Dermatopathology

The Diagnosis: Hyperkeratosis Lenticularis Perstans

A shave biopsy of a lesion on the right leg was performed. Histopathology revealed a discrete papule with overlying compact hyperkeratosis. There was parakeratosis with an absent granular layer and a lichenoid lymphocytic infiltrate within the papillary dermis (Figure). Given the clinical context, these changes were consistent with a diagnosis of hyperkeratosis lenticularis perstans (HLP), also known as Flegel disease.

The patient was started on tretinoin cream 0.1% nightly for 3 months and triamcinolone ointment 0.1% as needed for pruritus but showed no clinical response. Given the benign nature of the condition and because the lesions were asymptomatic, additional treatment options were not pursued.

Originally described by Flegel¹ in 1958, HLP is a rare skin disorder commonly seen in white individuals with onset in the fourth or fifth decades of life.^1,2 While most cases are sporadic,^3-6 HLP also has been associated with autosomal dominant inheritance.^7-10

Patients with HLP typically present with multiple 1- to 5-mm reddish-brown, hyperkeratotic, scaly papules that reveal a moist, erythematous base with pinpoint bleeding upon removal of the scale. Lesions usually are distributed symmetrically and most commonly present on the extensor surfaces of the lower legs and dorsal feet.^1,2,7 Lesions also may appear on the extensor surfaces of the arms, pinna, periocular region, antecubital and popliteal fossae, and oral mucosa and also may present as pits on the palms and soles.^2,4,7,8 Furthermore, unilateral and localized variants of HLP have been described.^11,12 Hyperkeratosis lenticularis perstans usually is asymptomatic but can present with mild pruritus or burning.^3,5,13

The etiology and pathogenesis of HLP are unknown. Exposure to UV light has been implicated as an inciting factor¹⁴; however, reports of spontaneous resolution in the summer¹³ and upon treatment with psoralen plus UVA therapy¹⁵ make the role of UV light unclear. Furthermore, investigators disagree as to whether the primary pathogenic event in HLP is an inflammatory process or one of abnormal keratinization.^1,3,7,10 Fernandez-Flores and Manjon¹⁶ suggested HLP is an inflammatory process with periods of exacerbations and remissions after finding mounds of parakeratosis with neutrophils arranged in different strata in the stratum corneum.

Histologically, compact hyperkeratosis usually is noted, often with associated parakeratosis, epidermal atrophy with thinning or absence of the granular layer, and a bandlike lymphohistiocytic infiltrate in the papillary dermis.^1-3 Histopathologic differences between recent-onset versus longstanding lesions have been found, with old lesions lacking an inflammatory infiltrate.³ Furthermore, new lesions often show abnormalities in quantity and/or morphology of membrane-coating granules, also known as Odland bodies, in keratinocytes on electron microscopy,^3,10,17 while old lesions do not.³ Odland bodies are involved in normal desquamation, leading some to speculate on their role in HLP.¹⁰ Currently, it is unclear whether abnormalities in these organelles cause the retention hyperkeratosis seen in HLP or if such abnormalities are a secondary phenomenon.^3,17

There are questionable associations between HLP and diabetes mellitus type 2, hyperthyroidism, basal and squamous cell carcinomas of the skin, and gastrointestinal malignancy.^4,9,18 Our patient had a history of basal cell carcinoma on the face, diet-controlled diabetes mellitus, and hypothyroidism. Given the high prevalence of these diseases in the general population, however, it is difficult to ascertain whether a true association with HLP exists.

While HLP can slowly progress to involve additional body sites, it is overall a benign condition that does not require treatment. Therapeutic options are based on case reports, with no single treatment showing a consistent response. From review of the literature, therapies that have been most effective include dermabrasion, excision,¹⁹ topical 5-fluorouracil,^2,17,20 and oral retinoids.⁸ Hyperkeratosis lenticularis perstans generally is resistant to topical steroids, retinoids, and vitamin D₃ analogs, although success with betamethasone dipropionate,⁵ isotretinoin  
gel 0.05%,¹¹ and calcipotriol have been reported.⁶ A case of HLP with clinical response to psoralen plus UVA therapy also has been described.¹⁵

The Diagnosis: Hyperkeratosis Lenticularis Perstans

A shave biopsy of a lesion on the right leg was performed. Histopathology revealed a discrete papule with overlying compact hyperkeratosis. There was parakeratosis with an absent granular layer and a lichenoid lymphocytic infiltrate within the papillary dermis (Figure). Given the clinical context, these changes were consistent with a diagnosis of hyperkeratosis lenticularis perstans (HLP), also known as Flegel disease.

The patient was started on tretinoin cream 0.1% nightly for 3 months and triamcinolone ointment 0.1% as needed for pruritus but showed no clinical response. Given the benign nature of the condition and because the lesions were asymptomatic, additional treatment options were not pursued.

Originally described by Flegel¹ in 1958, HLP is a rare skin disorder commonly seen in white individuals with onset in the fourth or fifth decades of life.^1,2 While most cases are sporadic,^3-6 HLP also has been associated with autosomal dominant inheritance.^7-10

Patients with HLP typically present with multiple 1- to 5-mm reddish-brown, hyperkeratotic, scaly papules that reveal a moist, erythematous base with pinpoint bleeding upon removal of the scale. Lesions usually are distributed symmetrically and most commonly present on the extensor surfaces of the lower legs and dorsal feet.^1,2,7 Lesions also may appear on the extensor surfaces of the arms, pinna, periocular region, antecubital and popliteal fossae, and oral mucosa and also may present as pits on the palms and soles.^2,4,7,8 Furthermore, unilateral and localized variants of HLP have been described.^11,12 Hyperkeratosis lenticularis perstans usually is asymptomatic but can present with mild pruritus or burning.^3,5,13

The etiology and pathogenesis of HLP are unknown. Exposure to UV light has been implicated as an inciting factor¹⁴; however, reports of spontaneous resolution in the summer¹³ and upon treatment with psoralen plus UVA therapy¹⁵ make the role of UV light unclear. Furthermore, investigators disagree as to whether the primary pathogenic event in HLP is an inflammatory process or one of abnormal keratinization.^1,3,7,10 Fernandez-Flores and Manjon¹⁶ suggested HLP is an inflammatory process with periods of exacerbations and remissions after finding mounds of parakeratosis with neutrophils arranged in different strata in the stratum corneum.

Histologically, compact hyperkeratosis usually is noted, often with associated parakeratosis, epidermal atrophy with thinning or absence of the granular layer, and a bandlike lymphohistiocytic infiltrate in the papillary dermis.^1-3 Histopathologic differences between recent-onset versus longstanding lesions have been found, with old lesions lacking an inflammatory infiltrate.³ Furthermore, new lesions often show abnormalities in quantity and/or morphology of membrane-coating granules, also known as Odland bodies, in keratinocytes on electron microscopy,^3,10,17 while old lesions do not.³ Odland bodies are involved in normal desquamation, leading some to speculate on their role in HLP.¹⁰ Currently, it is unclear whether abnormalities in these organelles cause the retention hyperkeratosis seen in HLP or if such abnormalities are a secondary phenomenon.^3,17

There are questionable associations between HLP and diabetes mellitus type 2, hyperthyroidism, basal and squamous cell carcinomas of the skin, and gastrointestinal malignancy.^4,9,18 Our patient had a history of basal cell carcinoma on the face, diet-controlled diabetes mellitus, and hypothyroidism. Given the high prevalence of these diseases in the general population, however, it is difficult to ascertain whether a true association with HLP exists.

While HLP can slowly progress to involve additional body sites, it is overall a benign condition that does not require treatment. Therapeutic options are based on case reports, with no single treatment showing a consistent response. From review of the literature, therapies that have been most effective include dermabrasion, excision,¹⁹ topical 5-fluorouracil,^2,17,20 and oral retinoids.⁸ Hyperkeratosis lenticularis perstans generally is resistant to topical steroids, retinoids, and vitamin D₃ analogs, although success with betamethasone dipropionate,⁵ isotretinoin  
gel 0.05%,¹¹ and calcipotriol have been reported.⁶ A case of HLP with clinical response to psoralen plus UVA therapy also has been described.¹⁵

The Diagnosis: Hyperkeratosis Lenticularis Perstans

A shave biopsy of a lesion on the right leg was performed. Histopathology revealed a discrete papule with overlying compact hyperkeratosis. There was parakeratosis with an absent granular layer and a lichenoid lymphocytic infiltrate within the papillary dermis (Figure). Given the clinical context, these changes were consistent with a diagnosis of hyperkeratosis lenticularis perstans (HLP), also known as Flegel disease.

The patient was started on tretinoin cream 0.1% nightly for 3 months and triamcinolone ointment 0.1% as needed for pruritus but showed no clinical response. Given the benign nature of the condition and because the lesions were asymptomatic, additional treatment options were not pursued.

Originally described by Flegel¹ in 1958, HLP is a rare skin disorder commonly seen in white individuals with onset in the fourth or fifth decades of life.^1,2 While most cases are sporadic,^3-6 HLP also has been associated with autosomal dominant inheritance.^7-10

Patients with HLP typically present with multiple 1- to 5-mm reddish-brown, hyperkeratotic, scaly papules that reveal a moist, erythematous base with pinpoint bleeding upon removal of the scale. Lesions usually are distributed symmetrically and most commonly present on the extensor surfaces of the lower legs and dorsal feet.^1,2,7 Lesions also may appear on the extensor surfaces of the arms, pinna, periocular region, antecubital and popliteal fossae, and oral mucosa and also may present as pits on the palms and soles.^2,4,7,8 Furthermore, unilateral and localized variants of HLP have been described.^11,12 Hyperkeratosis lenticularis perstans usually is asymptomatic but can present with mild pruritus or burning.^3,5,13

The etiology and pathogenesis of HLP are unknown. Exposure to UV light has been implicated as an inciting factor¹⁴; however, reports of spontaneous resolution in the summer¹³ and upon treatment with psoralen plus UVA therapy¹⁵ make the role of UV light unclear. Furthermore, investigators disagree as to whether the primary pathogenic event in HLP is an inflammatory process or one of abnormal keratinization.^1,3,7,10 Fernandez-Flores and Manjon¹⁶ suggested HLP is an inflammatory process with periods of exacerbations and remissions after finding mounds of parakeratosis with neutrophils arranged in different strata in the stratum corneum.

Histologically, compact hyperkeratosis usually is noted, often with associated parakeratosis, epidermal atrophy with thinning or absence of the granular layer, and a bandlike lymphohistiocytic infiltrate in the papillary dermis.^1-3 Histopathologic differences between recent-onset versus longstanding lesions have been found, with old lesions lacking an inflammatory infiltrate.³ Furthermore, new lesions often show abnormalities in quantity and/or morphology of membrane-coating granules, also known as Odland bodies, in keratinocytes on electron microscopy,^3,10,17 while old lesions do not.³ Odland bodies are involved in normal desquamation, leading some to speculate on their role in HLP.¹⁰ Currently, it is unclear whether abnormalities in these organelles cause the retention hyperkeratosis seen in HLP or if such abnormalities are a secondary phenomenon.^3,17

There are questionable associations between HLP and diabetes mellitus type 2, hyperthyroidism, basal and squamous cell carcinomas of the skin, and gastrointestinal malignancy.^4,9,18 Our patient had a history of basal cell carcinoma on the face, diet-controlled diabetes mellitus, and hypothyroidism. Given the high prevalence of these diseases in the general population, however, it is difficult to ascertain whether a true association with HLP exists.

While HLP can slowly progress to involve additional body sites, it is overall a benign condition that does not require treatment. Therapeutic options are based on case reports, with no single treatment showing a consistent response. From review of the literature, therapies that have been most effective include dermabrasion, excision,¹⁹ topical 5-fluorouracil,^2,17,20 and oral retinoids.⁸ Hyperkeratosis lenticularis perstans generally is resistant to topical steroids, retinoids, and vitamin D₃ analogs, although success with betamethasone dipropionate,⁵ isotretinoin  
gel 0.05%,¹¹ and calcipotriol have been reported.⁶ A case of HLP with clinical response to psoralen plus UVA therapy also has been described.¹⁵

Cutaneous leishmaniasis is a parasitic infection caused by intracellular organisms found in tropical climates. Old World leishmaniasis is endemic to Asia, Africa, and parts of Europe, while New World leishmaniasis is native to Central and South Americas.¹ Depending upon a host’s immune status and the specific Leishmania species, clinical presentations vary in appearance and severity, ranging from self-limited, localized cutaneous disease to potentially fatal visceral and mucocutaneous involvement. Most cutaneous manifestations of leishmaniasis begin as distinct, painless papules that may progress to nodules or become ulcerated over time.¹ Histologically, leishmaniasis is diagnosed by the identification of intracellular organisms that characteristically align along the peripheral rim inside the vacuole of a histiocyte.² This unique finding is called the “marquee sign” due to its resemblance to light bulbs arranged around a dressing room mirror (Figure 1).²Leishmania amastigotes (also known as Leishman-Donovan bodies) have kinetoplasts that are helpful in diagnosis but also may be difficult to detect.² Along with the Leishmania parasites, there typically is a mixed inflammatory infiltrate of plasma cells, lymphocytes, histiocytes, and neutrophils (Figure 2).^1,2 There also may be varying degrees of pseudoepitheliomatous hyperplasia and overlying epidermal ulceration.¹

Cutaneous botryomycosis can present clinically as a number of various primary lesions, including papules, nodules, or ulcers that may resemble leishmaniasis.³ Botryomycosis represents a specific histologic collection of bacterial granules, most commonly caused by Staphylococcus aureus.³ The dermal granulomatous infiltrate seen in botryomycosis often is similar to that seen in chronic leishmaniasis; however, one histologic feature unique to botryomycosis is the presence of characteristic basophilic staphylococcal grains that are arranged in clusters resembling bunches of grapes (the term botryo means “bunch of grapes” in Greek).³ A thin, eosinophilic rim consisting of antibodies, bacterial debris, and complement proteins and glycoproteins may encircle the basophilic grains but does not need to be present for diagnosis (Figure 3).³

Lepromatous leprosy presents as a symmetric, widespread eruption of macules, patches, plaques, or papules that are most prominent in acral areas.⁴ Perivascular infiltration of lymphocytes and histiocytes is characteristic of lepromatous leprosy.² Mycobacteria bacilli also are seen within histiocytic vacuoles, similarly to leishmaniasis; however, collections of these bacilli congregate within the center of a foamy histiocyte to form a distinctive histologic finding known as a globus. These individual histiocytes containing central globi are called Virchow cells (Figure 4).² However, lepromatous leprosy can be distinguished from leishmaniasis histologically by carefully observing the intracellular location of the infectious organism. Mycobacteria bacilli are located in the center of a histiocyte vacuole whereas Leishmania parasites demonstrate a peripheral alignment along a histiocyte vacuole. If any uncertainty remains between a diagnosis of leishmaniasis and lepromatous leprosy, positive Fite staining for mycobacteria easily differentiates between the 2 conditions.^2,4

Cutaneous lobomycosis, a rare fungal infection transmitted by dolphins, manifests clinically as an asymptomatic nodule that is similar in appearance to a keloid. Histologic similarities to leishmaniasis include pseudoepitheliomatous hyperplasia and dermal granulomatous inflammation.⁴ The most distinguishing characteristic of lobomycosis is the presence of round, thick-walled, white organisms connected in a “string of beads” or chainlike configuration (Figure 5).² Unlike leishmaniasis, lobomycosis fungal organisms would stain positive on periodic acid–Schiff staining.⁴

Cutaneous protothecosis is a rare clinical entity that presents as an isolated nodule or plaque or bursitis.⁴ It occurs following minor trauma and inoculation with Prototheca organisms, a genus of algae found in contaminated water.^2,4 In its morula form, Prototheca adopts a characteristic arrangement within histiocytes that strikingly resembles a soccer ball (Figure 6).² Conversely, nonmorulating forms of protothecosis can also be seen; these exhibit a central basophilic, dotlike structure within the histiocytes surrounded by a white halo.² Definitive diagnosis of protothecosis can only be made upon successful culture of the algae.⁵

Cutaneous leishmaniasis is a parasitic infection caused by intracellular organisms found in tropical climates. Old World leishmaniasis is endemic to Asia, Africa, and parts of Europe, while New World leishmaniasis is native to Central and South Americas.¹ Depending upon a host’s immune status and the specific Leishmania species, clinical presentations vary in appearance and severity, ranging from self-limited, localized cutaneous disease to potentially fatal visceral and mucocutaneous involvement. Most cutaneous manifestations of leishmaniasis begin as distinct, painless papules that may progress to nodules or become ulcerated over time.¹ Histologically, leishmaniasis is diagnosed by the identification of intracellular organisms that characteristically align along the peripheral rim inside the vacuole of a histiocyte.² This unique finding is called the “marquee sign” due to its resemblance to light bulbs arranged around a dressing room mirror (Figure 1).²Leishmania amastigotes (also known as Leishman-Donovan bodies) have kinetoplasts that are helpful in diagnosis but also may be difficult to detect.² Along with the Leishmania parasites, there typically is a mixed inflammatory infiltrate of plasma cells, lymphocytes, histiocytes, and neutrophils (Figure 2).^1,2 There also may be varying degrees of pseudoepitheliomatous hyperplasia and overlying epidermal ulceration.¹

Cutaneous botryomycosis can present clinically as a number of various primary lesions, including papules, nodules, or ulcers that may resemble leishmaniasis.³ Botryomycosis represents a specific histologic collection of bacterial granules, most commonly caused by Staphylococcus aureus.³ The dermal granulomatous infiltrate seen in botryomycosis often is similar to that seen in chronic leishmaniasis; however, one histologic feature unique to botryomycosis is the presence of characteristic basophilic staphylococcal grains that are arranged in clusters resembling bunches of grapes (the term botryo means “bunch of grapes” in Greek).³ A thin, eosinophilic rim consisting of antibodies, bacterial debris, and complement proteins and glycoproteins may encircle the basophilic grains but does not need to be present for diagnosis (Figure 3).³

Lepromatous leprosy presents as a symmetric, widespread eruption of macules, patches, plaques, or papules that are most prominent in acral areas.⁴ Perivascular infiltration of lymphocytes and histiocytes is characteristic of lepromatous leprosy.² Mycobacteria bacilli also are seen within histiocytic vacuoles, similarly to leishmaniasis; however, collections of these bacilli congregate within the center of a foamy histiocyte to form a distinctive histologic finding known as a globus. These individual histiocytes containing central globi are called Virchow cells (Figure 4).² However, lepromatous leprosy can be distinguished from leishmaniasis histologically by carefully observing the intracellular location of the infectious organism. Mycobacteria bacilli are located in the center of a histiocyte vacuole whereas Leishmania parasites demonstrate a peripheral alignment along a histiocyte vacuole. If any uncertainty remains between a diagnosis of leishmaniasis and lepromatous leprosy, positive Fite staining for mycobacteria easily differentiates between the 2 conditions.^2,4

Cutaneous lobomycosis, a rare fungal infection transmitted by dolphins, manifests clinically as an asymptomatic nodule that is similar in appearance to a keloid. Histologic similarities to leishmaniasis include pseudoepitheliomatous hyperplasia and dermal granulomatous inflammation.⁴ The most distinguishing characteristic of lobomycosis is the presence of round, thick-walled, white organisms connected in a “string of beads” or chainlike configuration (Figure 5).² Unlike leishmaniasis, lobomycosis fungal organisms would stain positive on periodic acid–Schiff staining.⁴

Cutaneous protothecosis is a rare clinical entity that presents as an isolated nodule or plaque or bursitis.⁴ It occurs following minor trauma and inoculation with Prototheca organisms, a genus of algae found in contaminated water.^2,4 In its morula form, Prototheca adopts a characteristic arrangement within histiocytes that strikingly resembles a soccer ball (Figure 6).² Conversely, nonmorulating forms of protothecosis can also be seen; these exhibit a central basophilic, dotlike structure within the histiocytes surrounded by a white halo.² Definitive diagnosis of protothecosis can only be made upon successful culture of the algae.⁵

Cutaneous leishmaniasis is a parasitic infection caused by intracellular organisms found in tropical climates. Old World leishmaniasis is endemic to Asia, Africa, and parts of Europe, while New World leishmaniasis is native to Central and South Americas.¹ Depending upon a host’s immune status and the specific Leishmania species, clinical presentations vary in appearance and severity, ranging from self-limited, localized cutaneous disease to potentially fatal visceral and mucocutaneous involvement. Most cutaneous manifestations of leishmaniasis begin as distinct, painless papules that may progress to nodules or become ulcerated over time.¹ Histologically, leishmaniasis is diagnosed by the identification of intracellular organisms that characteristically align along the peripheral rim inside the vacuole of a histiocyte.² This unique finding is called the “marquee sign” due to its resemblance to light bulbs arranged around a dressing room mirror (Figure 1).²Leishmania amastigotes (also known as Leishman-Donovan bodies) have kinetoplasts that are helpful in diagnosis but also may be difficult to detect.² Along with the Leishmania parasites, there typically is a mixed inflammatory infiltrate of plasma cells, lymphocytes, histiocytes, and neutrophils (Figure 2).^1,2 There also may be varying degrees of pseudoepitheliomatous hyperplasia and overlying epidermal ulceration.¹

Cutaneous botryomycosis can present clinically as a number of various primary lesions, including papules, nodules, or ulcers that may resemble leishmaniasis.³ Botryomycosis represents a specific histologic collection of bacterial granules, most commonly caused by Staphylococcus aureus.³ The dermal granulomatous infiltrate seen in botryomycosis often is similar to that seen in chronic leishmaniasis; however, one histologic feature unique to botryomycosis is the presence of characteristic basophilic staphylococcal grains that are arranged in clusters resembling bunches of grapes (the term botryo means “bunch of grapes” in Greek).³ A thin, eosinophilic rim consisting of antibodies, bacterial debris, and complement proteins and glycoproteins may encircle the basophilic grains but does not need to be present for diagnosis (Figure 3).³

Lepromatous leprosy presents as a symmetric, widespread eruption of macules, patches, plaques, or papules that are most prominent in acral areas.⁴ Perivascular infiltration of lymphocytes and histiocytes is characteristic of lepromatous leprosy.² Mycobacteria bacilli also are seen within histiocytic vacuoles, similarly to leishmaniasis; however, collections of these bacilli congregate within the center of a foamy histiocyte to form a distinctive histologic finding known as a globus. These individual histiocytes containing central globi are called Virchow cells (Figure 4).² However, lepromatous leprosy can be distinguished from leishmaniasis histologically by carefully observing the intracellular location of the infectious organism. Mycobacteria bacilli are located in the center of a histiocyte vacuole whereas Leishmania parasites demonstrate a peripheral alignment along a histiocyte vacuole. If any uncertainty remains between a diagnosis of leishmaniasis and lepromatous leprosy, positive Fite staining for mycobacteria easily differentiates between the 2 conditions.^2,4

Cutaneous lobomycosis, a rare fungal infection transmitted by dolphins, manifests clinically as an asymptomatic nodule that is similar in appearance to a keloid. Histologic similarities to leishmaniasis include pseudoepitheliomatous hyperplasia and dermal granulomatous inflammation.⁴ The most distinguishing characteristic of lobomycosis is the presence of round, thick-walled, white organisms connected in a “string of beads” or chainlike configuration (Figure 5).² Unlike leishmaniasis, lobomycosis fungal organisms would stain positive on periodic acid–Schiff staining.⁴

Cutaneous protothecosis is a rare clinical entity that presents as an isolated nodule or plaque or bursitis.⁴ It occurs following minor trauma and inoculation with Prototheca organisms, a genus of algae found in contaminated water.^2,4 In its morula form, Prototheca adopts a characteristic arrangement within histiocytes that strikingly resembles a soccer ball (Figure 6).² Conversely, nonmorulating forms of protothecosis can also be seen; these exhibit a central basophilic, dotlike structure within the histiocytes surrounded by a white halo.² Definitive diagnosis of protothecosis can only be made upon successful culture of the algae.⁵

The Diagnosis: Acrodermatitis Continua of Hallopeau

Acrodermatitis continua of Hallopeau (ACH) is considered to be a form of acropustular psoriasis that presents as a sterile, pustular eruption initially affecting the fingertips and/or toes.¹ The slow-growing pustules typically progress locally and can lead to onychodystrophy and/or osteolysis of the underlying bone.^2,3 Most commonly affecting adult women, ACH often begins following local trauma to or infection of a single digit.⁴ As the disease progresses proximally, the small pustules burst, leaving a shiny, erythematous surface on which new pustules can develop. These pustules have a tendency to amalgamate, leading to the characteristic clinical finding of lakes of pus. Pustules frequently appear on the nail matrix and nail bed presenting as severe onychodystrophy and ultimately anonychia.^5,6 Rarely, ACH can be associated with generalized pustular psoriasis as well as conjunctivitis, balanitis, and fissuring or annulus migrans of the tongue.^2,7

Diagnosis can be established based on clinical findings, biopsy, and bacterial and fungal cultures revealing sterile pustules.^8,9 Histologic findings are similar to those seen in pustular psoriasis, demonstrating subcorneal neutrophilic pustules, Munro microabscesses, and dilated blood vessels with lymphocytic infiltrate in the papillary dermis.¹⁰

Due to the refractory nature of the disease, there are no recommended guidelines for treatment of ACH. Most successful treatment regimens consist of topical psoriasis medications combined with systemic psoriatic therapies such as cyclosporine, methotrexate, acitretin, or biologic therapy.^8,11-16 Our patient achieved satisfactory clinical improvement with clobetasol propionate ointment 0.05% twice daily alternating with calcipotriene cream 0.005% twice daily.

The Diagnosis: Acrodermatitis Continua of Hallopeau

Acrodermatitis continua of Hallopeau (ACH) is considered to be a form of acropustular psoriasis that presents as a sterile, pustular eruption initially affecting the fingertips and/or toes.¹ The slow-growing pustules typically progress locally and can lead to onychodystrophy and/or osteolysis of the underlying bone.^2,3 Most commonly affecting adult women, ACH often begins following local trauma to or infection of a single digit.⁴ As the disease progresses proximally, the small pustules burst, leaving a shiny, erythematous surface on which new pustules can develop. These pustules have a tendency to amalgamate, leading to the characteristic clinical finding of lakes of pus. Pustules frequently appear on the nail matrix and nail bed presenting as severe onychodystrophy and ultimately anonychia.^5,6 Rarely, ACH can be associated with generalized pustular psoriasis as well as conjunctivitis, balanitis, and fissuring or annulus migrans of the tongue.^2,7

Diagnosis can be established based on clinical findings, biopsy, and bacterial and fungal cultures revealing sterile pustules.^8,9 Histologic findings are similar to those seen in pustular psoriasis, demonstrating subcorneal neutrophilic pustules, Munro microabscesses, and dilated blood vessels with lymphocytic infiltrate in the papillary dermis.¹⁰

Due to the refractory nature of the disease, there are no recommended guidelines for treatment of ACH. Most successful treatment regimens consist of topical psoriasis medications combined with systemic psoriatic therapies such as cyclosporine, methotrexate, acitretin, or biologic therapy.^8,11-16 Our patient achieved satisfactory clinical improvement with clobetasol propionate ointment 0.05% twice daily alternating with calcipotriene cream 0.005% twice daily.

The Diagnosis: Acrodermatitis Continua of Hallopeau

Acrodermatitis continua of Hallopeau (ACH) is considered to be a form of acropustular psoriasis that presents as a sterile, pustular eruption initially affecting the fingertips and/or toes.¹ The slow-growing pustules typically progress locally and can lead to onychodystrophy and/or osteolysis of the underlying bone.^2,3 Most commonly affecting adult women, ACH often begins following local trauma to or infection of a single digit.⁴ As the disease progresses proximally, the small pustules burst, leaving a shiny, erythematous surface on which new pustules can develop. These pustules have a tendency to amalgamate, leading to the characteristic clinical finding of lakes of pus. Pustules frequently appear on the nail matrix and nail bed presenting as severe onychodystrophy and ultimately anonychia.^5,6 Rarely, ACH can be associated with generalized pustular psoriasis as well as conjunctivitis, balanitis, and fissuring or annulus migrans of the tongue.^2,7

Diagnosis can be established based on clinical findings, biopsy, and bacterial and fungal cultures revealing sterile pustules.^8,9 Histologic findings are similar to those seen in pustular psoriasis, demonstrating subcorneal neutrophilic pustules, Munro microabscesses, and dilated blood vessels with lymphocytic infiltrate in the papillary dermis.¹⁰

Due to the refractory nature of the disease, there are no recommended guidelines for treatment of ACH. Most successful treatment regimens consist of topical psoriasis medications combined with systemic psoriatic therapies such as cyclosporine, methotrexate, acitretin, or biologic therapy.^8,11-16 Our patient achieved satisfactory clinical improvement with clobetasol propionate ointment 0.05% twice daily alternating with calcipotriene cream 0.005% twice daily.

The Diagnosis: Eccrine Poroma

A shave biopsy of the lesion was performed for definitive diagnosis and demonstrated a well-circumscribed tumor with cords and broad columns composed of uniform basaloid cells extending into the dermis and in areas connecting to the overlying epidermis (Figure). There also were small ducts and cysts admixed in the tumor columns that were embedded in a tumor stroma rich in blood vessels. A diagnosis of eccrine poroma was made based on these characteristic histologic features.

Biopsy revealed a basaloid tumor originating from the epidermis and extending into the dermis (A)(H&E, original magnification ×4). On higher magnification, ducts were evident amongst the tumor cells and a vascular rich stroma was revealed (B)(H&E, original magnification ×10).

First described by Pinkus et al¹ in 1956, eccrine poroma is a benign neoplasm of cells from the intraepidermal ductal portion of the eccrine sweat gland. Eccrine poroma (along with hidroacanthoma simplex, dermal duct tumor, and poroid hidradenoma) is one of the poroid neoplasms, which account for approximately 10% of all primary sweat gland tumors.² Eccrine poroma usually is seen in patients over 40 years of age without any predilection for race or sex.

Characteristically, eccrine poromas clinically manifest as solitary, firm, sharply demarcated papules or nodules that may be sessile or pedunculated and rarely exceed 2 cm in diameter. This entity classically presents on acral, non–hair-bearing areas (eg, palms and soles). Eccrine poromas have a wide range of clinical appearances that can lead to broad differential diagnoses³ and have been described as flesh-colored,³ pink to red,⁴ purple,⁵ and pigmented^3,4 papules or nodules depending on features such as blood vessel proliferation and pigment deposition.

Eccrine poromas also have been reported on hair-bearing areas of the body, including the head,³ neck,^3,6 chest,^4,6 hip,⁷ and pubic area,⁸ despite the paucity of eccrine glands in these areas on the body. These findings suggest that these neoplasms may not be purely eccrine in origin. The wide range of clinical presentations of eccrine poromas has prompted investigation into further classification and delineation of this neoplasm.³ The occurrence of eccrine poromas on areas of the skin known to have few eccrine glands suggests that eccrine poromas may not be purely comprised of eccrine ducts and instead may be of apocrine origin.^3,9,10 Histologic features of eccrine poromas that suggest apocrine origination include sebaceous and follicular differentiation (eg, folliculocentric distribution), the association with the follicular infundibulum, and the presence of follicular germ cells.^3,9,10 Thus, apocrine gland involvement in eccrine poromas may account for their appearance in anatomic areas that do not have high concentrations of eccrine glands, such as the trunk and pubic area.

Based on these findings, eccrine poromas may therefore be of eccrine and/or apocrine origin; however, the nomenclature of this neoplasm remains confusing and possibly misleading, as the term eccrine poroma continues to be accepted even in instances in which the differentiation appears to be largely apocrine. The terms poroma and eccrine poroma often are used interchangeably, which contributes to the confusion by failing to acknowledge the possibility of apocrine influence and possibly causing the clinician to exclude eccrine poromas from the differential diagnosis in areas that do not have high concentrations of eccrine glands.

Because of their high degree of clinical variability, characteristic acral location, and misleading nomenclature, eccrine poromas often are mistakenly confused with a long list of other cutaneous neoplasms, including hemangiomas, pyogenic granulomas, melanocytic nevi, warts, cysts, and other adnexal neoplasms.³ In our case, the lesion was abnormally large and was clinically concerning for an unusual sebaceous nevus. Its location on the lower back is not commonly noted and should remind the clinician of the possibility of apocrine differentiation. Clinicians should be aware of the wide phenotypic diversity of eccrine poromas, and therefore they should consider this diagnosis in their differential diagnosis for solitary papules or nodules occurring in any anatomic area.

The Diagnosis: Eccrine Poroma

A shave biopsy of the lesion was performed for definitive diagnosis and demonstrated a well-circumscribed tumor with cords and broad columns composed of uniform basaloid cells extending into the dermis and in areas connecting to the overlying epidermis (Figure). There also were small ducts and cysts admixed in the tumor columns that were embedded in a tumor stroma rich in blood vessels. A diagnosis of eccrine poroma was made based on these characteristic histologic features.

Biopsy revealed a basaloid tumor originating from the epidermis and extending into the dermis (A)(H&E, original magnification ×4). On higher magnification, ducts were evident amongst the tumor cells and a vascular rich stroma was revealed (B)(H&E, original magnification ×10).

First described by Pinkus et al¹ in 1956, eccrine poroma is a benign neoplasm of cells from the intraepidermal ductal portion of the eccrine sweat gland. Eccrine poroma (along with hidroacanthoma simplex, dermal duct tumor, and poroid hidradenoma) is one of the poroid neoplasms, which account for approximately 10% of all primary sweat gland tumors.² Eccrine poroma usually is seen in patients over 40 years of age without any predilection for race or sex.

Characteristically, eccrine poromas clinically manifest as solitary, firm, sharply demarcated papules or nodules that may be sessile or pedunculated and rarely exceed 2 cm in diameter. This entity classically presents on acral, non–hair-bearing areas (eg, palms and soles). Eccrine poromas have a wide range of clinical appearances that can lead to broad differential diagnoses³ and have been described as flesh-colored,³ pink to red,⁴ purple,⁵ and pigmented^3,4 papules or nodules depending on features such as blood vessel proliferation and pigment deposition.

Eccrine poromas also have been reported on hair-bearing areas of the body, including the head,³ neck,^3,6 chest,^4,6 hip,⁷ and pubic area,⁸ despite the paucity of eccrine glands in these areas on the body. These findings suggest that these neoplasms may not be purely eccrine in origin. The wide range of clinical presentations of eccrine poromas has prompted investigation into further classification and delineation of this neoplasm.³ The occurrence of eccrine poromas on areas of the skin known to have few eccrine glands suggests that eccrine poromas may not be purely comprised of eccrine ducts and instead may be of apocrine origin.^3,9,10 Histologic features of eccrine poromas that suggest apocrine origination include sebaceous and follicular differentiation (eg, folliculocentric distribution), the association with the follicular infundibulum, and the presence of follicular germ cells.^3,9,10 Thus, apocrine gland involvement in eccrine poromas may account for their appearance in anatomic areas that do not have high concentrations of eccrine glands, such as the trunk and pubic area.

Based on these findings, eccrine poromas may therefore be of eccrine and/or apocrine origin; however, the nomenclature of this neoplasm remains confusing and possibly misleading, as the term eccrine poroma continues to be accepted even in instances in which the differentiation appears to be largely apocrine. The terms poroma and eccrine poroma often are used interchangeably, which contributes to the confusion by failing to acknowledge the possibility of apocrine influence and possibly causing the clinician to exclude eccrine poromas from the differential diagnosis in areas that do not have high concentrations of eccrine glands.

Because of their high degree of clinical variability, characteristic acral location, and misleading nomenclature, eccrine poromas often are mistakenly confused with a long list of other cutaneous neoplasms, including hemangiomas, pyogenic granulomas, melanocytic nevi, warts, cysts, and other adnexal neoplasms.³ In our case, the lesion was abnormally large and was clinically concerning for an unusual sebaceous nevus. Its location on the lower back is not commonly noted and should remind the clinician of the possibility of apocrine differentiation. Clinicians should be aware of the wide phenotypic diversity of eccrine poromas, and therefore they should consider this diagnosis in their differential diagnosis for solitary papules or nodules occurring in any anatomic area.

The Diagnosis: Eccrine Poroma

A shave biopsy of the lesion was performed for definitive diagnosis and demonstrated a well-circumscribed tumor with cords and broad columns composed of uniform basaloid cells extending into the dermis and in areas connecting to the overlying epidermis (Figure). There also were small ducts and cysts admixed in the tumor columns that were embedded in a tumor stroma rich in blood vessels. A diagnosis of eccrine poroma was made based on these characteristic histologic features.

Biopsy revealed a basaloid tumor originating from the epidermis and extending into the dermis (A)(H&E, original magnification ×4). On higher magnification, ducts were evident amongst the tumor cells and a vascular rich stroma was revealed (B)(H&E, original magnification ×10).

First described by Pinkus et al¹ in 1956, eccrine poroma is a benign neoplasm of cells from the intraepidermal ductal portion of the eccrine sweat gland. Eccrine poroma (along with hidroacanthoma simplex, dermal duct tumor, and poroid hidradenoma) is one of the poroid neoplasms, which account for approximately 10% of all primary sweat gland tumors.² Eccrine poroma usually is seen in patients over 40 years of age without any predilection for race or sex.

Characteristically, eccrine poromas clinically manifest as solitary, firm, sharply demarcated papules or nodules that may be sessile or pedunculated and rarely exceed 2 cm in diameter. This entity classically presents on acral, non–hair-bearing areas (eg, palms and soles). Eccrine poromas have a wide range of clinical appearances that can lead to broad differential diagnoses³ and have been described as flesh-colored,³ pink to red,⁴ purple,⁵ and pigmented^3,4 papules or nodules depending on features such as blood vessel proliferation and pigment deposition.

Eccrine poromas also have been reported on hair-bearing areas of the body, including the head,³ neck,^3,6 chest,^4,6 hip,⁷ and pubic area,⁸ despite the paucity of eccrine glands in these areas on the body. These findings suggest that these neoplasms may not be purely eccrine in origin. The wide range of clinical presentations of eccrine poromas has prompted investigation into further classification and delineation of this neoplasm.³ The occurrence of eccrine poromas on areas of the skin known to have few eccrine glands suggests that eccrine poromas may not be purely comprised of eccrine ducts and instead may be of apocrine origin.^3,9,10 Histologic features of eccrine poromas that suggest apocrine origination include sebaceous and follicular differentiation (eg, folliculocentric distribution), the association with the follicular infundibulum, and the presence of follicular germ cells.^3,9,10 Thus, apocrine gland involvement in eccrine poromas may account for their appearance in anatomic areas that do not have high concentrations of eccrine glands, such as the trunk and pubic area.

Based on these findings, eccrine poromas may therefore be of eccrine and/or apocrine origin; however, the nomenclature of this neoplasm remains confusing and possibly misleading, as the term eccrine poroma continues to be accepted even in instances in which the differentiation appears to be largely apocrine. The terms poroma and eccrine poroma often are used interchangeably, which contributes to the confusion by failing to acknowledge the possibility of apocrine influence and possibly causing the clinician to exclude eccrine poromas from the differential diagnosis in areas that do not have high concentrations of eccrine glands.

Because of their high degree of clinical variability, characteristic acral location, and misleading nomenclature, eccrine poromas often are mistakenly confused with a long list of other cutaneous neoplasms, including hemangiomas, pyogenic granulomas, melanocytic nevi, warts, cysts, and other adnexal neoplasms.³ In our case, the lesion was abnormally large and was clinically concerning for an unusual sebaceous nevus. Its location on the lower back is not commonly noted and should remind the clinician of the possibility of apocrine differentiation. Clinicians should be aware of the wide phenotypic diversity of eccrine poromas, and therefore they should consider this diagnosis in their differential diagnosis for solitary papules or nodules occurring in any anatomic area.

Henoch-Schönlein purpura (HSP) is a systemic, small vessel vasculitis affecting the skin, joints, gastrointestinal tract, and kidneys. It usually is self-limited, but relapses can be seen in one-third of cases.¹ The classic cutaneous presentation includes palpable purpura localized to the legs and buttocks. Painful hemorrhagic bullae are uncommonly observed in childhood HSP and often could lead to a diagnostic dilemma. We report the case of a patient who presented with atypical features of painful hemorrhagic bullae and provide a review of the literature.

Case Report

An otherwise healthy 14-year-old adolescent girl presented to the hospital with painful ulcerative lesions covering the arms, legs, lower abdomen, and buttocks of 3 weeks’ duration. The rash first appeared on the ankles and spread in an ascending fashion, starting with bullous formation that was accompanied by joint pain, especially in the ankles and elbows. No abdominal pain was reported. The patient attributed the lesions to prolonged cold exposure followed by a hot bath. She had tried naproxen without any improvement of pain. She was afebrile with normal blood pressure.

On physical examination, numerous petechiae, palpable purpura, hemorrhagic bullae, and ulcers with surrounding erythematous to violaceous induration as well as central necrosis were noted on the arms, legs (Figure 1), abdomen, and buttocks. The palms, soles, trunk, and face were spared.

Laboratory values on admission revealed leukocytosis (17,500/μL [reference range, 4500–11,000/μL]), elevated erythrocyte sedimentation rate (42 mm/h [reference range, 0–20 mm/h]), elevated C-reactive protein 
(15.59 mg/L [reference range, 0.08–3.1 mg/L]), elevated C3 (174 mg/dL [reference range, 75–135 mg/dL]), normal C4 (32 mg/dL [reference range, 3–75 mg/dL]), normal blood urea nitrogen (13 mg/dL [reference range, 8–23 mg/dL]), and normal creatinine (0.72 mg/dL [reference range, 0.6–1.2 mg/dL]). Urinalysis showed microscopic hematuria and trace proteinuria. Platelet count was normal.

Diagnostic considerations included HSP, drug-induced leukocytoclastic vasculitis, and bullous pyoderma gangrenosum. The patient was started on oral prednisone 80 mg once daily. Additionally, oral doxycycline 100 mg twice daily was added for prevention of secondary bacterial infections and for anti-inflammatory effects. All nonsteroidal 
anti-inflammatory drugs were avoided. A commercial ointment containing 8-hydroxyquinoline sulfate 0.3% and triamcinolone acetonide ointment 0.1% were used to minimize skin irritation. Morphine, 
oxycodone-acetaminophen, and pregabalin followed by gabapentin were used for pain control. Hydrotherapy also was used for the treatment of skin lesions.

Two skin punch biopsies were performed at different stages. Biopsy of an early palpable purpuric lesion showed small vessel leukocytoclastic vasculitis with perivascular IgA on direct immunofluorescence. A 
second biopsy from a more hemorrhagic lesion performed 96 hours after admission to the hospital showed subepidermal vesicles with partial epidermal necrosis, confluent neutrophilic infiltrate in the papillary dermis, and small vessel vasculitis (Figures 2 and 3). Gram, periodic acid–Schiff, and acid-fast bacilli staining and cultures were negative. With continued treatment for 7 days, the clinical appearance of the lesions improved. On the tenth day of hospitalization, oral dapsone 
25 mg once daily was initiated with the goal of weaning the patient off the prednisone as tolerated. She was discharged on prednisone (60 mg once daily) after 
14 days of hospitalization. Dapsone also was continued.

Figure 2. Biopsy of a subepidermal bulla revealed neutrophilic inflammation within bullous space and evidence of dermal hemorrhage (H&E, original magnification ×100).		Figure 3. Leukocytoclastic vasculitis on biopsy (H&E, original magnification ×400).

At 4-week follow-up, the lesions showed healing with mild residual pigmentation. The patient’s blood pressure and serum urea and creatinine levels were normal but the proteinuria was persistent, so the patient was started on oral lisinopril 5 mg once daily. Tapering of steroids over several months was initiated and the dose of dapsone was increased to 50 mg daily. Follow-up with a nephrologist was arranged to monitor renal function. She continued on lisinopril 5 mg once daily for treatment of nonnephrotic-range proteinuria, which was detected at 6 months following discharge.

Comment

The presence of atypical symptoms such as bullae and painful lesions in patients with suspected HSP can complicate the diagnosis. Initially, one of the top diagnostic considerations in our patient was bullous pyoderma gangrenosum, a neutrophilic dermatosis that typically presents with painful ulcerative lesions and inflammatory bullae. Other causes of bullae in children include erythema multiforme, toxic epidermal necrolysis, epidermolysis bullosa, bullous mastocytosis, pemphigus, bullous pemphigoid, dermatitis herpetiformis, linear IgA dermatosis, bullous impetigo, gangrenous cellulitis, and Vibrio vulnificus infection. However, the clinical symptoms of joint pain and hematuria/proteinuria in our patient as well as the punch biopsy findings pointed toward HSP as the most likely diagnosis.

Although bullous lesions are relatively common in adult-onset HSP (16%–60% of patients), they are very rare in pediatric patients (2% of patients).2-4 We performed a PubMed search of articles indexed for MEDLINE for bullous Henoch-Schönlein purpura in childhood using the search term 
Henoch-Schönlein purpura and bullous. The Table provides a summary of our search results from the English-language literature.^5-22

Bullae often develop on several parts of the body but are more commonly observed on the legs.¹⁷ Pathergy and edema have been implicated in the pathogenesis, as these findings have been observed in sites such as malleoli and legs, respectively.¹² Matrix metalloproteinases secreted in polymorphonuclear neutrophils have been found to be elevated in blister fluid and can cause bullae formation via degrading collagen in the basement membrane.⁹ Corticosteroids, by virtue of their inhibition of proinflammatory transcription factors 
(eg, nuclear factor κβ, intranuclear activator protein 1) 
and decreasing metalloproteinase levels, may be efficacious in bullous HSP. Although there is no consensus, corticosteroid therapy seems to be efficacious in treating the bullae, according to several reports.^17-22

The use of glucocorticoids in bullous HSP in childhood remains controversial. Studies report shortening of the duration of abdominal pain, reducing risk of intussusception, decreasing recurrence risk, and reducing the risk of renal involvement with use of steroids in HSP.^23-25 The use of systemic steroids has been described in children with bullous HSP to reduce the severity of 
HSP-related bullae and its associated painful ulcers and necrosis.^16,21,25,26 The duration of steroid use ranged from a short burst to a prolonged course of weaning over weeks. Azathioprine also has been used in conjunction with methylprednisolone, prednisone, and dexamethasone.^17,22 Because of its anti-IgA antioxidant antineutrophil effects, dapsone has been shown to be effective in the treatment of cutaneous HSP.²⁷ In our patient, we used dapsone to help in weaning the patient off the prednisone. Based on our review of the literature, few cases of bullous HSP in children have reported remission without drug therapy. IgA was not found in all the reported cases in which a skin biopsy was done. As shown by the comparison of the 
2 biopsies in our patient, biopsying an early lesion within 48 hours of appearance is essential to make a diagnosis because the biopsy of the older lesion could not rule out bullous pyoderma gangrenosum. Immunoreactants (IgA, C3) are destroyed within 48 hours and might lead to false-negative results on immunofluorescence in old and necrotic lesions.^28,29 Most reported cases of bullous HSP showed resolution, but few resulted in scarring and/or pigmentation.^10,17,18 Henoch-Schönlein purpura usually is self-limited but relapses can be seen in one-third of cases.¹ One of the reported cases of bullous HSP showed recurrence of lesions.¹⁵ One of the cases showed persistent hematuria.8 Our patient also was started on lisinopril for persistent proteinuria.

Henoch-Schönlein purpura (HSP) is a systemic, small vessel vasculitis affecting the skin, joints, gastrointestinal tract, and kidneys. It usually is self-limited, but relapses can be seen in one-third of cases.¹ The classic cutaneous presentation includes palpable purpura localized to the legs and buttocks. Painful hemorrhagic bullae are uncommonly observed in childhood HSP and often could lead to a diagnostic dilemma. We report the case of a patient who presented with atypical features of painful hemorrhagic bullae and provide a review of the literature.

Case Report

An otherwise healthy 14-year-old adolescent girl presented to the hospital with painful ulcerative lesions covering the arms, legs, lower abdomen, and buttocks of 3 weeks’ duration. The rash first appeared on the ankles and spread in an ascending fashion, starting with bullous formation that was accompanied by joint pain, especially in the ankles and elbows. No abdominal pain was reported. The patient attributed the lesions to prolonged cold exposure followed by a hot bath. She had tried naproxen without any improvement of pain. She was afebrile with normal blood pressure.

On physical examination, numerous petechiae, palpable purpura, hemorrhagic bullae, and ulcers with surrounding erythematous to violaceous induration as well as central necrosis were noted on the arms, legs (Figure 1), abdomen, and buttocks. The palms, soles, trunk, and face were spared.

Laboratory values on admission revealed leukocytosis (17,500/μL [reference range, 4500–11,000/μL]), elevated erythrocyte sedimentation rate (42 mm/h [reference range, 0–20 mm/h]), elevated C-reactive protein 
(15.59 mg/L [reference range, 0.08–3.1 mg/L]), elevated C3 (174 mg/dL [reference range, 75–135 mg/dL]), normal C4 (32 mg/dL [reference range, 3–75 mg/dL]), normal blood urea nitrogen (13 mg/dL [reference range, 8–23 mg/dL]), and normal creatinine (0.72 mg/dL [reference range, 0.6–1.2 mg/dL]). Urinalysis showed microscopic hematuria and trace proteinuria. Platelet count was normal.

Diagnostic considerations included HSP, drug-induced leukocytoclastic vasculitis, and bullous pyoderma gangrenosum. The patient was started on oral prednisone 80 mg once daily. Additionally, oral doxycycline 100 mg twice daily was added for prevention of secondary bacterial infections and for anti-inflammatory effects. All nonsteroidal 
anti-inflammatory drugs were avoided. A commercial ointment containing 8-hydroxyquinoline sulfate 0.3% and triamcinolone acetonide ointment 0.1% were used to minimize skin irritation. Morphine, 
oxycodone-acetaminophen, and pregabalin followed by gabapentin were used for pain control. Hydrotherapy also was used for the treatment of skin lesions.

Two skin punch biopsies were performed at different stages. Biopsy of an early palpable purpuric lesion showed small vessel leukocytoclastic vasculitis with perivascular IgA on direct immunofluorescence. A 
second biopsy from a more hemorrhagic lesion performed 96 hours after admission to the hospital showed subepidermal vesicles with partial epidermal necrosis, confluent neutrophilic infiltrate in the papillary dermis, and small vessel vasculitis (Figures 2 and 3). Gram, periodic acid–Schiff, and acid-fast bacilli staining and cultures were negative. With continued treatment for 7 days, the clinical appearance of the lesions improved. On the tenth day of hospitalization, oral dapsone 
25 mg once daily was initiated with the goal of weaning the patient off the prednisone as tolerated. She was discharged on prednisone (60 mg once daily) after 
14 days of hospitalization. Dapsone also was continued.

Figure 2. Biopsy of a subepidermal bulla revealed neutrophilic inflammation within bullous space and evidence of dermal hemorrhage (H&E, original magnification ×100).		Figure 3. Leukocytoclastic vasculitis on biopsy (H&E, original magnification ×400).

At 4-week follow-up, the lesions showed healing with mild residual pigmentation. The patient’s blood pressure and serum urea and creatinine levels were normal but the proteinuria was persistent, so the patient was started on oral lisinopril 5 mg once daily. Tapering of steroids over several months was initiated and the dose of dapsone was increased to 50 mg daily. Follow-up with a nephrologist was arranged to monitor renal function. She continued on lisinopril 5 mg once daily for treatment of nonnephrotic-range proteinuria, which was detected at 6 months following discharge.

Comment

The presence of atypical symptoms such as bullae and painful lesions in patients with suspected HSP can complicate the diagnosis. Initially, one of the top diagnostic considerations in our patient was bullous pyoderma gangrenosum, a neutrophilic dermatosis that typically presents with painful ulcerative lesions and inflammatory bullae. Other causes of bullae in children include erythema multiforme, toxic epidermal necrolysis, epidermolysis bullosa, bullous mastocytosis, pemphigus, bullous pemphigoid, dermatitis herpetiformis, linear IgA dermatosis, bullous impetigo, gangrenous cellulitis, and Vibrio vulnificus infection. However, the clinical symptoms of joint pain and hematuria/proteinuria in our patient as well as the punch biopsy findings pointed toward HSP as the most likely diagnosis.

Although bullous lesions are relatively common in adult-onset HSP (16%–60% of patients), they are very rare in pediatric patients (2% of patients).2-4 We performed a PubMed search of articles indexed for MEDLINE for bullous Henoch-Schönlein purpura in childhood using the search term 
Henoch-Schönlein purpura and bullous. The Table provides a summary of our search results from the English-language literature.^5-22

Bullae often develop on several parts of the body but are more commonly observed on the legs.¹⁷ Pathergy and edema have been implicated in the pathogenesis, as these findings have been observed in sites such as malleoli and legs, respectively.¹² Matrix metalloproteinases secreted in polymorphonuclear neutrophils have been found to be elevated in blister fluid and can cause bullae formation via degrading collagen in the basement membrane.⁹ Corticosteroids, by virtue of their inhibition of proinflammatory transcription factors 
(eg, nuclear factor κβ, intranuclear activator protein 1) 
and decreasing metalloproteinase levels, may be efficacious in bullous HSP. Although there is no consensus, corticosteroid therapy seems to be efficacious in treating the bullae, according to several reports.^17-22

The use of glucocorticoids in bullous HSP in childhood remains controversial. Studies report shortening of the duration of abdominal pain, reducing risk of intussusception, decreasing recurrence risk, and reducing the risk of renal involvement with use of steroids in HSP.^23-25 The use of systemic steroids has been described in children with bullous HSP to reduce the severity of 
HSP-related bullae and its associated painful ulcers and necrosis.^16,21,25,26 The duration of steroid use ranged from a short burst to a prolonged course of weaning over weeks. Azathioprine also has been used in conjunction with methylprednisolone, prednisone, and dexamethasone.^17,22 Because of its anti-IgA antioxidant antineutrophil effects, dapsone has been shown to be effective in the treatment of cutaneous HSP.²⁷ In our patient, we used dapsone to help in weaning the patient off the prednisone. Based on our review of the literature, few cases of bullous HSP in children have reported remission without drug therapy. IgA was not found in all the reported cases in which a skin biopsy was done. As shown by the comparison of the 
2 biopsies in our patient, biopsying an early lesion within 48 hours of appearance is essential to make a diagnosis because the biopsy of the older lesion could not rule out bullous pyoderma gangrenosum. Immunoreactants (IgA, C3) are destroyed within 48 hours and might lead to false-negative results on immunofluorescence in old and necrotic lesions.^28,29 Most reported cases of bullous HSP showed resolution, but few resulted in scarring and/or pigmentation.^10,17,18 Henoch-Schönlein purpura usually is self-limited but relapses can be seen in one-third of cases.¹ One of the reported cases of bullous HSP showed recurrence of lesions.¹⁵ One of the cases showed persistent hematuria.8 Our patient also was started on lisinopril for persistent proteinuria.

Henoch-Schönlein purpura (HSP) is a systemic, small vessel vasculitis affecting the skin, joints, gastrointestinal tract, and kidneys. It usually is self-limited, but relapses can be seen in one-third of cases.¹ The classic cutaneous presentation includes palpable purpura localized to the legs and buttocks. Painful hemorrhagic bullae are uncommonly observed in childhood HSP and often could lead to a diagnostic dilemma. We report the case of a patient who presented with atypical features of painful hemorrhagic bullae and provide a review of the literature.

Case Report

An otherwise healthy 14-year-old adolescent girl presented to the hospital with painful ulcerative lesions covering the arms, legs, lower abdomen, and buttocks of 3 weeks’ duration. The rash first appeared on the ankles and spread in an ascending fashion, starting with bullous formation that was accompanied by joint pain, especially in the ankles and elbows. No abdominal pain was reported. The patient attributed the lesions to prolonged cold exposure followed by a hot bath. She had tried naproxen without any improvement of pain. She was afebrile with normal blood pressure.

On physical examination, numerous petechiae, palpable purpura, hemorrhagic bullae, and ulcers with surrounding erythematous to violaceous induration as well as central necrosis were noted on the arms, legs (Figure 1), abdomen, and buttocks. The palms, soles, trunk, and face were spared.

Laboratory values on admission revealed leukocytosis (17,500/μL [reference range, 4500–11,000/μL]), elevated erythrocyte sedimentation rate (42 mm/h [reference range, 0–20 mm/h]), elevated C-reactive protein 
(15.59 mg/L [reference range, 0.08–3.1 mg/L]), elevated C3 (174 mg/dL [reference range, 75–135 mg/dL]), normal C4 (32 mg/dL [reference range, 3–75 mg/dL]), normal blood urea nitrogen (13 mg/dL [reference range, 8–23 mg/dL]), and normal creatinine (0.72 mg/dL [reference range, 0.6–1.2 mg/dL]). Urinalysis showed microscopic hematuria and trace proteinuria. Platelet count was normal.

Diagnostic considerations included HSP, drug-induced leukocytoclastic vasculitis, and bullous pyoderma gangrenosum. The patient was started on oral prednisone 80 mg once daily. Additionally, oral doxycycline 100 mg twice daily was added for prevention of secondary bacterial infections and for anti-inflammatory effects. All nonsteroidal 
anti-inflammatory drugs were avoided. A commercial ointment containing 8-hydroxyquinoline sulfate 0.3% and triamcinolone acetonide ointment 0.1% were used to minimize skin irritation. Morphine, 
oxycodone-acetaminophen, and pregabalin followed by gabapentin were used for pain control. Hydrotherapy also was used for the treatment of skin lesions.

Two skin punch biopsies were performed at different stages. Biopsy of an early palpable purpuric lesion showed small vessel leukocytoclastic vasculitis with perivascular IgA on direct immunofluorescence. A 
second biopsy from a more hemorrhagic lesion performed 96 hours after admission to the hospital showed subepidermal vesicles with partial epidermal necrosis, confluent neutrophilic infiltrate in the papillary dermis, and small vessel vasculitis (Figures 2 and 3). Gram, periodic acid–Schiff, and acid-fast bacilli staining and cultures were negative. With continued treatment for 7 days, the clinical appearance of the lesions improved. On the tenth day of hospitalization, oral dapsone 
25 mg once daily was initiated with the goal of weaning the patient off the prednisone as tolerated. She was discharged on prednisone (60 mg once daily) after 
14 days of hospitalization. Dapsone also was continued.

Figure 2. Biopsy of a subepidermal bulla revealed neutrophilic inflammation within bullous space and evidence of dermal hemorrhage (H&E, original magnification ×100).		Figure 3. Leukocytoclastic vasculitis on biopsy (H&E, original magnification ×400).

At 4-week follow-up, the lesions showed healing with mild residual pigmentation. The patient’s blood pressure and serum urea and creatinine levels were normal but the proteinuria was persistent, so the patient was started on oral lisinopril 5 mg once daily. Tapering of steroids over several months was initiated and the dose of dapsone was increased to 50 mg daily. Follow-up with a nephrologist was arranged to monitor renal function. She continued on lisinopril 5 mg once daily for treatment of nonnephrotic-range proteinuria, which was detected at 6 months following discharge.

Comment

The presence of atypical symptoms such as bullae and painful lesions in patients with suspected HSP can complicate the diagnosis. Initially, one of the top diagnostic considerations in our patient was bullous pyoderma gangrenosum, a neutrophilic dermatosis that typically presents with painful ulcerative lesions and inflammatory bullae. Other causes of bullae in children include erythema multiforme, toxic epidermal necrolysis, epidermolysis bullosa, bullous mastocytosis, pemphigus, bullous pemphigoid, dermatitis herpetiformis, linear IgA dermatosis, bullous impetigo, gangrenous cellulitis, and Vibrio vulnificus infection. However, the clinical symptoms of joint pain and hematuria/proteinuria in our patient as well as the punch biopsy findings pointed toward HSP as the most likely diagnosis.

Although bullous lesions are relatively common in adult-onset HSP (16%–60% of patients), they are very rare in pediatric patients (2% of patients).2-4 We performed a PubMed search of articles indexed for MEDLINE for bullous Henoch-Schönlein purpura in childhood using the search term 
Henoch-Schönlein purpura and bullous. The Table provides a summary of our search results from the English-language literature.^5-22

Bullae often develop on several parts of the body but are more commonly observed on the legs.¹⁷ Pathergy and edema have been implicated in the pathogenesis, as these findings have been observed in sites such as malleoli and legs, respectively.¹² Matrix metalloproteinases secreted in polymorphonuclear neutrophils have been found to be elevated in blister fluid and can cause bullae formation via degrading collagen in the basement membrane.⁹ Corticosteroids, by virtue of their inhibition of proinflammatory transcription factors 
(eg, nuclear factor κβ, intranuclear activator protein 1) 
and decreasing metalloproteinase levels, may be efficacious in bullous HSP. Although there is no consensus, corticosteroid therapy seems to be efficacious in treating the bullae, according to several reports.^17-22

The use of glucocorticoids in bullous HSP in childhood remains controversial. Studies report shortening of the duration of abdominal pain, reducing risk of intussusception, decreasing recurrence risk, and reducing the risk of renal involvement with use of steroids in HSP.^23-25 The use of systemic steroids has been described in children with bullous HSP to reduce the severity of 
HSP-related bullae and its associated painful ulcers and necrosis.^16,21,25,26 The duration of steroid use ranged from a short burst to a prolonged course of weaning over weeks. Azathioprine also has been used in conjunction with methylprednisolone, prednisone, and dexamethasone.^17,22 Because of its anti-IgA antioxidant antineutrophil effects, dapsone has been shown to be effective in the treatment of cutaneous HSP.²⁷ In our patient, we used dapsone to help in weaning the patient off the prednisone. Based on our review of the literature, few cases of bullous HSP in children have reported remission without drug therapy. IgA was not found in all the reported cases in which a skin biopsy was done. As shown by the comparison of the 
2 biopsies in our patient, biopsying an early lesion within 48 hours of appearance is essential to make a diagnosis because the biopsy of the older lesion could not rule out bullous pyoderma gangrenosum. Immunoreactants (IgA, C3) are destroyed within 48 hours and might lead to false-negative results on immunofluorescence in old and necrotic lesions.^28,29 Most reported cases of bullous HSP showed resolution, but few resulted in scarring and/or pigmentation.^10,17,18 Henoch-Schönlein purpura usually is self-limited but relapses can be seen in one-third of cases.¹ One of the reported cases of bullous HSP showed recurrence of lesions.¹⁵ One of the cases showed persistent hematuria.8 Our patient also was started on lisinopril for persistent proteinuria.

Chromoblastomycosis is a chronic fungal infection of the skin and subcutaneous tissues that demonstrates characteristic Medlar or sclerotic bodies that resemble copper pennies on histopathology.¹ Cutaneous infection often results from direct inoculation, such as from a wood splinter. Clinically, the lesion typically is a pink papule that progresses to a verrucous plaque on the legs of farmers or rural workers in the tropics or subtropics. There usually are no associated constitutional symptoms. Several dematiaceous (darkly pigmented) fungi cause chromoblastomycosis, including Fonsecaea compacta, Cladophialophora carrionii, Rhinocladiella aquaspersa, Phialophora verrucosa, and Fonsecaea pedrosoi. Cellular division occurs by internal septation rather than budding. Skin biopsy can confirm the diagnosis.¹ Chromoblastomycosis is histopathologically characterized by pseudoepitheli-
omatous hyperplasia (Figure 1) with histiocytes and neutrophils surrounding distinct copper-colored 
Medlar bodies (6–12 μm)(Figure 2), which are fungal spores.^1-3 Several conditions demonstrate pseudoepitheliomatous hyperplasia with intraepidermal pustules and can be remembered by the mnemonic “here come big green leafy vegetables”: halogenoderma, chromoblastomycosis, blastomycosis, granuloma inguinale, leishmaniasis, and pemphigus vegetans.² Treatment of chromoblastomycosis can be challenging, as no standard treatment has been established and therapy can be complicated by low cure rates and high relapse rates, especially in chronic and extensive disease. Treatment can include cryotherapy or surgical excision for small lesions in combination with systemic antifungals.⁴ Itraconazole (200–400 mg daily) for at least 
6 months has been reported to have up to a 
90% cure rate with mild to moderate disease and 44% with severe disease.⁵ Combination oral antifungal treatment with itraconazole and terbinafine has been recommended.⁶ There are reports of progression of chromoblastomycosis to squamous cell carcinoma, which is rare and occurred after 
long-standing, inadequately treated lesions.⁷

Blastomycosis also presents with pseudoepitheliomatous hyperplasia, as seen in chromoblastomycosis, but organisms typically are few in number 
and demonstrate a thick, asymmetrical, refractile wall and a dark nucleus. Although chromoblastomycosis and blastomycosis are similar in 
size (8–15 μm), the broad-based budding of blastomycosis (Figure 3) is a key feature and the yeast 
are not pigmented.^1-3 Blastomycosis is caused by Blastomyces dermatitidis and is endemic to the Mississippi and Ohio River valleys, Great Lakes region, and Southeastern United States. Cutaneous infection typically occurs from inhalation of the dimorphic fungi into the lungs and occasional dissemination involving the skin, causing papulopustules and 
thick, crusted, warty plaques with central ulceration. 
Rarely, primary cutaneous blastomycosis can occur from direct inoculation, typically in a laboratory. Treatment of disseminated blastomycosis includes systemic antifungals.¹

Coccidioidomycosis is characterized by large spherules (10–80 μm) with refractile walls and granular gray cytoplasm.^2,3 Coccidioidomycosis spherules occasionally contain endospores² and often are noticeably larger than surrounding histiocyte nuclei (Figure 4), whereas chromoblastomycosis, blastomycosis, cryptococcosis, and lobomycosis are more similar in size to histiocyte nuclei. Coccidioidomycosis is caused by Coccidioides immitis, a highly virulent dimorphic fungus found in the Southwestern United States, northern Mexico, and Central and South America. Pulmonary infection occurs by inhalation of arthroconidia, often from soil, and is asymptomatic in most patients; however, immunocompromised patients are predisposed to disseminated cutaneous infection. Facial lesions are most common and can present as papules, pustules, plaques, abscesses, sinus tracts, and/or ulcerations. Treatment of disseminated infection requires systemic antifungals; amphotericin B has proven most effective.¹

Cryptococcosis is characterized by vacuoles 
with small (2–20 μm), central, pleomorphic 
yeast (Figure 5). The vacuole is due to a gelati-
nous capsule that stains red with mucicarmine 
 and blue with Alcian blue.^2,3 Cryptococcosis is caused by Cryptococcus neoformans and is associated with pigeon droppings. Disseminated infection in patients with human immunodefi-
ciency virus often presents as umbilicated 
molluscumlike lesions and portends a poor prognosis with a mortality rate of up to 80%.⁸ Disseminated 
infection necessitates aggressive treatment with systemic antifungals.¹

Lobomycosis demonstrates thick-walled, refractile spherules with surrounding histiocytes and multinucleated giant cells. The yeast of lobomycosis (6–12 μm) is of similar size to chromoblastomycosis and blastomycosis, but linear chains resembling 
a child’s pop beads are characteristic of this 
condition (Figure 6).^2,3 Lobomycosis is caused by Lacazia loboi and is acquired most frequently through contact with dolphins in Central 
and South America. Clinically, lesions present as slow-growing, keloidlike nodules, often on the 
face, ears, and distal extremities. Surgical treatment may be required given that oral antifungals typically are ineffective.¹

Chromoblastomycosis is a chronic fungal infection of the skin and subcutaneous tissues that demonstrates characteristic Medlar or sclerotic bodies that resemble copper pennies on histopathology.¹ Cutaneous infection often results from direct inoculation, such as from a wood splinter. Clinically, the lesion typically is a pink papule that progresses to a verrucous plaque on the legs of farmers or rural workers in the tropics or subtropics. There usually are no associated constitutional symptoms. Several dematiaceous (darkly pigmented) fungi cause chromoblastomycosis, including Fonsecaea compacta, Cladophialophora carrionii, Rhinocladiella aquaspersa, Phialophora verrucosa, and Fonsecaea pedrosoi. Cellular division occurs by internal septation rather than budding. Skin biopsy can confirm the diagnosis.¹ Chromoblastomycosis is histopathologically characterized by pseudoepitheli-
omatous hyperplasia (Figure 1) with histiocytes and neutrophils surrounding distinct copper-colored 
Medlar bodies (6–12 μm)(Figure 2), which are fungal spores.^1-3 Several conditions demonstrate pseudoepitheliomatous hyperplasia with intraepidermal pustules and can be remembered by the mnemonic “here come big green leafy vegetables”: halogenoderma, chromoblastomycosis, blastomycosis, granuloma inguinale, leishmaniasis, and pemphigus vegetans.² Treatment of chromoblastomycosis can be challenging, as no standard treatment has been established and therapy can be complicated by low cure rates and high relapse rates, especially in chronic and extensive disease. Treatment can include cryotherapy or surgical excision for small lesions in combination with systemic antifungals.⁴ Itraconazole (200–400 mg daily) for at least 
6 months has been reported to have up to a 
90% cure rate with mild to moderate disease and 44% with severe disease.⁵ Combination oral antifungal treatment with itraconazole and terbinafine has been recommended.⁶ There are reports of progression of chromoblastomycosis to squamous cell carcinoma, which is rare and occurred after 
long-standing, inadequately treated lesions.⁷

Blastomycosis also presents with pseudoepitheliomatous hyperplasia, as seen in chromoblastomycosis, but organisms typically are few in number 
and demonstrate a thick, asymmetrical, refractile wall and a dark nucleus. Although chromoblastomycosis and blastomycosis are similar in 
size (8–15 μm), the broad-based budding of blastomycosis (Figure 3) is a key feature and the yeast 
are not pigmented.^1-3 Blastomycosis is caused by Blastomyces dermatitidis and is endemic to the Mississippi and Ohio River valleys, Great Lakes region, and Southeastern United States. Cutaneous infection typically occurs from inhalation of the dimorphic fungi into the lungs and occasional dissemination involving the skin, causing papulopustules and 
thick, crusted, warty plaques with central ulceration. 
Rarely, primary cutaneous blastomycosis can occur from direct inoculation, typically in a laboratory. Treatment of disseminated blastomycosis includes systemic antifungals.¹

Coccidioidomycosis is characterized by large spherules (10–80 μm) with refractile walls and granular gray cytoplasm.^2,3 Coccidioidomycosis spherules occasionally contain endospores² and often are noticeably larger than surrounding histiocyte nuclei (Figure 4), whereas chromoblastomycosis, blastomycosis, cryptococcosis, and lobomycosis are more similar in size to histiocyte nuclei. Coccidioidomycosis is caused by Coccidioides immitis, a highly virulent dimorphic fungus found in the Southwestern United States, northern Mexico, and Central and South America. Pulmonary infection occurs by inhalation of arthroconidia, often from soil, and is asymptomatic in most patients; however, immunocompromised patients are predisposed to disseminated cutaneous infection. Facial lesions are most common and can present as papules, pustules, plaques, abscesses, sinus tracts, and/or ulcerations. Treatment of disseminated infection requires systemic antifungals; amphotericin B has proven most effective.¹

Cryptococcosis is characterized by vacuoles 
with small (2–20 μm), central, pleomorphic 
yeast (Figure 5). The vacuole is due to a gelati-
nous capsule that stains red with mucicarmine 
 and blue with Alcian blue.^2,3 Cryptococcosis is caused by Cryptococcus neoformans and is associated with pigeon droppings. Disseminated infection in patients with human immunodefi-
ciency virus often presents as umbilicated 
molluscumlike lesions and portends a poor prognosis with a mortality rate of up to 80%.⁸ Disseminated 
infection necessitates aggressive treatment with systemic antifungals.¹

Lobomycosis demonstrates thick-walled, refractile spherules with surrounding histiocytes and multinucleated giant cells. The yeast of lobomycosis (6–12 μm) is of similar size to chromoblastomycosis and blastomycosis, but linear chains resembling 
a child’s pop beads are characteristic of this 
condition (Figure 6).^2,3 Lobomycosis is caused by Lacazia loboi and is acquired most frequently through contact with dolphins in Central 
and South America. Clinically, lesions present as slow-growing, keloidlike nodules, often on the 
face, ears, and distal extremities. Surgical treatment may be required given that oral antifungals typically are ineffective.¹

Chromoblastomycosis is a chronic fungal infection of the skin and subcutaneous tissues that demonstrates characteristic Medlar or sclerotic bodies that resemble copper pennies on histopathology.¹ Cutaneous infection often results from direct inoculation, such as from a wood splinter. Clinically, the lesion typically is a pink papule that progresses to a verrucous plaque on the legs of farmers or rural workers in the tropics or subtropics. There usually are no associated constitutional symptoms. Several dematiaceous (darkly pigmented) fungi cause chromoblastomycosis, including Fonsecaea compacta, Cladophialophora carrionii, Rhinocladiella aquaspersa, Phialophora verrucosa, and Fonsecaea pedrosoi. Cellular division occurs by internal septation rather than budding. Skin biopsy can confirm the diagnosis.¹ Chromoblastomycosis is histopathologically characterized by pseudoepitheli-
omatous hyperplasia (Figure 1) with histiocytes and neutrophils surrounding distinct copper-colored 
Medlar bodies (6–12 μm)(Figure 2), which are fungal spores.^1-3 Several conditions demonstrate pseudoepitheliomatous hyperplasia with intraepidermal pustules and can be remembered by the mnemonic “here come big green leafy vegetables”: halogenoderma, chromoblastomycosis, blastomycosis, granuloma inguinale, leishmaniasis, and pemphigus vegetans.² Treatment of chromoblastomycosis can be challenging, as no standard treatment has been established and therapy can be complicated by low cure rates and high relapse rates, especially in chronic and extensive disease. Treatment can include cryotherapy or surgical excision for small lesions in combination with systemic antifungals.⁴ Itraconazole (200–400 mg daily) for at least 
6 months has been reported to have up to a 
90% cure rate with mild to moderate disease and 44% with severe disease.⁵ Combination oral antifungal treatment with itraconazole and terbinafine has been recommended.⁶ There are reports of progression of chromoblastomycosis to squamous cell carcinoma, which is rare and occurred after 
long-standing, inadequately treated lesions.⁷

Blastomycosis also presents with pseudoepitheliomatous hyperplasia, as seen in chromoblastomycosis, but organisms typically are few in number 
and demonstrate a thick, asymmetrical, refractile wall and a dark nucleus. Although chromoblastomycosis and blastomycosis are similar in 
size (8–15 μm), the broad-based budding of blastomycosis (Figure 3) is a key feature and the yeast 
are not pigmented.^1-3 Blastomycosis is caused by Blastomyces dermatitidis and is endemic to the Mississippi and Ohio River valleys, Great Lakes region, and Southeastern United States. Cutaneous infection typically occurs from inhalation of the dimorphic fungi into the lungs and occasional dissemination involving the skin, causing papulopustules and 
thick, crusted, warty plaques with central ulceration. 
Rarely, primary cutaneous blastomycosis can occur from direct inoculation, typically in a laboratory. Treatment of disseminated blastomycosis includes systemic antifungals.¹

Coccidioidomycosis is characterized by large spherules (10–80 μm) with refractile walls and granular gray cytoplasm.^2,3 Coccidioidomycosis spherules occasionally contain endospores² and often are noticeably larger than surrounding histiocyte nuclei (Figure 4), whereas chromoblastomycosis, blastomycosis, cryptococcosis, and lobomycosis are more similar in size to histiocyte nuclei. Coccidioidomycosis is caused by Coccidioides immitis, a highly virulent dimorphic fungus found in the Southwestern United States, northern Mexico, and Central and South America. Pulmonary infection occurs by inhalation of arthroconidia, often from soil, and is asymptomatic in most patients; however, immunocompromised patients are predisposed to disseminated cutaneous infection. Facial lesions are most common and can present as papules, pustules, plaques, abscesses, sinus tracts, and/or ulcerations. Treatment of disseminated infection requires systemic antifungals; amphotericin B has proven most effective.¹

Cryptococcosis is characterized by vacuoles 
with small (2–20 μm), central, pleomorphic 
yeast (Figure 5). The vacuole is due to a gelati-
nous capsule that stains red with mucicarmine 
 and blue with Alcian blue.^2,3 Cryptococcosis is caused by Cryptococcus neoformans and is associated with pigeon droppings. Disseminated infection in patients with human immunodefi-
ciency virus often presents as umbilicated 
molluscumlike lesions and portends a poor prognosis with a mortality rate of up to 80%.⁸ Disseminated 
infection necessitates aggressive treatment with systemic antifungals.¹

Lobomycosis demonstrates thick-walled, refractile spherules with surrounding histiocytes and multinucleated giant cells. The yeast of lobomycosis (6–12 μm) is of similar size to chromoblastomycosis and blastomycosis, but linear chains resembling 
a child’s pop beads are characteristic of this 
condition (Figure 6).^2,3 Lobomycosis is caused by Lacazia loboi and is acquired most frequently through contact with dolphins in Central 
and South America. Clinically, lesions present as slow-growing, keloidlike nodules, often on the 
face, ears, and distal extremities. Surgical treatment may be required given that oral antifungals typically are ineffective.¹

Syringoid eccrine carcinoma is a rare malignant adnexal tumor with eccrine differentiation that histologically resembles a syringoma.¹ Originally described as eccrine epithelioma by Freeman and Winklemann² in 1969, syringoid eccrine carcinoma has been reported in the literature as eccrine carcinoma, eccrine syringomatous carcinoma, and sclerosing sweat duct carcinoma.³ Clinically, syringoid eccrine carcinoma most 
commonly presents as a tender plaque or nodule on the scalp, and histologic examination generally reveals a dermal-based lesion that rarely shows epidermal connection. It demonstrates 
syringomalike tadpole morphology (epithelial strands 
with lumen formation) composed of basaloid epithelium with uniform hyperchromatic nuclei 
(Figure 1). There usually is an infiltrative growth pattern to the subcutis (Figure 2 [left]) or skeletal muscle as well as remarkable perineural invasion 
(Figure 2 [right]). Mitotic activity is minimal to absent. The tumor cells of syringoid eccrine 
carcinoma typically show positive immuno-staining for high- and low-molecular-weight cytokeratin, while the lumina are highlighted 
by epithelial membrane antigen and carcinoembryonic antigen.⁴ However, immunohistochemistry 
often is not contributory in diagnosing primary eccrine carcinomas.

Figure 1. Dermal infiltrate with tadpole morphology (arrow) characteristic of syringoid eccrine carcinoma (left)(H&E, original magnification ×40). High-power view shows an epithelial infiltrate and tadpole morphology (arrow)(right)(H&E, original magnification ×400).

Figure 2. Syringoid eccrine carcinoma extending to the junction of the reticular dermis and subcutaneous fat (left) (H&E, original magnification ×100). Nerve with adjacent and invasive basaloid nests of syringoid carcinoma (right)(H&E, original magnification ×100). The tumor consists of monomorphic cells with oval hyperchromatic nuclei.

The differential diagnosis of syringoid eccrine carcinoma includes cutaneous adenoid cystic carcinoma, metastatic adenocarcinoma, sclerosing basal cell carcinoma, and syringoma. Cutaneous adenoid cystic carcinoma is a rare, slow-growing, 
flesh-colored tumor that consists of lobules, islands, and cords of basaloid cells with prominent cystic cribriforming (Figure 3). The tumor cells typically are small, cuboidal, and monomorphic. Metastatic adenoid cystic carcinoma, such as from a primary tumor of the salivary glands or breasts, must be excluded before rendering a diagnosis of primary cutaneous disease.

Figure 3. Striking cribriform architecture of cutaneous adenoid cystic carcinoma (H&E, original magnification ×40). The tumor is well circumscribed and consists of multiple cystic spaces lined by flattened to cuboidal basaloid epithelium.

Metastatic adenocarcinoma of the skin usually presents in patients with a clinical history of preexisting disease. The breasts, colon, stomach, and ovaries are common origins of metastases. The histopathologic and immunohistochemical findings depend on the particular site of origin of the metastasis. Compared with primary eccrine carcinomas, metastatic adenocarcinomas of the skin generally are high-grade lesions with prominent atypia, mitosis, and necrosis (Figure 4).

Figure 4. Metastatic adenocarcinoma of the skin with dermal infiltrating glands (H&E, original magnification ×100). The nuclei are highly atypical. The tumor cells are cytokeratin 7 positive, cytokeratin 20 negative, estrogen-receptor positive, and gross cystic disease fluid protein positive, which is consistent with metastasis from a primary carcinoma of the breast (not shown).

Sclerosing basal cell carcinoma shows basaloid tumor cells with deep infiltration. Unlike syringoid eccrine carcinoma, basal cell carcinoma is an epidermal tumor that does not have true lumen formation. Furthermore, other variants of basal cell carcinoma, including nodular, micronodular, or superficial multicentric tumors, often coexist with the sclerosing variant in the same lesion and constitute a useful diagnostic clue (Figure 5). Staining for epithelial membrane antigen may be useful in identifying the absence of lumen formation, and Ber-EP4 highlights the epidermal origin of the lesion.⁵

Figure 5. Deeply invasive tumor with multiple architectures (sclerosing and micronodular) in a case of sclerosing basal cell carcinoma (H&E, original magnification ×40). Basaloid nests without true lumen formation invade subcutaneous adipose tissue.

Syringomas most commonly present as multiple small flesh-colored papules on the eyelids. On histology, syringomas present as small superficial dermal lesions composed of small ducts that may form tadpolelike structures in a fibrotic stroma (Figure 6). The ducts are lined by benign cuboidal cells. In contrast to syringoid eccrine carcinomas, syringomas usually present as multiple lesions that are microscopically superficial without perineural involvement.

Figure 6. Syringoma is composed of dilated ducts in a fibrotic stroma (H&E, original magnification ×40). Careful microscopic examination would reveal no perineural or deep subcutaneous tumor involvement.

Syringoid eccrine carcinoma is a rare malignant adnexal tumor with eccrine differentiation that histologically resembles a syringoma.¹ Originally described as eccrine epithelioma by Freeman and Winklemann² in 1969, syringoid eccrine carcinoma has been reported in the literature as eccrine carcinoma, eccrine syringomatous carcinoma, and sclerosing sweat duct carcinoma.³ Clinically, syringoid eccrine carcinoma most 
commonly presents as a tender plaque or nodule on the scalp, and histologic examination generally reveals a dermal-based lesion that rarely shows epidermal connection. It demonstrates 
syringomalike tadpole morphology (epithelial strands 
with lumen formation) composed of basaloid epithelium with uniform hyperchromatic nuclei 
(Figure 1). There usually is an infiltrative growth pattern to the subcutis (Figure 2 [left]) or skeletal muscle as well as remarkable perineural invasion 
(Figure 2 [right]). Mitotic activity is minimal to absent. The tumor cells of syringoid eccrine 
carcinoma typically show positive immuno-staining for high- and low-molecular-weight cytokeratin, while the lumina are highlighted 
by epithelial membrane antigen and carcinoembryonic antigen.⁴ However, immunohistochemistry 
often is not contributory in diagnosing primary eccrine carcinomas.

Figure 1. Dermal infiltrate with tadpole morphology (arrow) characteristic of syringoid eccrine carcinoma (left)(H&E, original magnification ×40). High-power view shows an epithelial infiltrate and tadpole morphology (arrow)(right)(H&E, original magnification ×400).

Figure 2. Syringoid eccrine carcinoma extending to the junction of the reticular dermis and subcutaneous fat (left) (H&E, original magnification ×100). Nerve with adjacent and invasive basaloid nests of syringoid carcinoma (right)(H&E, original magnification ×100). The tumor consists of monomorphic cells with oval hyperchromatic nuclei.

The differential diagnosis of syringoid eccrine carcinoma includes cutaneous adenoid cystic carcinoma, metastatic adenocarcinoma, sclerosing basal cell carcinoma, and syringoma. Cutaneous adenoid cystic carcinoma is a rare, slow-growing, 
flesh-colored tumor that consists of lobules, islands, and cords of basaloid cells with prominent cystic cribriforming (Figure 3). The tumor cells typically are small, cuboidal, and monomorphic. Metastatic adenoid cystic carcinoma, such as from a primary tumor of the salivary glands or breasts, must be excluded before rendering a diagnosis of primary cutaneous disease.

Figure 3. Striking cribriform architecture of cutaneous adenoid cystic carcinoma (H&E, original magnification ×40). The tumor is well circumscribed and consists of multiple cystic spaces lined by flattened to cuboidal basaloid epithelium.

Metastatic adenocarcinoma of the skin usually presents in patients with a clinical history of preexisting disease. The breasts, colon, stomach, and ovaries are common origins of metastases. The histopathologic and immunohistochemical findings depend on the particular site of origin of the metastasis. Compared with primary eccrine carcinomas, metastatic adenocarcinomas of the skin generally are high-grade lesions with prominent atypia, mitosis, and necrosis (Figure 4).

Figure 4. Metastatic adenocarcinoma of the skin with dermal infiltrating glands (H&E, original magnification ×100). The nuclei are highly atypical. The tumor cells are cytokeratin 7 positive, cytokeratin 20 negative, estrogen-receptor positive, and gross cystic disease fluid protein positive, which is consistent with metastasis from a primary carcinoma of the breast (not shown).

Sclerosing basal cell carcinoma shows basaloid tumor cells with deep infiltration. Unlike syringoid eccrine carcinoma, basal cell carcinoma is an epidermal tumor that does not have true lumen formation. Furthermore, other variants of basal cell carcinoma, including nodular, micronodular, or superficial multicentric tumors, often coexist with the sclerosing variant in the same lesion and constitute a useful diagnostic clue (Figure 5). Staining for epithelial membrane antigen may be useful in identifying the absence of lumen formation, and Ber-EP4 highlights the epidermal origin of the lesion.⁵

Figure 5. Deeply invasive tumor with multiple architectures (sclerosing and micronodular) in a case of sclerosing basal cell carcinoma (H&E, original magnification ×40). Basaloid nests without true lumen formation invade subcutaneous adipose tissue.

Syringomas most commonly present as multiple small flesh-colored papules on the eyelids. On histology, syringomas present as small superficial dermal lesions composed of small ducts that may form tadpolelike structures in a fibrotic stroma (Figure 6). The ducts are lined by benign cuboidal cells. In contrast to syringoid eccrine carcinomas, syringomas usually present as multiple lesions that are microscopically superficial without perineural involvement.

Figure 6. Syringoma is composed of dilated ducts in a fibrotic stroma (H&E, original magnification ×40). Careful microscopic examination would reveal no perineural or deep subcutaneous tumor involvement.

Syringoid eccrine carcinoma is a rare malignant adnexal tumor with eccrine differentiation that histologically resembles a syringoma.¹ Originally described as eccrine epithelioma by Freeman and Winklemann² in 1969, syringoid eccrine carcinoma has been reported in the literature as eccrine carcinoma, eccrine syringomatous carcinoma, and sclerosing sweat duct carcinoma.³ Clinically, syringoid eccrine carcinoma most 
commonly presents as a tender plaque or nodule on the scalp, and histologic examination generally reveals a dermal-based lesion that rarely shows epidermal connection. It demonstrates 
syringomalike tadpole morphology (epithelial strands 
with lumen formation) composed of basaloid epithelium with uniform hyperchromatic nuclei 
(Figure 1). There usually is an infiltrative growth pattern to the subcutis (Figure 2 [left]) or skeletal muscle as well as remarkable perineural invasion 
(Figure 2 [right]). Mitotic activity is minimal to absent. The tumor cells of syringoid eccrine 
carcinoma typically show positive immuno-staining for high- and low-molecular-weight cytokeratin, while the lumina are highlighted 
by epithelial membrane antigen and carcinoembryonic antigen.⁴ However, immunohistochemistry 
often is not contributory in diagnosing primary eccrine carcinomas.

Figure 1. Dermal infiltrate with tadpole morphology (arrow) characteristic of syringoid eccrine carcinoma (left)(H&E, original magnification ×40). High-power view shows an epithelial infiltrate and tadpole morphology (arrow)(right)(H&E, original magnification ×400).

Figure 2. Syringoid eccrine carcinoma extending to the junction of the reticular dermis and subcutaneous fat (left) (H&E, original magnification ×100). Nerve with adjacent and invasive basaloid nests of syringoid carcinoma (right)(H&E, original magnification ×100). The tumor consists of monomorphic cells with oval hyperchromatic nuclei.

The differential diagnosis of syringoid eccrine carcinoma includes cutaneous adenoid cystic carcinoma, metastatic adenocarcinoma, sclerosing basal cell carcinoma, and syringoma. Cutaneous adenoid cystic carcinoma is a rare, slow-growing, 
flesh-colored tumor that consists of lobules, islands, and cords of basaloid cells with prominent cystic cribriforming (Figure 3). The tumor cells typically are small, cuboidal, and monomorphic. Metastatic adenoid cystic carcinoma, such as from a primary tumor of the salivary glands or breasts, must be excluded before rendering a diagnosis of primary cutaneous disease.

Figure 3. Striking cribriform architecture of cutaneous adenoid cystic carcinoma (H&E, original magnification ×40). The tumor is well circumscribed and consists of multiple cystic spaces lined by flattened to cuboidal basaloid epithelium.

Metastatic adenocarcinoma of the skin usually presents in patients with a clinical history of preexisting disease. The breasts, colon, stomach, and ovaries are common origins of metastases. The histopathologic and immunohistochemical findings depend on the particular site of origin of the metastasis. Compared with primary eccrine carcinomas, metastatic adenocarcinomas of the skin generally are high-grade lesions with prominent atypia, mitosis, and necrosis (Figure 4).

Figure 4. Metastatic adenocarcinoma of the skin with dermal infiltrating glands (H&E, original magnification ×100). The nuclei are highly atypical. The tumor cells are cytokeratin 7 positive, cytokeratin 20 negative, estrogen-receptor positive, and gross cystic disease fluid protein positive, which is consistent with metastasis from a primary carcinoma of the breast (not shown).

Sclerosing basal cell carcinoma shows basaloid tumor cells with deep infiltration. Unlike syringoid eccrine carcinoma, basal cell carcinoma is an epidermal tumor that does not have true lumen formation. Furthermore, other variants of basal cell carcinoma, including nodular, micronodular, or superficial multicentric tumors, often coexist with the sclerosing variant in the same lesion and constitute a useful diagnostic clue (Figure 5). Staining for epithelial membrane antigen may be useful in identifying the absence of lumen formation, and Ber-EP4 highlights the epidermal origin of the lesion.⁵

Figure 5. Deeply invasive tumor with multiple architectures (sclerosing and micronodular) in a case of sclerosing basal cell carcinoma (H&E, original magnification ×40). Basaloid nests without true lumen formation invade subcutaneous adipose tissue.

Syringomas most commonly present as multiple small flesh-colored papules on the eyelids. On histology, syringomas present as small superficial dermal lesions composed of small ducts that may form tadpolelike structures in a fibrotic stroma (Figure 6). The ducts are lined by benign cuboidal cells. In contrast to syringoid eccrine carcinomas, syringomas usually present as multiple lesions that are microscopically superficial without perineural involvement.

Figure 6. Syringoma is composed of dilated ducts in a fibrotic stroma (H&E, original magnification ×40). Careful microscopic examination would reveal no perineural or deep subcutaneous tumor involvement.

To the Editor:

A 51-year-old woman presented to her dermatologist with recurrent and progressive upper lip swelling of 2 years’ duration. Her condition was previously evaluated by several other physicians without a diagnosis or resolution of the symptoms. The swelling began on the right side of the upper lip and right cheek; however, over the course of 2 years, the swelling had progressed to involve the entire upper lip with complete sparing of the lower lip. She denied pain but reported numbness of the upper lip. The patient visited her dentist who ruled out periodontal infection as the cause of the swelling. Diphenhydramine provided no relief; however, the cheek swelling resolved after a course of antibiotics prescribed by an ear, nose, and throat physician.

She consulted her primary care physician and was subsequently referred to a neurologist and allergist who were unable to provide a definitive diagnosis or complete relief of the symptoms. She denied any history of hypersensitivity reactions, odontogenic infections, gastrointestinal concerns, or any other signs or symptoms of systemic granulomatous disease.

Figure 1. Upper lip swelling without ulceration, fissuring, or scaling. The lower lip was completely spared.

On physical examination, the upper lip was swollen symmetrically without evidence of ulceration, fissuring, or scaling (Figure 1). Palpation of the upper lip was notable for firm, nontender, nonpitting edema without nodularity. The oral mucosa did not appear swollen or erythematous. Examination did not reveal ulceration or a cobblestone appearance.

A full-thickness skin biopsy of the upper lip was performed. Histopathology revealed perivascular nonnecrotizing granulomas adjacent to ectatic vascular channels with associated lymphoplasmacytic infiltrate (Figure 2). Periodic acid–Schiff stain was negative for fungal hyphae, tissue Gram stain was negative for bacteria, Fite and acid-fast bacillus stains were both negative for acid-fast organisms, and polariscopy was negative for polarizable foreign material. In this clinical context, the morphologic findings were consistent with the diagnosis of granulomatous cheilitis (GC).

Figure 2. Upper lip biopsy showed dermal edema, vascular ectasia, perivascular nonnecrotizing granulomas, and perivascular lymphocyte predominant inflammatory infiltrate (A)(H&E, original magnification ×100). Higher magnification of granulomas with perivascular lymphoplasmacytic infiltrate (B)(H&E, original magnification ×200).

Granulomatous cheilitis is a rare disorder of the lips and orofacial mucosa that was first described by Meischer¹ in 1945 as persistent or recurrent orofacial swelling secondary to lymphatic obstruction by granulomatous proliferation. It often has been described as a monosymptomatic form of Melkersson-Rosenthal syndrome (MRS). In its entirety, MRS constitutes a triad of GC, facial nerve palsy, and lingua plicata (also known as fissured tongue).^2,3 Although many authors agree that GC is associated with MRS, some believe that GC is a distinct entity because the majority of patients who present with GC subsequently do not develop MRS.⁴ Despite its relationship to MRS, the true incidence of GC largely is unknown. The onset of disease usually occurs in early adulthood but can present in middle-aged or older individuals.

The typical course of GC is relapsing and remitting, nontender and nonpitting swelling of the lips that eventually becomes permanent, leading to possible facial distortion and disability. Involvement of the upper lip is the most common, followed by (in order of decreasing frequency) the lower lip and cheeks.⁵ The swelling may be unilateral or bilateral and generally is not associated with ulceration, fissuring, or scaling; however, these complications have been reported in the terminal stages of the disease in which the macrocheilia has become permanent.

Despite the controversy over the etiology, pathophysiology, and classification of GC, it largely is accepted that when a patient presents clinically with a history of recurrent or persistent lip swelling, a 
full-thickness skin biopsy of the involved oral mucosa should be taken. Conditions that are considered in the differential diagnosis of orofacial granulomatosis are systemic granulomatous diseases that are known to have oral manifestations including Crohn disease, sarcoidosis, and mycobacterial infections. Given the many causes of orofacial and labial swelling, GC is a diagnosis of exclusion based on a thorough history and physical examination as well as appropriate diagnostic studies, with the cornerstone of the diagnosis resting on the histologic appearance of the lesion. Histologically, the diagnosis lies in the demonstration of granuloma formation, consisting of collections of epithelioid histiocytes and Langerhans giant cells. Once granuloma formation is documented, special stains are used to rule out other granulomatous diseases.

Intralesional steroids have been reported to provide the greatest improvement; however, in the majority of patients, multiple treatments are required.^6,7 Allen et al⁸ suggested that the efficacy of intralesional therapy increases when preceded by local anesthesia of the lip, thus allowing larger doses of triamcinolone to be tolerated by the patient. Systemic corticosteroids also have been used with moderate success, but the side effects of long-term systemic corticosteroid therapy make this treatment option less appealing.⁹ Other agents with known anti-inflammatory properties also have been used that may offer better side-effect profiles when used for long-term suppressive therapy, including 
clofazimine, dapsone, sulfapyridine, danazol, hydroxychloroquine, and antibiotics such as doxycycline and metronidazole.¹⁰

In severe or recalcitrant cases, surgical intervention by way of a reduction cheiloplasty is considered by some to be an appropriate next step in therapy but is rarely needed. Postoperative intralesional steroid injections are necessary due to reported cases of worsening disease when injections are discontinued after cheiloplasty.^11,12

Our patient was treated with 5 mg of intralesional triamcinolone acetonide with 10 separate injections of 0.5 cc each along the affected portions of the upper lip. She also was given doxycycline 100 mg once daily for 30 days. The patient reported complete resolution of the upper lip swelling 7 days after the initiation of therapy. At 1-month follow-up, she reported that the swelling had completely resolved. However, 1 day prior to the scheduled visit, shortly after finishing the course of doxycycline, she noted recurrent swelling. Due to the concomitant initial administration of both the steroid injections and doxycycline, it was unclear which treatment had provided relief. To avoid, or at least delay, the need for chronic intralesional steroid injections, another course of 40 mg doxycycline daily was prescribed. After 2 weeks, the patient reported that the swelling had markedly improved. The patient has 
maintained remission of the symptoms for approximately 6 months on daily suppressive therapy with 40 mg of doxycycline.

The recurrence of lip swelling after therapy, as in our patient, is typical of GC, and most cases require multiple follow-up visits and frequent alterations in therapy, which is often frustrating for both the patient and physician. However, awareness of this disease entity, its natural course, and the therapeutic options will allow physicians to more appropriately counsel and educate patients of this uncommon 
disease process.

To the Editor:

A 51-year-old woman presented to her dermatologist with recurrent and progressive upper lip swelling of 2 years’ duration. Her condition was previously evaluated by several other physicians without a diagnosis or resolution of the symptoms. The swelling began on the right side of the upper lip and right cheek; however, over the course of 2 years, the swelling had progressed to involve the entire upper lip with complete sparing of the lower lip. She denied pain but reported numbness of the upper lip. The patient visited her dentist who ruled out periodontal infection as the cause of the swelling. Diphenhydramine provided no relief; however, the cheek swelling resolved after a course of antibiotics prescribed by an ear, nose, and throat physician.

She consulted her primary care physician and was subsequently referred to a neurologist and allergist who were unable to provide a definitive diagnosis or complete relief of the symptoms. She denied any history of hypersensitivity reactions, odontogenic infections, gastrointestinal concerns, or any other signs or symptoms of systemic granulomatous disease.

Figure 1. Upper lip swelling without ulceration, fissuring, or scaling. The lower lip was completely spared.

On physical examination, the upper lip was swollen symmetrically without evidence of ulceration, fissuring, or scaling (Figure 1). Palpation of the upper lip was notable for firm, nontender, nonpitting edema without nodularity. The oral mucosa did not appear swollen or erythematous. Examination did not reveal ulceration or a cobblestone appearance.

A full-thickness skin biopsy of the upper lip was performed. Histopathology revealed perivascular nonnecrotizing granulomas adjacent to ectatic vascular channels with associated lymphoplasmacytic infiltrate (Figure 2). Periodic acid–Schiff stain was negative for fungal hyphae, tissue Gram stain was negative for bacteria, Fite and acid-fast bacillus stains were both negative for acid-fast organisms, and polariscopy was negative for polarizable foreign material. In this clinical context, the morphologic findings were consistent with the diagnosis of granulomatous cheilitis (GC).

Figure 2. Upper lip biopsy showed dermal edema, vascular ectasia, perivascular nonnecrotizing granulomas, and perivascular lymphocyte predominant inflammatory infiltrate (A)(H&E, original magnification ×100). Higher magnification of granulomas with perivascular lymphoplasmacytic infiltrate (B)(H&E, original magnification ×200).

Granulomatous cheilitis is a rare disorder of the lips and orofacial mucosa that was first described by Meischer¹ in 1945 as persistent or recurrent orofacial swelling secondary to lymphatic obstruction by granulomatous proliferation. It often has been described as a monosymptomatic form of Melkersson-Rosenthal syndrome (MRS). In its entirety, MRS constitutes a triad of GC, facial nerve palsy, and lingua plicata (also known as fissured tongue).^2,3 Although many authors agree that GC is associated with MRS, some believe that GC is a distinct entity because the majority of patients who present with GC subsequently do not develop MRS.⁴ Despite its relationship to MRS, the true incidence of GC largely is unknown. The onset of disease usually occurs in early adulthood but can present in middle-aged or older individuals.

The typical course of GC is relapsing and remitting, nontender and nonpitting swelling of the lips that eventually becomes permanent, leading to possible facial distortion and disability. Involvement of the upper lip is the most common, followed by (in order of decreasing frequency) the lower lip and cheeks.⁵ The swelling may be unilateral or bilateral and generally is not associated with ulceration, fissuring, or scaling; however, these complications have been reported in the terminal stages of the disease in which the macrocheilia has become permanent.

Despite the controversy over the etiology, pathophysiology, and classification of GC, it largely is accepted that when a patient presents clinically with a history of recurrent or persistent lip swelling, a 
full-thickness skin biopsy of the involved oral mucosa should be taken. Conditions that are considered in the differential diagnosis of orofacial granulomatosis are systemic granulomatous diseases that are known to have oral manifestations including Crohn disease, sarcoidosis, and mycobacterial infections. Given the many causes of orofacial and labial swelling, GC is a diagnosis of exclusion based on a thorough history and physical examination as well as appropriate diagnostic studies, with the cornerstone of the diagnosis resting on the histologic appearance of the lesion. Histologically, the diagnosis lies in the demonstration of granuloma formation, consisting of collections of epithelioid histiocytes and Langerhans giant cells. Once granuloma formation is documented, special stains are used to rule out other granulomatous diseases.

Intralesional steroids have been reported to provide the greatest improvement; however, in the majority of patients, multiple treatments are required.^6,7 Allen et al⁸ suggested that the efficacy of intralesional therapy increases when preceded by local anesthesia of the lip, thus allowing larger doses of triamcinolone to be tolerated by the patient. Systemic corticosteroids also have been used with moderate success, but the side effects of long-term systemic corticosteroid therapy make this treatment option less appealing.⁹ Other agents with known anti-inflammatory properties also have been used that may offer better side-effect profiles when used for long-term suppressive therapy, including 
clofazimine, dapsone, sulfapyridine, danazol, hydroxychloroquine, and antibiotics such as doxycycline and metronidazole.¹⁰

In severe or recalcitrant cases, surgical intervention by way of a reduction cheiloplasty is considered by some to be an appropriate next step in therapy but is rarely needed. Postoperative intralesional steroid injections are necessary due to reported cases of worsening disease when injections are discontinued after cheiloplasty.^11,12

Our patient was treated with 5 mg of intralesional triamcinolone acetonide with 10 separate injections of 0.5 cc each along the affected portions of the upper lip. She also was given doxycycline 100 mg once daily for 30 days. The patient reported complete resolution of the upper lip swelling 7 days after the initiation of therapy. At 1-month follow-up, she reported that the swelling had completely resolved. However, 1 day prior to the scheduled visit, shortly after finishing the course of doxycycline, she noted recurrent swelling. Due to the concomitant initial administration of both the steroid injections and doxycycline, it was unclear which treatment had provided relief. To avoid, or at least delay, the need for chronic intralesional steroid injections, another course of 40 mg doxycycline daily was prescribed. After 2 weeks, the patient reported that the swelling had markedly improved. The patient has 
maintained remission of the symptoms for approximately 6 months on daily suppressive therapy with 40 mg of doxycycline.

The recurrence of lip swelling after therapy, as in our patient, is typical of GC, and most cases require multiple follow-up visits and frequent alterations in therapy, which is often frustrating for both the patient and physician. However, awareness of this disease entity, its natural course, and the therapeutic options will allow physicians to more appropriately counsel and educate patients of this uncommon 
disease process.

To the Editor:

A 51-year-old woman presented to her dermatologist with recurrent and progressive upper lip swelling of 2 years’ duration. Her condition was previously evaluated by several other physicians without a diagnosis or resolution of the symptoms. The swelling began on the right side of the upper lip and right cheek; however, over the course of 2 years, the swelling had progressed to involve the entire upper lip with complete sparing of the lower lip. She denied pain but reported numbness of the upper lip. The patient visited her dentist who ruled out periodontal infection as the cause of the swelling. Diphenhydramine provided no relief; however, the cheek swelling resolved after a course of antibiotics prescribed by an ear, nose, and throat physician.

She consulted her primary care physician and was subsequently referred to a neurologist and allergist who were unable to provide a definitive diagnosis or complete relief of the symptoms. She denied any history of hypersensitivity reactions, odontogenic infections, gastrointestinal concerns, or any other signs or symptoms of systemic granulomatous disease.

Figure 1. Upper lip swelling without ulceration, fissuring, or scaling. The lower lip was completely spared.

On physical examination, the upper lip was swollen symmetrically without evidence of ulceration, fissuring, or scaling (Figure 1). Palpation of the upper lip was notable for firm, nontender, nonpitting edema without nodularity. The oral mucosa did not appear swollen or erythematous. Examination did not reveal ulceration or a cobblestone appearance.

A full-thickness skin biopsy of the upper lip was performed. Histopathology revealed perivascular nonnecrotizing granulomas adjacent to ectatic vascular channels with associated lymphoplasmacytic infiltrate (Figure 2). Periodic acid–Schiff stain was negative for fungal hyphae, tissue Gram stain was negative for bacteria, Fite and acid-fast bacillus stains were both negative for acid-fast organisms, and polariscopy was negative for polarizable foreign material. In this clinical context, the morphologic findings were consistent with the diagnosis of granulomatous cheilitis (GC).

Figure 2. Upper lip biopsy showed dermal edema, vascular ectasia, perivascular nonnecrotizing granulomas, and perivascular lymphocyte predominant inflammatory infiltrate (A)(H&E, original magnification ×100). Higher magnification of granulomas with perivascular lymphoplasmacytic infiltrate (B)(H&E, original magnification ×200).

Granulomatous cheilitis is a rare disorder of the lips and orofacial mucosa that was first described by Meischer¹ in 1945 as persistent or recurrent orofacial swelling secondary to lymphatic obstruction by granulomatous proliferation. It often has been described as a monosymptomatic form of Melkersson-Rosenthal syndrome (MRS). In its entirety, MRS constitutes a triad of GC, facial nerve palsy, and lingua plicata (also known as fissured tongue).^2,3 Although many authors agree that GC is associated with MRS, some believe that GC is a distinct entity because the majority of patients who present with GC subsequently do not develop MRS.⁴ Despite its relationship to MRS, the true incidence of GC largely is unknown. The onset of disease usually occurs in early adulthood but can present in middle-aged or older individuals.

The typical course of GC is relapsing and remitting, nontender and nonpitting swelling of the lips that eventually becomes permanent, leading to possible facial distortion and disability. Involvement of the upper lip is the most common, followed by (in order of decreasing frequency) the lower lip and cheeks.⁵ The swelling may be unilateral or bilateral and generally is not associated with ulceration, fissuring, or scaling; however, these complications have been reported in the terminal stages of the disease in which the macrocheilia has become permanent.

Despite the controversy over the etiology, pathophysiology, and classification of GC, it largely is accepted that when a patient presents clinically with a history of recurrent or persistent lip swelling, a 
full-thickness skin biopsy of the involved oral mucosa should be taken. Conditions that are considered in the differential diagnosis of orofacial granulomatosis are systemic granulomatous diseases that are known to have oral manifestations including Crohn disease, sarcoidosis, and mycobacterial infections. Given the many causes of orofacial and labial swelling, GC is a diagnosis of exclusion based on a thorough history and physical examination as well as appropriate diagnostic studies, with the cornerstone of the diagnosis resting on the histologic appearance of the lesion. Histologically, the diagnosis lies in the demonstration of granuloma formation, consisting of collections of epithelioid histiocytes and Langerhans giant cells. Once granuloma formation is documented, special stains are used to rule out other granulomatous diseases.

Intralesional steroids have been reported to provide the greatest improvement; however, in the majority of patients, multiple treatments are required.^6,7 Allen et al⁸ suggested that the efficacy of intralesional therapy increases when preceded by local anesthesia of the lip, thus allowing larger doses of triamcinolone to be tolerated by the patient. Systemic corticosteroids also have been used with moderate success, but the side effects of long-term systemic corticosteroid therapy make this treatment option less appealing.⁹ Other agents with known anti-inflammatory properties also have been used that may offer better side-effect profiles when used for long-term suppressive therapy, including 
clofazimine, dapsone, sulfapyridine, danazol, hydroxychloroquine, and antibiotics such as doxycycline and metronidazole.¹⁰

In severe or recalcitrant cases, surgical intervention by way of a reduction cheiloplasty is considered by some to be an appropriate next step in therapy but is rarely needed. Postoperative intralesional steroid injections are necessary due to reported cases of worsening disease when injections are discontinued after cheiloplasty.^11,12

Our patient was treated with 5 mg of intralesional triamcinolone acetonide with 10 separate injections of 0.5 cc each along the affected portions of the upper lip. She also was given doxycycline 100 mg once daily for 30 days. The patient reported complete resolution of the upper lip swelling 7 days after the initiation of therapy. At 1-month follow-up, she reported that the swelling had completely resolved. However, 1 day prior to the scheduled visit, shortly after finishing the course of doxycycline, she noted recurrent swelling. Due to the concomitant initial administration of both the steroid injections and doxycycline, it was unclear which treatment had provided relief. To avoid, or at least delay, the need for chronic intralesional steroid injections, another course of 40 mg doxycycline daily was prescribed. After 2 weeks, the patient reported that the swelling had markedly improved. The patient has 
maintained remission of the symptoms for approximately 6 months on daily suppressive therapy with 40 mg of doxycycline.

The recurrence of lip swelling after therapy, as in our patient, is typical of GC, and most cases require multiple follow-up visits and frequent alterations in therapy, which is often frustrating for both the patient and physician. However, awareness of this disease entity, its natural course, and the therapeutic options will allow physicians to more appropriately counsel and educate patients of this uncommon 
disease process.

An 81-year-old woman presented for evaluation of a nodule on the right labia majora that had been present for 1 year. She had a history of intertriginous psoriasis, and several biopsies were performed at an outside facility over the last 5 years that revealed psoriasis but were otherwise noncontributory. Physical examination revealed erythema and scaling on the buttocks with maceration in the intertriginous area (top) and the perineum associated with a verrucous nodule (bottom).

The Diagnosis: Verrucous Carcinoma

Biopsies of early lesions often may be difficult to interpret without clinicopathological correlation. Our patient’s tumor was associated with intertriginous psoriasis, which was the only abnormality previously noted on superficial biopsies performed at an outside facility. The patient was scheduled for an excisional biopsy due to the large tumor size and clinical suspicion that the prior biopsies were inadequate and failed to demonstrate the primary underlying pathology. Excisional biopsy of the verrucous tumor revealed epithelium composed of keratinocytes with glassy cytoplasm. Papillomatosis was noted along with an endophytic component of well-differentiated epithelial cells extending into the dermis in a bulbous pattern consistent with the verrucous carcinoma variant of squamous cell carcinoma (SCC)(Figure). Verrucous carcinoma often requires correlation with both the clinical and histopathologic findings for definitive diagnosis, as keratinocytes often appear to be well differentiated.¹

Excisional biopsy of the verrucous nodule revealed marked acanthosis of the epidermis and bulbous projections of epithelium extending into the dermis. The endophytic “pushing border” supported a diagnosis of verrucous carcinoma (H&E, original magnification ×100).

Verrucous carcinoma may begin as an innocuous papule that slowly grows into a large fungating tumor. Verrucous carcinomas typically are slow growing, exophytic, and low grade. The etiology of verrucous carcinoma is not clear, and the role of human papillomavirus (HPV) infection is controversial.² Best classified as a well-differentiated SCC, verrucous carcinoma rarely metastasizes but may invade adjacent tissues.

Differential diagnoses include a giant inflamed seborrheic keratosis, condyloma acuminatum, rupioid psoriasis, and inflammatory linear verrucous epidermal nevus (ILVEN). Although large and inflamed seborrheic keratoses may have squamous eddies that mimic SCC, seborrheic keratoses do not invade the dermis and typically have a well-circumscribed stuck-on appearance. Abnormal mitotic figures are not identified. Condylomas are genital warts caused by HPV infection that often are clustered, well circumscribed, and exophytic. Large lesions can be difficult to distinguish from verrucous carcinomas, and biopsy generally reveals koilocytes identified by perinuclear clearing and raisinlike nuclei. Immunohistochemical staining and in situ hybridization studies can be of value in diagnosis and in identifying those lesions that are at high risk for malignant transformation. High-risk condylomas are associated with HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, and HPV-39, as well as other types, whereas low-risk condylomas are associated with HPV-6, HPV-11, HPV-42, and others.² Differentiating squamous cell hyperplasia from squamous cell carcinoma in situ also can be aided by immunohistochemistry. Squamous cell hyperplasia is usually negative for INK4 p16^Ink4A and p53 and exhibits variable Ki-67 staining. Differentiated squamous cell carcinoma in situ exhibits a profile that is p16^Ink4A negative, Ki-67 positive, and exhibits variable p53 staining.³ Basaloid and warty intraepithelial neoplasia is consistently p16^Ink4A positive, Ki-67 positive, and variably positive for p53.³ Therefore, p16 staining of high-grade areas is a useful biomarker that can help establish diagnosis of associated squamous cell carcinoma.⁴ The role of papillomaviruses in the development of nonmelanoma skin cancer is an area of active study, and research suggests that papillomaviruses may have a much greater role than previously suspected.⁵

At times, psoriasis may be markedly hyperkeratotic, clinically mimicking a verrucous neoplasm. This hyperkeratotic type of psoriasis is known as rupioid psoriasis. However, these psoriatic lesions are exophytic, are associated with spongiform pustules, and lack the atypia and endophytic pattern typically seen with verrucous carcinoma. An ILVEN also lacks atypia and an endophytic pattern and usually presents in childhood as a persistent linear plaque, rather than the verrucous plaque noted in our patient. Squamous cell carcinoma has been reported to arise in the setting of verrucoid ILVEN but is exceptionally uncommon.⁶

Successful treatment of verrucous carcinoma is best achieved by complete excision. Oral retinoids and immunomodulators such as imiquimod also may be of value.⁷ Our patient’s tumor qualifies as T2N0M0 because it was greater than 2 cm in size.⁸ A Breslow thickness of 2 mm or greater and Clark level IV are high-risk features associated with a worse prognosis, but clinical evaluation of our patient’s lymph nodes was unremarkable and no distant metastases were identified. Our patient continues to do well with no evidence of recurrence.

An 81-year-old woman presented for evaluation of a nodule on the right labia majora that had been present for 1 year. She had a history of intertriginous psoriasis, and several biopsies were performed at an outside facility over the last 5 years that revealed psoriasis but were otherwise noncontributory. Physical examination revealed erythema and scaling on the buttocks with maceration in the intertriginous area (top) and the perineum associated with a verrucous nodule (bottom).

The Diagnosis: Verrucous Carcinoma

Biopsies of early lesions often may be difficult to interpret without clinicopathological correlation. Our patient’s tumor was associated with intertriginous psoriasis, which was the only abnormality previously noted on superficial biopsies performed at an outside facility. The patient was scheduled for an excisional biopsy due to the large tumor size and clinical suspicion that the prior biopsies were inadequate and failed to demonstrate the primary underlying pathology. Excisional biopsy of the verrucous tumor revealed epithelium composed of keratinocytes with glassy cytoplasm. Papillomatosis was noted along with an endophytic component of well-differentiated epithelial cells extending into the dermis in a bulbous pattern consistent with the verrucous carcinoma variant of squamous cell carcinoma (SCC)(Figure). Verrucous carcinoma often requires correlation with both the clinical and histopathologic findings for definitive diagnosis, as keratinocytes often appear to be well differentiated.¹

Excisional biopsy of the verrucous nodule revealed marked acanthosis of the epidermis and bulbous projections of epithelium extending into the dermis. The endophytic “pushing border” supported a diagnosis of verrucous carcinoma (H&E, original magnification ×100).

Verrucous carcinoma may begin as an innocuous papule that slowly grows into a large fungating tumor. Verrucous carcinomas typically are slow growing, exophytic, and low grade. The etiology of verrucous carcinoma is not clear, and the role of human papillomavirus (HPV) infection is controversial.² Best classified as a well-differentiated SCC, verrucous carcinoma rarely metastasizes but may invade adjacent tissues.

Differential diagnoses include a giant inflamed seborrheic keratosis, condyloma acuminatum, rupioid psoriasis, and inflammatory linear verrucous epidermal nevus (ILVEN). Although large and inflamed seborrheic keratoses may have squamous eddies that mimic SCC, seborrheic keratoses do not invade the dermis and typically have a well-circumscribed stuck-on appearance. Abnormal mitotic figures are not identified. Condylomas are genital warts caused by HPV infection that often are clustered, well circumscribed, and exophytic. Large lesions can be difficult to distinguish from verrucous carcinomas, and biopsy generally reveals koilocytes identified by perinuclear clearing and raisinlike nuclei. Immunohistochemical staining and in situ hybridization studies can be of value in diagnosis and in identifying those lesions that are at high risk for malignant transformation. High-risk condylomas are associated with HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, and HPV-39, as well as other types, whereas low-risk condylomas are associated with HPV-6, HPV-11, HPV-42, and others.² Differentiating squamous cell hyperplasia from squamous cell carcinoma in situ also can be aided by immunohistochemistry. Squamous cell hyperplasia is usually negative for INK4 p16^Ink4A and p53 and exhibits variable Ki-67 staining. Differentiated squamous cell carcinoma in situ exhibits a profile that is p16^Ink4A negative, Ki-67 positive, and exhibits variable p53 staining.³ Basaloid and warty intraepithelial neoplasia is consistently p16^Ink4A positive, Ki-67 positive, and variably positive for p53.³ Therefore, p16 staining of high-grade areas is a useful biomarker that can help establish diagnosis of associated squamous cell carcinoma.⁴ The role of papillomaviruses in the development of nonmelanoma skin cancer is an area of active study, and research suggests that papillomaviruses may have a much greater role than previously suspected.⁵

At times, psoriasis may be markedly hyperkeratotic, clinically mimicking a verrucous neoplasm. This hyperkeratotic type of psoriasis is known as rupioid psoriasis. However, these psoriatic lesions are exophytic, are associated with spongiform pustules, and lack the atypia and endophytic pattern typically seen with verrucous carcinoma. An ILVEN also lacks atypia and an endophytic pattern and usually presents in childhood as a persistent linear plaque, rather than the verrucous plaque noted in our patient. Squamous cell carcinoma has been reported to arise in the setting of verrucoid ILVEN but is exceptionally uncommon.⁶

Successful treatment of verrucous carcinoma is best achieved by complete excision. Oral retinoids and immunomodulators such as imiquimod also may be of value.⁷ Our patient’s tumor qualifies as T2N0M0 because it was greater than 2 cm in size.⁸ A Breslow thickness of 2 mm or greater and Clark level IV are high-risk features associated with a worse prognosis, but clinical evaluation of our patient’s lymph nodes was unremarkable and no distant metastases were identified. Our patient continues to do well with no evidence of recurrence.

An 81-year-old woman presented for evaluation of a nodule on the right labia majora that had been present for 1 year. She had a history of intertriginous psoriasis, and several biopsies were performed at an outside facility over the last 5 years that revealed psoriasis but were otherwise noncontributory. Physical examination revealed erythema and scaling on the buttocks with maceration in the intertriginous area (top) and the perineum associated with a verrucous nodule (bottom).

The Diagnosis: Verrucous Carcinoma

Biopsies of early lesions often may be difficult to interpret without clinicopathological correlation. Our patient’s tumor was associated with intertriginous psoriasis, which was the only abnormality previously noted on superficial biopsies performed at an outside facility. The patient was scheduled for an excisional biopsy due to the large tumor size and clinical suspicion that the prior biopsies were inadequate and failed to demonstrate the primary underlying pathology. Excisional biopsy of the verrucous tumor revealed epithelium composed of keratinocytes with glassy cytoplasm. Papillomatosis was noted along with an endophytic component of well-differentiated epithelial cells extending into the dermis in a bulbous pattern consistent with the verrucous carcinoma variant of squamous cell carcinoma (SCC)(Figure). Verrucous carcinoma often requires correlation with both the clinical and histopathologic findings for definitive diagnosis, as keratinocytes often appear to be well differentiated.¹

Excisional biopsy of the verrucous nodule revealed marked acanthosis of the epidermis and bulbous projections of epithelium extending into the dermis. The endophytic “pushing border” supported a diagnosis of verrucous carcinoma (H&E, original magnification ×100).

Verrucous carcinoma may begin as an innocuous papule that slowly grows into a large fungating tumor. Verrucous carcinomas typically are slow growing, exophytic, and low grade. The etiology of verrucous carcinoma is not clear, and the role of human papillomavirus (HPV) infection is controversial.² Best classified as a well-differentiated SCC, verrucous carcinoma rarely metastasizes but may invade adjacent tissues.

Differential diagnoses include a giant inflamed seborrheic keratosis, condyloma acuminatum, rupioid psoriasis, and inflammatory linear verrucous epidermal nevus (ILVEN). Although large and inflamed seborrheic keratoses may have squamous eddies that mimic SCC, seborrheic keratoses do not invade the dermis and typically have a well-circumscribed stuck-on appearance. Abnormal mitotic figures are not identified. Condylomas are genital warts caused by HPV infection that often are clustered, well circumscribed, and exophytic. Large lesions can be difficult to distinguish from verrucous carcinomas, and biopsy generally reveals koilocytes identified by perinuclear clearing and raisinlike nuclei. Immunohistochemical staining and in situ hybridization studies can be of value in diagnosis and in identifying those lesions that are at high risk for malignant transformation. High-risk condylomas are associated with HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, and HPV-39, as well as other types, whereas low-risk condylomas are associated with HPV-6, HPV-11, HPV-42, and others.² Differentiating squamous cell hyperplasia from squamous cell carcinoma in situ also can be aided by immunohistochemistry. Squamous cell hyperplasia is usually negative for INK4 p16^Ink4A and p53 and exhibits variable Ki-67 staining. Differentiated squamous cell carcinoma in situ exhibits a profile that is p16^Ink4A negative, Ki-67 positive, and exhibits variable p53 staining.³ Basaloid and warty intraepithelial neoplasia is consistently p16^Ink4A positive, Ki-67 positive, and variably positive for p53.³ Therefore, p16 staining of high-grade areas is a useful biomarker that can help establish diagnosis of associated squamous cell carcinoma.⁴ The role of papillomaviruses in the development of nonmelanoma skin cancer is an area of active study, and research suggests that papillomaviruses may have a much greater role than previously suspected.⁵

At times, psoriasis may be markedly hyperkeratotic, clinically mimicking a verrucous neoplasm. This hyperkeratotic type of psoriasis is known as rupioid psoriasis. However, these psoriatic lesions are exophytic, are associated with spongiform pustules, and lack the atypia and endophytic pattern typically seen with verrucous carcinoma. An ILVEN also lacks atypia and an endophytic pattern and usually presents in childhood as a persistent linear plaque, rather than the verrucous plaque noted in our patient. Squamous cell carcinoma has been reported to arise in the setting of verrucoid ILVEN but is exceptionally uncommon.⁶

Successful treatment of verrucous carcinoma is best achieved by complete excision. Oral retinoids and immunomodulators such as imiquimod also may be of value.⁷ Our patient’s tumor qualifies as T2N0M0 because it was greater than 2 cm in size.⁸ A Breslow thickness of 2 mm or greater and Clark level IV are high-risk features associated with a worse prognosis, but clinical evaluation of our patient’s lymph nodes was unremarkable and no distant metastases were identified. Our patient continues to do well with no evidence of recurrence.

Trichilemmomas are benign follicular neoplasms that exhibit differentiation toward the outer root sheath of the pilosebaceous follicular epithelium.¹ Trichilemmomas clinically present as individual or multiple, slowly growing, verrucous papules appearing most commonly on the face or neck. The lesions may coalesce to form small plaques. Although trichilemmomas typically are isolated, patients with multiple trichilemmomas require a cancer screening workup due to their association with Cowden disease, which results from a mutation in the phosphatase and tensin homolog tumor suppressor gene, PTEN.² An easy way to remember the association between trichilemmomas and Cowden disease is to alter the spelling to “trichile-moo-moo,” using the “moo moo” sound of an animal cow as a clue linking the tumor to Cowden disease.

Histologically, trichilemmomas exhibit a lobular epidermal downgrowth into the dermis (Figure 1). The surface of the lesion may be hyperkeratotic and somewhat papillomatous. Cells toward the center of the lobule are pale staining, periodic acid–Schiff positive, and diastase labile due to high levels of intracellular glycogen (Figure 2). Cells toward the periphery of the lobule usually appear basophilic with a palisading arrangement of the peripheral cells. The entire lobule is enclosed within an eosinophilic basement membrane that stains positively with periodic acid–Schiff (Figure 2).¹ Consistent with the tumor’s differentiation toward the outer root sheath of the hair follicle, trichilemmomas have been reported to express CD34 focally or diffusely.³

Figure 1. A lobular trichilemmoma composed of aggregates of epithelial cells extending from the epidermis into the dermis. The cells of the tumor are composed of squamoid cells showing variable glycogen vacuolation (pale-staining cytoplasm) and there is a surrounding prominent basement membrane (arrow)(H&E, original magnification ×40).

Figure 2. High-power magnification showing the pale-staining cells comprising a trichilemmoma (asterisk) as well as peripheral palisading of the cells at the periphery of the lesion and a thickened surrounding membrane (arrow)(H&E, original magnification ×200).

Similar to trichilemmoma, inverted follicular keratosis (IFK) commonly presents as a solitary asymptomatic papule on the face. Inverted follicular keratosis is a somewhat controversial entity, with some authorities arguing IFK is a variant of verruca vulgaris or seborrheic keratosis. Histologically, IFKs can be differentiated by the presence of squamous eddies (concentric layers of squamous cells in a whorled pattern), which are diagnostic, and central longitudinal crypts that contain keratin and are lined by squamous epithelium.⁴ Basaloid cells can be seen at the periphery of the tumors; however, IFKs lack an eosinophilic basement membrane surrounding the tumor (Figure 3).

Figure 3. Sections of a biopsy from an inverted follicular keratosis show an endophytic lesion with acanthosis consisting of fairly uniform squamous cells with eosinophilic cytoplasm. Numerous squamous eddies can be seen (H&E, original magnification ×100).

Squamous cell carcinoma in situ classically appears as an erythematous hyperkeratotic papule or plaque on sun-exposed sites that can become crusted or ulcerated. Microscopically, squamous cell carcinoma in situ displays full-thickness disorderly maturation of keratinocytes. The keratinocytes exhibit nuclear pleomorphism. Atypical mitotic figures and dyskeratotic keratinocytes also can be seen throughout the full thickness of the epidermis (Figure 4).⁵

Figure 4. The epidermis is acanthotic and shows full-thickness disorderly maturation of keratinocytes, mitoses at different levels, and dyskeratotic cells in a squamous cell carcinoma in situ. Overlying parakeratosis also can be noted (H&E, original magnification ×100).

Verruca vulgaris (Figure 5) histologically demonstrates hyperkeratosis with tiers of parakeratosis, digitated epidermal hyperplasia, and dilated tortuous capillaries within the dermal papillae. At the edges of the lesion there often is inward turning of elongated rete ridges,^6,7 which can be thought of as the rete reaching out for a hug of sorts to spread the human papillomavirus infection. Although the surface of a trichilemmoma can bear resemblance to a verruca vulgaris, the remainder of the histologic features can be used to help differentiate these tumors. Additionally, there has been no evidence suggestive of a viral etiology for trichilemmomas.⁸

Figure 5. Compact hyperorthokeratosis with tiers of parakeratosis (arrow), digitated epidermal hyperplasia, hypergranulosis, vacuolated granular layer cells, and small blood vessels extending into the tips of the dermal papillae (asterisk) in the setting of a verruca vulgaris (H&E, original magnification ×100).

Warty dyskeratoma features an umbilicated papule, usually on the face, head, or neck, that is associated with a follicular unit. The papule shows a cup-shaped, keratin-filled invagination; suprabasilar clefting; and acantholytic dyskeratotic cells, which are features that are not seen in trichilemmomas (Figure 6).⁹

Figure 6. A cup-shaped invagination filled with cornified material and surrounded by slight epidermal hyperplasia in association with acantholytic dyskeratosis in a warty dyskeratoma (H&E, original magnifi-cation ×100).

Acknowledgment—The authors would like to thank Brandon Litzner, MD, St Louis, Missouri, for proofreading the manuscript.

Trichilemmomas are benign follicular neoplasms that exhibit differentiation toward the outer root sheath of the pilosebaceous follicular epithelium.¹ Trichilemmomas clinically present as individual or multiple, slowly growing, verrucous papules appearing most commonly on the face or neck. The lesions may coalesce to form small plaques. Although trichilemmomas typically are isolated, patients with multiple trichilemmomas require a cancer screening workup due to their association with Cowden disease, which results from a mutation in the phosphatase and tensin homolog tumor suppressor gene, PTEN.² An easy way to remember the association between trichilemmomas and Cowden disease is to alter the spelling to “trichile-moo-moo,” using the “moo moo” sound of an animal cow as a clue linking the tumor to Cowden disease.

Histologically, trichilemmomas exhibit a lobular epidermal downgrowth into the dermis (Figure 1). The surface of the lesion may be hyperkeratotic and somewhat papillomatous. Cells toward the center of the lobule are pale staining, periodic acid–Schiff positive, and diastase labile due to high levels of intracellular glycogen (Figure 2). Cells toward the periphery of the lobule usually appear basophilic with a palisading arrangement of the peripheral cells. The entire lobule is enclosed within an eosinophilic basement membrane that stains positively with periodic acid–Schiff (Figure 2).¹ Consistent with the tumor’s differentiation toward the outer root sheath of the hair follicle, trichilemmomas have been reported to express CD34 focally or diffusely.³

Figure 1. A lobular trichilemmoma composed of aggregates of epithelial cells extending from the epidermis into the dermis. The cells of the tumor are composed of squamoid cells showing variable glycogen vacuolation (pale-staining cytoplasm) and there is a surrounding prominent basement membrane (arrow)(H&E, original magnification ×40).

Figure 2. High-power magnification showing the pale-staining cells comprising a trichilemmoma (asterisk) as well as peripheral palisading of the cells at the periphery of the lesion and a thickened surrounding membrane (arrow)(H&E, original magnification ×200).

Similar to trichilemmoma, inverted follicular keratosis (IFK) commonly presents as a solitary asymptomatic papule on the face. Inverted follicular keratosis is a somewhat controversial entity, with some authorities arguing IFK is a variant of verruca vulgaris or seborrheic keratosis. Histologically, IFKs can be differentiated by the presence of squamous eddies (concentric layers of squamous cells in a whorled pattern), which are diagnostic, and central longitudinal crypts that contain keratin and are lined by squamous epithelium.⁴ Basaloid cells can be seen at the periphery of the tumors; however, IFKs lack an eosinophilic basement membrane surrounding the tumor (Figure 3).

Figure 3. Sections of a biopsy from an inverted follicular keratosis show an endophytic lesion with acanthosis consisting of fairly uniform squamous cells with eosinophilic cytoplasm. Numerous squamous eddies can be seen (H&E, original magnification ×100).

Squamous cell carcinoma in situ classically appears as an erythematous hyperkeratotic papule or plaque on sun-exposed sites that can become crusted or ulcerated. Microscopically, squamous cell carcinoma in situ displays full-thickness disorderly maturation of keratinocytes. The keratinocytes exhibit nuclear pleomorphism. Atypical mitotic figures and dyskeratotic keratinocytes also can be seen throughout the full thickness of the epidermis (Figure 4).⁵

Figure 4. The epidermis is acanthotic and shows full-thickness disorderly maturation of keratinocytes, mitoses at different levels, and dyskeratotic cells in a squamous cell carcinoma in situ. Overlying parakeratosis also can be noted (H&E, original magnification ×100).

Verruca vulgaris (Figure 5) histologically demonstrates hyperkeratosis with tiers of parakeratosis, digitated epidermal hyperplasia, and dilated tortuous capillaries within the dermal papillae. At the edges of the lesion there often is inward turning of elongated rete ridges,^6,7 which can be thought of as the rete reaching out for a hug of sorts to spread the human papillomavirus infection. Although the surface of a trichilemmoma can bear resemblance to a verruca vulgaris, the remainder of the histologic features can be used to help differentiate these tumors. Additionally, there has been no evidence suggestive of a viral etiology for trichilemmomas.⁸

Figure 5. Compact hyperorthokeratosis with tiers of parakeratosis (arrow), digitated epidermal hyperplasia, hypergranulosis, vacuolated granular layer cells, and small blood vessels extending into the tips of the dermal papillae (asterisk) in the setting of a verruca vulgaris (H&E, original magnification ×100).

Warty dyskeratoma features an umbilicated papule, usually on the face, head, or neck, that is associated with a follicular unit. The papule shows a cup-shaped, keratin-filled invagination; suprabasilar clefting; and acantholytic dyskeratotic cells, which are features that are not seen in trichilemmomas (Figure 6).⁹

Figure 6. A cup-shaped invagination filled with cornified material and surrounded by slight epidermal hyperplasia in association with acantholytic dyskeratosis in a warty dyskeratoma (H&E, original magnifi-cation ×100).

Acknowledgment—The authors would like to thank Brandon Litzner, MD, St Louis, Missouri, for proofreading the manuscript.

Trichilemmomas are benign follicular neoplasms that exhibit differentiation toward the outer root sheath of the pilosebaceous follicular epithelium.¹ Trichilemmomas clinically present as individual or multiple, slowly growing, verrucous papules appearing most commonly on the face or neck. The lesions may coalesce to form small plaques. Although trichilemmomas typically are isolated, patients with multiple trichilemmomas require a cancer screening workup due to their association with Cowden disease, which results from a mutation in the phosphatase and tensin homolog tumor suppressor gene, PTEN.² An easy way to remember the association between trichilemmomas and Cowden disease is to alter the spelling to “trichile-moo-moo,” using the “moo moo” sound of an animal cow as a clue linking the tumor to Cowden disease.

Histologically, trichilemmomas exhibit a lobular epidermal downgrowth into the dermis (Figure 1). The surface of the lesion may be hyperkeratotic and somewhat papillomatous. Cells toward the center of the lobule are pale staining, periodic acid–Schiff positive, and diastase labile due to high levels of intracellular glycogen (Figure 2). Cells toward the periphery of the lobule usually appear basophilic with a palisading arrangement of the peripheral cells. The entire lobule is enclosed within an eosinophilic basement membrane that stains positively with periodic acid–Schiff (Figure 2).¹ Consistent with the tumor’s differentiation toward the outer root sheath of the hair follicle, trichilemmomas have been reported to express CD34 focally or diffusely.³

Figure 1. A lobular trichilemmoma composed of aggregates of epithelial cells extending from the epidermis into the dermis. The cells of the tumor are composed of squamoid cells showing variable glycogen vacuolation (pale-staining cytoplasm) and there is a surrounding prominent basement membrane (arrow)(H&E, original magnification ×40).

Figure 2. High-power magnification showing the pale-staining cells comprising a trichilemmoma (asterisk) as well as peripheral palisading of the cells at the periphery of the lesion and a thickened surrounding membrane (arrow)(H&E, original magnification ×200).

Similar to trichilemmoma, inverted follicular keratosis (IFK) commonly presents as a solitary asymptomatic papule on the face. Inverted follicular keratosis is a somewhat controversial entity, with some authorities arguing IFK is a variant of verruca vulgaris or seborrheic keratosis. Histologically, IFKs can be differentiated by the presence of squamous eddies (concentric layers of squamous cells in a whorled pattern), which are diagnostic, and central longitudinal crypts that contain keratin and are lined by squamous epithelium.⁴ Basaloid cells can be seen at the periphery of the tumors; however, IFKs lack an eosinophilic basement membrane surrounding the tumor (Figure 3).

Figure 3. Sections of a biopsy from an inverted follicular keratosis show an endophytic lesion with acanthosis consisting of fairly uniform squamous cells with eosinophilic cytoplasm. Numerous squamous eddies can be seen (H&E, original magnification ×100).

Squamous cell carcinoma in situ classically appears as an erythematous hyperkeratotic papule or plaque on sun-exposed sites that can become crusted or ulcerated. Microscopically, squamous cell carcinoma in situ displays full-thickness disorderly maturation of keratinocytes. The keratinocytes exhibit nuclear pleomorphism. Atypical mitotic figures and dyskeratotic keratinocytes also can be seen throughout the full thickness of the epidermis (Figure 4).⁵

Figure 4. The epidermis is acanthotic and shows full-thickness disorderly maturation of keratinocytes, mitoses at different levels, and dyskeratotic cells in a squamous cell carcinoma in situ. Overlying parakeratosis also can be noted (H&E, original magnification ×100).

Verruca vulgaris (Figure 5) histologically demonstrates hyperkeratosis with tiers of parakeratosis, digitated epidermal hyperplasia, and dilated tortuous capillaries within the dermal papillae. At the edges of the lesion there often is inward turning of elongated rete ridges,^6,7 which can be thought of as the rete reaching out for a hug of sorts to spread the human papillomavirus infection. Although the surface of a trichilemmoma can bear resemblance to a verruca vulgaris, the remainder of the histologic features can be used to help differentiate these tumors. Additionally, there has been no evidence suggestive of a viral etiology for trichilemmomas.⁸

Figure 5. Compact hyperorthokeratosis with tiers of parakeratosis (arrow), digitated epidermal hyperplasia, hypergranulosis, vacuolated granular layer cells, and small blood vessels extending into the tips of the dermal papillae (asterisk) in the setting of a verruca vulgaris (H&E, original magnification ×100).

Warty dyskeratoma features an umbilicated papule, usually on the face, head, or neck, that is associated with a follicular unit. The papule shows a cup-shaped, keratin-filled invagination; suprabasilar clefting; and acantholytic dyskeratotic cells, which are features that are not seen in trichilemmomas (Figure 6).⁹

Figure 6. A cup-shaped invagination filled with cornified material and surrounded by slight epidermal hyperplasia in association with acantholytic dyskeratosis in a warty dyskeratoma (H&E, original magnifi-cation ×100).

Acknowledgment—The authors would like to thank Brandon Litzner, MD, St Louis, Missouri, for proofreading the manuscript.