 More than 50% of the lesions develop on the tongue, specifically the dorsal or lateral surfaces, but they may present anywhere in the oral mucosa.⁷ Traumatic ulcerative granuloma with stromal eosinophilia is a fast-growing lesion, typically developing in days to weeks. Although it spontaneously regresses, the lesion may take weeks or months to resolve. In one case, it resolved 1 year later.¹ Traumatic ulcerative granuloma with stromal eosinophilia has a bimodal age distribution, generally appearing in the first 2 years of life and later in the fifth through seventh decades. The male-to-female predominance is equal.^1,7,11 Reoccurrence is rare, but some reports have shown patients with multiple episodes of TUGSE.^13,14

Differential Diagnosis
The clinical differential diagnosis for TUGSE includes squamous cell carcinoma, pyogenic granuloma, lymphoproliferative disorder, traumatic neuroma, Langerhans cell histiocytosis, granulomatous disorders, and oral lymphoma. Inflammatory disorders such as syphilis, Behçet’s disease, herpes, histoplasmosis, Wegener granulomatosis, and others also should be considered.

Immunohistochemistry
Immunohistochemical analysis of TUGSE lesions recently has revealed the presence of CD30⁺ cells. These cells are associated with cutaneous lymphoproliferative disorders including LyP, anaplastic large cell lymphoma (ALCL), and borderline CD30⁺ lesions, among others. Systemic diseases with CD30⁺ cells include mycosis fungoides, other T-cell lymphomas, and Hodgkin lymphoma.^15,16 Once CD30⁺ cells were recognized, multiple authors began speculating there was a correlation between TUGSE and the CD30⁺ lymphoproliferative disorders.^1,2,13 Anaplastic large cell lymphoma and LyP of the oral mucosa have been reported in several cases.^17-20 One report described 2 cases of ulcerated CD30⁺ T-cell non-Hodgkin lymphoma of the oral mucosa, one of which showed eosinophilic infiltrates and was initially thought to be TUGSE. Based on these overlapping clinical and histologic features, the authors hypothesized there was a correlation between oral ALCL, LyP, and TUGSE.¹⁷ In one report, a patient developed multiple TUGSE lesions throughout his life, suggesting a pathologic process similar to LyP. The lesion biopsied showed that 70% of the T cells expressed CD30 (Ki-1) antigen.¹³

Underlying Causes
In support of an underlying immunologic process that augments the growth of these lesions, 2 separate case reports of TUGSE in the presence of human T-lymphotropic virus 1 (HTLV-1) and Epstein-Barr virus have been documented.^2,21 Concurrent presentation of TUGSE and HTLV-1 in one report demonstrated eosinophilia in both the oral lesion and peripheral blood, suggesting an immunologic relationship. Furthermore, the authors postulated that local trauma initiated the development of TUGSE, providing the catalyst for the HTLV-1 carrier to develop peripheral eosinophilia.²¹

In the second case, a 12-year-old boy developed TUGSE in the presence of Epstein-Barr virus.² Immunologically, this virus can be reactivated from its latent stage during immunosuppression. Epstein-Barr virus has been implicated in lymphoproliferative diseases of both B- and T-cell origin, including CD30⁺ ALCL and LyP.^22,23 The authors in this report again hypothesized there was a correlation between lymphoproliferative disorders and TUGSE lesions.^2,24

Alternatively, TUGSE may simply be a reactive process to trauma or another underlying trigger. It has been speculated that the presence of eosinophils correlates with antigen insertion into the oral mucosa, whereas other ulcers of the oral mucosa are devoid of eosinophils.¹ These antigens may include microorganisms, endogenous degradation products, or foreign proteins.^7,25 Additionally, the presence of CD30⁺ lymphocytes is not isolated to lymphoproliferative disorders. CD30⁺ cells have been documented in arthropod bite reactions, atopic dermatitis, drug reactions, molluscum contagiosum, and scabies, among others.^1,26

Healing and Management
The length of healing in TUGSE ulcers has substantial variability, from days to up to 1 year in an isolated case.^1,24 Sequential expression of transforming growth factor (TGF) α and TGF-β expressed by tissue eosinophils may be underlying factors associated with a quicker healing response as demonstrated by similar ulcers in hamsters.²⁷ Chronic nonhealing oral ulcers, particularly TUGSE lesions that demonstrated the typical increase in eosinophils in 11 of 12 cases, showed minimal TGF-α or TGF-β expression by eosinophils, perhaps indicating a possible mechanism leading to delayed wound healing in some cases. Interestingly, incisional biopsies often led to rapid wound healing, suggesting that the biopsy itself allowed for a transition back to the regular wound-healing processes.²⁸

Traumatic ulcerative granuloma with stromal eosinophilia spontaneously resolves on its own in most cases; however, because of the concern for malignancy, it has the potential to be overtreated.²⁶ Symptomatic treatment only is the mainstay of therapy. The patient should be instructed to avoid trauma, and referral to a dental professional is indicated when associated with dentures or other periprosthetic devices. Diet should consist of soft foods while avoiding spicy foods. Topical or oral analgesics may be necessary if substantial pain is associated with the lesion.² Oral prednisolone was used in a patient with concurrent HTLV-1 and TUGSE to treat peripheral eosinophilia.²¹ The patient’s peripheral eosinophils dropped to 1% in 1 day, and the patient’s oral lesion began to improve at day 3 and disappeared by day 10. Although TUGSE may spontaneously resolve within a 10-day period without steroids, it may be a reasonable treatment to improve healing time in an otherwise healthy individual.^21,26 If there is concern for malignancy, the patient should have the lesion biopsied to provide reassurance and for the added benefit of a transition to normal healing response and decreased healing time.²⁸

Clinical Recognition
The clinician should be aware of the possibility of a CD30⁺ lymphoproliferative disorder, which has been associated with TUGSE in some cases, or may simulate TUGSE both clinically and histologically. Further studies are needed to clarify the relationship between these 2 entities. Whether it is a true relationship, simple coincidence, or simply overlapping clinical and histologic features remains to be determined.

Traumatic ulcerative granuloma with stromal eosinophilia (TUGSE) is an uncommon, benign, self-limited condition that is restricted to the oral mucosa, most commonly seen in the fifth to seventh decades of life.^1-3 The pathogenesis of TUGSE is unknown, but current theory suggests trauma is the instigating factor. The presence of CD30⁺ mononuclear cells within TUGSE raises the possibility of a CD30⁺ lymphoproliferative disorder in some cases.⁴ However, because CD30⁺ cells are not uncommon in other benign reactive processes, they may simply represent a reactive phenomenon.³

Traumatic ulcerative granuloma with stromal eosinophilia traverses multiple disciplines, including dermatology, oral surgery, dentistry, and pathology, resulting in a diverse nomenclature including traumatic granuloma of the tongue, traumatic eosinophilic granuloma of the oral mucosa, ulcerated granuloma eosinophilicum diutinum, and eosinophilic ulcer of the oral mucosa.^1,4-6 It is important to differentiate eosinophilic granuloma of the oral mucosa from the eosinophilic granuloma that is associated with Langerhans cell histiocytosis. Although both may present with oral ulceration, Langerhans cell–associated eosinophilic granuloma typically develops from underlying bone, whereas eosinophilic granuloma of the oral mucosa (TUGSE) is described as nonosseous.^7,8 Furthermore, the gingiva is the most common oral site in Langerhans cell–associated eosinophilic granuloma, whereas the tongue is most commonly involved in TUGSE.⁸ Shapiro and Juhlin⁹ clearly distinguished TUGSE from Langerhans cell–associated eosinophilic granuloma in 1970. Histologically, the 2 conditions are completely different.

When ulcerative granulomas develop in the pediatric population, usually in children younger than 2 years, it is termed Riga-Fede disease.¹⁰ These children were typically breastfeeding, suckling, or teething, suggesting trauma as a triggering event. In 1961, Hjorting-Hansen and Schmidt⁵ described 3 separate lesions similar to Riga-Fede disease in an adult patient. Subsequently, Riga-Fede disease was grouped under TUGSE.³

Histologically, TUGSE shows an ulcerated epithelium with a polymorphic inflammatory cell infiltrate that has a large predominance of eosinophils. The infiltrate affects the superficial and deep layers of the muscle tissue and penetrates into the salivary glands. Large atypical mononuclear cells with an ovoid and pale-appearing nucleus often are present. These cells may be mitotically active and stain positively for CD30.^1,4,11 CD68⁺ macrophages, T lymphocytes, and factor XIIIa–positive dendritic cells commonly are present.¹²

Given the presence of large atypical CD30⁺ cells in many lesions, the possibility of a CD30⁺ lymphoproliferative disorder has been postulated by some authors. Indeed, lymphomatoid papulosis (LyP) has been documented to involve the oral mucosa.^2,4

Case Report

An 81-year-old man presented with a rapidly enlarging, 1.7×1.3-cm, vascular-appearing nodule with a collarette of mucosal epithelium on the left side of the dorsal surface of the tongue of 2 weeks’ duration (Figure 1). He denied any history of trauma, tobacco chewing, weight change, fever, or fatigue; however, he did report a 30 pack-year smoking history. There was no other pertinent medical history to include medications or allergies.

The differential diagnosis included pyogenic granuloma, granular cell tumor, squamous cell carcinoma, other neoplasms (eg, oral lymphoma, salivary gland tumors), and a traumatic blood blister from tongue biting. The patient was referred to the oral maxillofacial surgery department for an excisional biopsy, which showed a solitary ulcerated nodule with associated granulation tissue, thrombus, and fibrinoid debris (Figure 2). A surrounding dense mixed inflammatory cell infiltrate composed of lymphocytes, histiocytes, and numerous eosinophils was noted extending through the submucosal tissue and underlying striated muscle fibers (Figure 3). The adjacent mucosal epithelium appeared normal. CD30 staining showed only rare positive cells. These findings were consistent with TUGSE.

Due to the benign nature of TUGSE, the patient was released with symptomatic care and instructed to return for any new growth. The growth spontaneously resolved over 1 month and no recurrence or new lesions were reported 1 year later.

Comment

Despite encompassing multiple disciplines of medicine, TUGSE has minimal exposure in the dermatologic literature. It is an important clinical and histologic diagnosis that will provide reassurance to the patient when accurately identified and reduce potentially harmful treatments.

Clinical Presentation
Typically, TUGSE presents as a painful solitary nodule with a central ulcer and yellow fibrinous base. The margins of the ulcer typically have an indurated and rolled appearance.^1,4 More than 50% of the lesions develop on the tongue, specifically the dorsal or lateral surfaces, but they may present anywhere in the oral mucosa.⁷ Traumatic ulcerative granuloma with stromal eosinophilia is a fast-growing lesion, typically developing in days to weeks. Although it spontaneously regresses, the lesion may take weeks or months to resolve. In one case, it resolved 1 year later.¹ Traumatic ulcerative granuloma with stromal eosinophilia has a bimodal age distribution, generally appearing in the first 2 years of life and later in the fifth through seventh decades. The male-to-female predominance is equal.^1,7,11 Reoccurrence is rare, but some reports have shown patients with multiple episodes of TUGSE.^13,14

Differential Diagnosis
The clinical differential diagnosis for TUGSE includes squamous cell carcinoma, pyogenic granuloma, lymphoproliferative disorder, traumatic neuroma, Langerhans cell histiocytosis, granulomatous disorders, and oral lymphoma. Inflammatory disorders such as syphilis, Behçet’s disease, herpes, histoplasmosis, Wegener granulomatosis, and others also should be considered.

Immunohistochemistry
Immunohistochemical analysis of TUGSE lesions recently has revealed the presence of CD30⁺ cells. These cells are associated with cutaneous lymphoproliferative disorders including LyP, anaplastic large cell lymphoma (ALCL), and borderline CD30⁺ lesions, among others. Systemic diseases with CD30⁺ cells include mycosis fungoides, other T-cell lymphomas, and Hodgkin lymphoma.^15,16 Once CD30⁺ cells were recognized, multiple authors began speculating there was a correlation between TUGSE and the CD30⁺ lymphoproliferative disorders.^1,2,13 Anaplastic large cell lymphoma and LyP of the oral mucosa have been reported in several cases.^17-20 One report described 2 cases of ulcerated CD30⁺ T-cell non-Hodgkin lymphoma of the oral mucosa, one of which showed eosinophilic infiltrates and was initially thought to be TUGSE. Based on these overlapping clinical and histologic features, the authors hypothesized there was a correlation between oral ALCL, LyP, and TUGSE.¹⁷ In one report, a patient developed multiple TUGSE lesions throughout his life, suggesting a pathologic process similar to LyP. The lesion biopsied showed that 70% of the T cells expressed CD30 (Ki-1) antigen.¹³

Underlying Causes
In support of an underlying immunologic process that augments the growth of these lesions, 2 separate case reports of TUGSE in the presence of human T-lymphotropic virus 1 (HTLV-1) and Epstein-Barr virus have been documented.^2,21 Concurrent presentation of TUGSE and HTLV-1 in one report demonstrated eosinophilia in both the oral lesion and peripheral blood, suggesting an immunologic relationship. Furthermore, the authors postulated that local trauma initiated the development of TUGSE, providing the catalyst for the HTLV-1 carrier to develop peripheral eosinophilia.²¹

In the second case, a 12-year-old boy developed TUGSE in the presence of Epstein-Barr virus.² Immunologically, this virus can be reactivated from its latent stage during immunosuppression. Epstein-Barr virus has been implicated in lymphoproliferative diseases of both B- and T-cell origin, including CD30⁺ ALCL and LyP.^22,23 The authors in this report again hypothesized there was a correlation between lymphoproliferative disorders and TUGSE lesions.^2,24

Alternatively, TUGSE may simply be a reactive process to trauma or another underlying trigger. It has been speculated that the presence of eosinophils correlates with antigen insertion into the oral mucosa, whereas other ulcers of the oral mucosa are devoid of eosinophils.¹ These antigens may include microorganisms, endogenous degradation products, or foreign proteins.^7,25 Additionally, the presence of CD30⁺ lymphocytes is not isolated to lymphoproliferative disorders. CD30⁺ cells have been documented in arthropod bite reactions, atopic dermatitis, drug reactions, molluscum contagiosum, and scabies, among others.^1,26

Healing and Management
The length of healing in TUGSE ulcers has substantial variability, from days to up to 1 year in an isolated case.^1,24 Sequential expression of transforming growth factor (TGF) α and TGF-β expressed by tissue eosinophils may be underlying factors associated with a quicker healing response as demonstrated by similar ulcers in hamsters.²⁷ Chronic nonhealing oral ulcers, particularly TUGSE lesions that demonstrated the typical increase in eosinophils in 11 of 12 cases, showed minimal TGF-α or TGF-β expression by eosinophils, perhaps indicating a possible mechanism leading to delayed wound healing in some cases. Interestingly, incisional biopsies often led to rapid wound healing, suggesting that the biopsy itself allowed for a transition back to the regular wound-healing processes.²⁸

Traumatic ulcerative granuloma with stromal eosinophilia spontaneously resolves on its own in most cases; however, because of the concern for malignancy, it has the potential to be overtreated.²⁶ Symptomatic treatment only is the mainstay of therapy. The patient should be instructed to avoid trauma, and referral to a dental professional is indicated when associated with dentures or other periprosthetic devices. Diet should consist of soft foods while avoiding spicy foods. Topical or oral analgesics may be necessary if substantial pain is associated with the lesion.² Oral prednisolone was used in a patient with concurrent HTLV-1 and TUGSE to treat peripheral eosinophilia.²¹ The patient’s peripheral eosinophils dropped to 1% in 1 day, and the patient’s oral lesion began to improve at day 3 and disappeared by day 10. Although TUGSE may spontaneously resolve within a 10-day period without steroids, it may be a reasonable treatment to improve healing time in an otherwise healthy individual.^21,26 If there is concern for malignancy, the patient should have the lesion biopsied to provide reassurance and for the added benefit of a transition to normal healing response and decreased healing time.²⁸

Clinical Recognition
The clinician should be aware of the possibility of a CD30⁺ lymphoproliferative disorder, which has been associated with TUGSE in some cases, or may simulate TUGSE both clinically and histologically. Further studies are needed to clarify the relationship between these 2 entities. Whether it is a true relationship, simple coincidence, or simply overlapping clinical and histologic features remains to be determined.