Dermatopathology

Practice Gap

Warts may negatively impact a patient's quality of life, as they may cause not only discomfort and pain but also embarrassment and low self-esteem.¹ Moreover, Ciconte et al¹ demonstrated that study participants with warts on their feet were more likely to report physical discomfort than those with warts on their hands. Therefore, plantar warts should be diagnosed promptly to allow for proper treatment.

Warts may be identified by viewing the dilated capillaries that lie on their surface, which appear as small black dots to the naked eye.¹ The formation of a plantar wart obliterates the normal plantar creases, thereby flattening the skin’s natural markings. However, a plantar wart may appear clinically similar to a callus and both lesions typically form in pressure point areas, warranting the use of a tool that aids in its diagnostic evaluation.^1,2

Diagnostic Tools

Dermoscopy, a noninvasive tool that creates a microscopic visualization of lesions, is commonly used to distinguish dermatologic pathology if the clinical presentation overlaps with a similar lesion, such as a callus, corn, or plantar wart.^1,3 However, there is another way of differentiating plantar warts from calluses using a simple 2-step clinical maneuver that we learned from Dr. Lewis Kaplan at the University of Miami.

Using the thumb or index finger, apply pressure at a perpendicular angle to the lesion on the sole of the patient’s foot, which will not create substantial discomfort or pain in a patient who has a plantar wart (Figure) but will be painful in a patient who has a callus due to the underlying bony spur. The next step involves applying pressure to the left and right sides of the lesion by squeezing toward the center with the thumb and index finger at a 45° angle. This maneuver will create substantial discomfort and pain in patients with plantar warts, thus helping to confirm the diagnosis.

A plantar wart before (A) and after undergoing the squeeze maneuver (B). The patient denied feelings of discomfort or pain.

Practice Implications

Rarely, a plantar wart can progress to form a verrucous carcinoma if left untreated.² Thus, it is important to diagnose and treat plantar warts to avoid pain and potential complications. The technique discussed here, which we are coining as the “squeeze maneuver,” allows for easy diagnosis and negates the need for an expensive diagnostic tool.To submit a clinical pearl, contact our Editorial Office.

Practice Gap

Warts may negatively impact a patient's quality of life, as they may cause not only discomfort and pain but also embarrassment and low self-esteem.¹ Moreover, Ciconte et al¹ demonstrated that study participants with warts on their feet were more likely to report physical discomfort than those with warts on their hands. Therefore, plantar warts should be diagnosed promptly to allow for proper treatment.

Warts may be identified by viewing the dilated capillaries that lie on their surface, which appear as small black dots to the naked eye.¹ The formation of a plantar wart obliterates the normal plantar creases, thereby flattening the skin’s natural markings. However, a plantar wart may appear clinically similar to a callus and both lesions typically form in pressure point areas, warranting the use of a tool that aids in its diagnostic evaluation.^1,2

Diagnostic Tools

Dermoscopy, a noninvasive tool that creates a microscopic visualization of lesions, is commonly used to distinguish dermatologic pathology if the clinical presentation overlaps with a similar lesion, such as a callus, corn, or plantar wart.^1,3 However, there is another way of differentiating plantar warts from calluses using a simple 2-step clinical maneuver that we learned from Dr. Lewis Kaplan at the University of Miami.

Using the thumb or index finger, apply pressure at a perpendicular angle to the lesion on the sole of the patient’s foot, which will not create substantial discomfort or pain in a patient who has a plantar wart (Figure) but will be painful in a patient who has a callus due to the underlying bony spur. The next step involves applying pressure to the left and right sides of the lesion by squeezing toward the center with the thumb and index finger at a 45° angle. This maneuver will create substantial discomfort and pain in patients with plantar warts, thus helping to confirm the diagnosis.

A plantar wart before (A) and after undergoing the squeeze maneuver (B). The patient denied feelings of discomfort or pain.

Practice Implications

Rarely, a plantar wart can progress to form a verrucous carcinoma if left untreated.² Thus, it is important to diagnose and treat plantar warts to avoid pain and potential complications. The technique discussed here, which we are coining as the “squeeze maneuver,” allows for easy diagnosis and negates the need for an expensive diagnostic tool.To submit a clinical pearl, contact our Editorial Office.

Practice Gap

Warts may negatively impact a patient's quality of life, as they may cause not only discomfort and pain but also embarrassment and low self-esteem.¹ Moreover, Ciconte et al¹ demonstrated that study participants with warts on their feet were more likely to report physical discomfort than those with warts on their hands. Therefore, plantar warts should be diagnosed promptly to allow for proper treatment.

Warts may be identified by viewing the dilated capillaries that lie on their surface, which appear as small black dots to the naked eye.¹ The formation of a plantar wart obliterates the normal plantar creases, thereby flattening the skin’s natural markings. However, a plantar wart may appear clinically similar to a callus and both lesions typically form in pressure point areas, warranting the use of a tool that aids in its diagnostic evaluation.^1,2

Diagnostic Tools

Dermoscopy, a noninvasive tool that creates a microscopic visualization of lesions, is commonly used to distinguish dermatologic pathology if the clinical presentation overlaps with a similar lesion, such as a callus, corn, or plantar wart.^1,3 However, there is another way of differentiating plantar warts from calluses using a simple 2-step clinical maneuver that we learned from Dr. Lewis Kaplan at the University of Miami.

Using the thumb or index finger, apply pressure at a perpendicular angle to the lesion on the sole of the patient’s foot, which will not create substantial discomfort or pain in a patient who has a plantar wart (Figure) but will be painful in a patient who has a callus due to the underlying bony spur. The next step involves applying pressure to the left and right sides of the lesion by squeezing toward the center with the thumb and index finger at a 45° angle. This maneuver will create substantial discomfort and pain in patients with plantar warts, thus helping to confirm the diagnosis.

A plantar wart before (A) and after undergoing the squeeze maneuver (B). The patient denied feelings of discomfort or pain.

Practice Implications

Rarely, a plantar wart can progress to form a verrucous carcinoma if left untreated.² Thus, it is important to diagnose and treat plantar warts to avoid pain and potential complications. The technique discussed here, which we are coining as the “squeeze maneuver,” allows for easy diagnosis and negates the need for an expensive diagnostic tool.To submit a clinical pearl, contact our Editorial Office.

Porokeratosis of Mibelli (PM) is a lesion characterized by a surrounding cornoid lamella with variable nonspecific findings (eg, atrophy, acanthosis, verrucous hyperplasia) in the center of the lesion that typically presents in infancy to early childhood.¹ We report a case of PM in which a prior biopsy from the center of the lesion demonstrated papulosquamous dermatitis. We propose a 3-step technique to ensure proper orientation of a punch biopsy in cases of suspected PM.

Case Report

A 3-year-old girl presented with an erythematous, hypopigmented, scaling plaque on the posterior aspect of the left ankle surrounded by a hard rim. The plaque was first noted at 12 months of age and had slowly enlarged as the patient grew. Six months prior, a biopsy from the center of the lesion performed at another facility demonstrated a papulosquamous dermatitis.

Physical examination revealed a lesion that was 4.2-cm long, 2.2-cm wide at the superior pole, and 3.5-cm wide at the inferior pole (Figure 1). A line was drawn with a skin marker perpendicular to the rim of the lesion (Figure 2A) and a 6-mm punch biopsy was performed, centered at the intersection of the drawn line and the cornoid lamella (Figure 2B). The tissue was then bisected at the bedside along the skin marker line with a #15 blade (Figure 2C) and submitted in formalin for histologic processing. Histologic examination revealed an invagination of the epidermis producing a tier of parakeratotic cells with its apex pointed away from the center of the lesion. Dyskeratotic cells were noted at the base of the parakeratosis (Figure 3). Verrucous hyperplasia was present in the central portion of the specimen adjacent to the cornoid lamella. Based on these histopathologic findings, the correct diagnosis of PM was made.

Comment

Porokeratosis of Mibelli is a rare condition that typically presents in infancy to early childhood.¹ It may appear as small keratotic papules or larger plaques that reach several centimeters in diameter.² There is a 7.5% risk for malignant transformation (eg, basal cell carcinoma, squamous cell carcinoma, Bowen disease).³ Variable nonspecific findings (eg, atrophy, acanthosis, verrucous hyperplasia) typically are present in the center of the lesion. In our case, a biopsy from the center of the plaque demonstrated verrucous hyperplasia. The incorrect diagnosis of PM as psoriasis also has been reported.⁴

We propose a 3-step technique to ensure proper orientation of a punch biopsy in cases of suspected PM. First, draw a line perpendicular to the rim of the lesion to mark the biopsy site (Figure 2A). Second, perform a punch biopsy centered at the intersection of the drawn line and the cornoid lamella (Figure 2B). Third, section the biopsied tissue with a #15 blade along the perpendicular line at the bedside (Figure 2C). The surgical pathology requisition should mention that the specimen has been transected and the cut edges should be placed down in the cassette, ensuring that the cornoid lamella will be present in cross-section on the slides.

If the punch biopsy specimen is not bisected, it can be difficult to orient it in the pathology laboratory, especially if the cornoid lamellae are not prominent. Furthermore, the technician processing the tissue may not be aware of the importance of sectioning the specimen perpendicular to the cornoid lamella. Following this procedure, diagnosis can be confirmed in virtually every case of PM.

Porokeratosis of Mibelli (PM) is a lesion characterized by a surrounding cornoid lamella with variable nonspecific findings (eg, atrophy, acanthosis, verrucous hyperplasia) in the center of the lesion that typically presents in infancy to early childhood.¹ We report a case of PM in which a prior biopsy from the center of the lesion demonstrated papulosquamous dermatitis. We propose a 3-step technique to ensure proper orientation of a punch biopsy in cases of suspected PM.

Case Report

A 3-year-old girl presented with an erythematous, hypopigmented, scaling plaque on the posterior aspect of the left ankle surrounded by a hard rim. The plaque was first noted at 12 months of age and had slowly enlarged as the patient grew. Six months prior, a biopsy from the center of the lesion performed at another facility demonstrated a papulosquamous dermatitis.

Physical examination revealed a lesion that was 4.2-cm long, 2.2-cm wide at the superior pole, and 3.5-cm wide at the inferior pole (Figure 1). A line was drawn with a skin marker perpendicular to the rim of the lesion (Figure 2A) and a 6-mm punch biopsy was performed, centered at the intersection of the drawn line and the cornoid lamella (Figure 2B). The tissue was then bisected at the bedside along the skin marker line with a #15 blade (Figure 2C) and submitted in formalin for histologic processing. Histologic examination revealed an invagination of the epidermis producing a tier of parakeratotic cells with its apex pointed away from the center of the lesion. Dyskeratotic cells were noted at the base of the parakeratosis (Figure 3). Verrucous hyperplasia was present in the central portion of the specimen adjacent to the cornoid lamella. Based on these histopathologic findings, the correct diagnosis of PM was made.

Comment

Porokeratosis of Mibelli is a rare condition that typically presents in infancy to early childhood.¹ It may appear as small keratotic papules or larger plaques that reach several centimeters in diameter.² There is a 7.5% risk for malignant transformation (eg, basal cell carcinoma, squamous cell carcinoma, Bowen disease).³ Variable nonspecific findings (eg, atrophy, acanthosis, verrucous hyperplasia) typically are present in the center of the lesion. In our case, a biopsy from the center of the plaque demonstrated verrucous hyperplasia. The incorrect diagnosis of PM as psoriasis also has been reported.⁴

We propose a 3-step technique to ensure proper orientation of a punch biopsy in cases of suspected PM. First, draw a line perpendicular to the rim of the lesion to mark the biopsy site (Figure 2A). Second, perform a punch biopsy centered at the intersection of the drawn line and the cornoid lamella (Figure 2B). Third, section the biopsied tissue with a #15 blade along the perpendicular line at the bedside (Figure 2C). The surgical pathology requisition should mention that the specimen has been transected and the cut edges should be placed down in the cassette, ensuring that the cornoid lamella will be present in cross-section on the slides.

If the punch biopsy specimen is not bisected, it can be difficult to orient it in the pathology laboratory, especially if the cornoid lamellae are not prominent. Furthermore, the technician processing the tissue may not be aware of the importance of sectioning the specimen perpendicular to the cornoid lamella. Following this procedure, diagnosis can be confirmed in virtually every case of PM.

Porokeratosis of Mibelli (PM) is a lesion characterized by a surrounding cornoid lamella with variable nonspecific findings (eg, atrophy, acanthosis, verrucous hyperplasia) in the center of the lesion that typically presents in infancy to early childhood.¹ We report a case of PM in which a prior biopsy from the center of the lesion demonstrated papulosquamous dermatitis. We propose a 3-step technique to ensure proper orientation of a punch biopsy in cases of suspected PM.

Case Report

A 3-year-old girl presented with an erythematous, hypopigmented, scaling plaque on the posterior aspect of the left ankle surrounded by a hard rim. The plaque was first noted at 12 months of age and had slowly enlarged as the patient grew. Six months prior, a biopsy from the center of the lesion performed at another facility demonstrated a papulosquamous dermatitis.

Physical examination revealed a lesion that was 4.2-cm long, 2.2-cm wide at the superior pole, and 3.5-cm wide at the inferior pole (Figure 1). A line was drawn with a skin marker perpendicular to the rim of the lesion (Figure 2A) and a 6-mm punch biopsy was performed, centered at the intersection of the drawn line and the cornoid lamella (Figure 2B). The tissue was then bisected at the bedside along the skin marker line with a #15 blade (Figure 2C) and submitted in formalin for histologic processing. Histologic examination revealed an invagination of the epidermis producing a tier of parakeratotic cells with its apex pointed away from the center of the lesion. Dyskeratotic cells were noted at the base of the parakeratosis (Figure 3). Verrucous hyperplasia was present in the central portion of the specimen adjacent to the cornoid lamella. Based on these histopathologic findings, the correct diagnosis of PM was made.

Comment

Porokeratosis of Mibelli is a rare condition that typically presents in infancy to early childhood.¹ It may appear as small keratotic papules or larger plaques that reach several centimeters in diameter.² There is a 7.5% risk for malignant transformation (eg, basal cell carcinoma, squamous cell carcinoma, Bowen disease).³ Variable nonspecific findings (eg, atrophy, acanthosis, verrucous hyperplasia) typically are present in the center of the lesion. In our case, a biopsy from the center of the plaque demonstrated verrucous hyperplasia. The incorrect diagnosis of PM as psoriasis also has been reported.⁴

We propose a 3-step technique to ensure proper orientation of a punch biopsy in cases of suspected PM. First, draw a line perpendicular to the rim of the lesion to mark the biopsy site (Figure 2A). Second, perform a punch biopsy centered at the intersection of the drawn line and the cornoid lamella (Figure 2B). Third, section the biopsied tissue with a #15 blade along the perpendicular line at the bedside (Figure 2C). The surgical pathology requisition should mention that the specimen has been transected and the cut edges should be placed down in the cassette, ensuring that the cornoid lamella will be present in cross-section on the slides.

If the punch biopsy specimen is not bisected, it can be difficult to orient it in the pathology laboratory, especially if the cornoid lamellae are not prominent. Furthermore, the technician processing the tissue may not be aware of the importance of sectioning the specimen perpendicular to the cornoid lamella. Following this procedure, diagnosis can be confirmed in virtually every case of PM.

The best diagnosis is:

a. granular cell tumor
b. intradermal nevus
c. Langerhans cell disease
d. mastocytosis
e. multicentric reticulohistiocytosis

Monomorphic cell infiltrate in the upper dermis (H&E, original magnification ×100).

A closer view reveals cuboidal or spindle cells with basal hyperpigmentation (H&E, original magnification ×200).

Continue to the next page for the diagnosis >>

Mastocytosis

Mastocytosis is a clonal proliferation of mast cells in the skin and various systems of the body including the bone marrow, liver, lymph nodes, and gastrointestinal tract.^1,2 Mast cell proliferation is closely associated with germline and acquired activating KIT mutations.^3-5 Adult-onset mastocytosis is likely to involve several organs, whereas pediatric mastocytosis usually affects only the skin and is self-limiting. Patients with profound mast cell infiltration in the skin or other organs are likely to have attacks of flushing, palpitation, or diarrhea resulting from the degranulation of mast cells and release of histamine.^6,7 In a majority of patients with advanced systemic mastocytosis, mast cells are positive for the Ki-1 antigen (CD30), whereas in most patients with indolent systemic mastocytosis, only a few mast cells are positive for CD30.⁸ Recently, CD30 was reported as a new drug target in patients with CD30⁺ advanced systemic mastocytosis.⁹ Because the skin frequently is involved and easily accessible in comparison with other organs, skin biopsy often is performed to establish a diagnosis of mastocytosis. Cutaneous mastocytosis comprises urticaria pigmentosa, solitary mastocytoma, diffuse cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans; approximately 80% of all cases have urticaria pigmentosa.^10-12 In cutaneous mastocytosis, skin biopsy typically shows monomorphous mast cell infiltrate mostly in the upper third of the dermis. The density of mast cells varies according to the clinical variant. For example, a lesion of telangiectasia macularis eruptiva perstans has only a perivascular mast cell infiltrate, whereas a solitary mastocytoma has sheets of mast cells in the dermis, sometimes extending into the subcutis. A skin biopsy of the brown macule on the waist showed a number of cuboidal or spindle mast cells in the upper dermis with occasional eosinophils. These mast cells are monomorphous, and no mitotic figures, necrotic cells, or atypical cells are seen. Mast cells have metachromatic granules in the cytoplasm, which can be seen with toluidine blue or Giemsa stain. CD117 (c-kit) also is positive. Mast cells in urticaria pigmentosa easily may be mistaken for nevus cells. Hyperpigmentation of the basal layer, a characteristic feature seen in urticaria pigmentosa, also may erroneously suggest a diagnosis of a melanocytic nevus.

Granular cell tumors predominantly affect the oral cavity, but the skin also can be involved. It comprises a fascicular infiltrate of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (Figure 1).¹³ Cell membranes are not always distinct. Although the nuclei usually are small and centrally located, irregular and plump nuclei with distinct nucleoli also may be seen. The overlying epidermis tends to be hyperplastic. Granular cell tumor is considered a group of lesions of varying histogenesis. Cases in which tumors originated from a neural crest–derived peripheral nerve–related cell as well as a Schwann cell have been reported.^14,15 The origin of granular cell tumors is controversial.

Figure 1. Granular cell tumor showing fascicles of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (H&E, original magnification ×200).

Figure 2. Intradermal nevus showing nests with melanin in the uppermost area of the lesion and neurotized nevus cells in the lower part (H&E, original magnification ×100). Pseudovascular spaces are seen on the right side.

Intradermal nevus usually has nests and cords of nevus cells in the upper dermis. The uppermost melanocytes often contain a moderate amount of melanin, whereas nevus cells in the mid and lower dermis usually do not contain melanin (Figure 2). Shrinkage during tissue processing maycause clefts between nevus cells, resulting in pseudovascular spaces.¹⁶ The deeper dermis may have a neuroid appearance with spindle-shaped cells and Meissner corpuscle–like structures.¹⁷

Although Langerhans cell disease was formerly known as Langerhans cell histiocytosis and subdivided into several clinical subtypes, including Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma, these clinical subtypes commonly overlapped. Langerhans cell disease is now used as a terminology that encompasses all subtypes.^18,19 Langerhans cell disease is characterized by a proliferation of Langerhans cells with a variable mixture of other inflammatory cells. The constituent cells are large and ovoid with a distinct folded or lobulated, often kidney-shaped nucleus.²⁰ Langerhans cells usually infiltrate the upper dermis and occasionally the epidermis (Figure 3). CD1a, HLA-DR, S-100 protein, and langerin are positive in Langerhans cells.²¹

Figure 3. Langerhans cell disease showing an infiltrate of large and ovoid Langerhans cells with a distinct folded or lobulated, often kidney-shaped nucleus in the upper dermis and epidermis (H&E, original magnification ×200).

Figure 4. Multicentric reticulohistiocytosis showing a mixture of mononuclear and multinucleate histiocytes with abundant eosinophilic and finely granular cytoplasm (H&E, original magnification ×200).

Multicentric reticulohistiocytosis is characterized by a combination of papulonodular cutaneous lesions and severe arthropathy.²² An irregular mixture of mononuclear and multinucleate histiocytes showing abundant eosinophilic and finely granular cytoplasm, often with a ground-glass appearance, is seen along with lymphocytic infiltration (Figure 4).²³ A few giant cells may be seen in early lesions; older lesions more commonly have giant cells and fibrosis.

The best diagnosis is:

a. granular cell tumor
b. intradermal nevus
c. Langerhans cell disease
d. mastocytosis
e. multicentric reticulohistiocytosis

Monomorphic cell infiltrate in the upper dermis (H&E, original magnification ×100).

A closer view reveals cuboidal or spindle cells with basal hyperpigmentation (H&E, original magnification ×200).

Continue to the next page for the diagnosis >>

Mastocytosis

Mastocytosis is a clonal proliferation of mast cells in the skin and various systems of the body including the bone marrow, liver, lymph nodes, and gastrointestinal tract.^1,2 Mast cell proliferation is closely associated with germline and acquired activating KIT mutations.^3-5 Adult-onset mastocytosis is likely to involve several organs, whereas pediatric mastocytosis usually affects only the skin and is self-limiting. Patients with profound mast cell infiltration in the skin or other organs are likely to have attacks of flushing, palpitation, or diarrhea resulting from the degranulation of mast cells and release of histamine.^6,7 In a majority of patients with advanced systemic mastocytosis, mast cells are positive for the Ki-1 antigen (CD30), whereas in most patients with indolent systemic mastocytosis, only a few mast cells are positive for CD30.⁸ Recently, CD30 was reported as a new drug target in patients with CD30⁺ advanced systemic mastocytosis.⁹ Because the skin frequently is involved and easily accessible in comparison with other organs, skin biopsy often is performed to establish a diagnosis of mastocytosis. Cutaneous mastocytosis comprises urticaria pigmentosa, solitary mastocytoma, diffuse cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans; approximately 80% of all cases have urticaria pigmentosa.^10-12 In cutaneous mastocytosis, skin biopsy typically shows monomorphous mast cell infiltrate mostly in the upper third of the dermis. The density of mast cells varies according to the clinical variant. For example, a lesion of telangiectasia macularis eruptiva perstans has only a perivascular mast cell infiltrate, whereas a solitary mastocytoma has sheets of mast cells in the dermis, sometimes extending into the subcutis. A skin biopsy of the brown macule on the waist showed a number of cuboidal or spindle mast cells in the upper dermis with occasional eosinophils. These mast cells are monomorphous, and no mitotic figures, necrotic cells, or atypical cells are seen. Mast cells have metachromatic granules in the cytoplasm, which can be seen with toluidine blue or Giemsa stain. CD117 (c-kit) also is positive. Mast cells in urticaria pigmentosa easily may be mistaken for nevus cells. Hyperpigmentation of the basal layer, a characteristic feature seen in urticaria pigmentosa, also may erroneously suggest a diagnosis of a melanocytic nevus.

Granular cell tumors predominantly affect the oral cavity, but the skin also can be involved. It comprises a fascicular infiltrate of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (Figure 1).¹³ Cell membranes are not always distinct. Although the nuclei usually are small and centrally located, irregular and plump nuclei with distinct nucleoli also may be seen. The overlying epidermis tends to be hyperplastic. Granular cell tumor is considered a group of lesions of varying histogenesis. Cases in which tumors originated from a neural crest–derived peripheral nerve–related cell as well as a Schwann cell have been reported.^14,15 The origin of granular cell tumors is controversial.

Figure 1. Granular cell tumor showing fascicles of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (H&E, original magnification ×200).

Figure 2. Intradermal nevus showing nests with melanin in the uppermost area of the lesion and neurotized nevus cells in the lower part (H&E, original magnification ×100). Pseudovascular spaces are seen on the right side.

Intradermal nevus usually has nests and cords of nevus cells in the upper dermis. The uppermost melanocytes often contain a moderate amount of melanin, whereas nevus cells in the mid and lower dermis usually do not contain melanin (Figure 2). Shrinkage during tissue processing maycause clefts between nevus cells, resulting in pseudovascular spaces.¹⁶ The deeper dermis may have a neuroid appearance with spindle-shaped cells and Meissner corpuscle–like structures.¹⁷

Although Langerhans cell disease was formerly known as Langerhans cell histiocytosis and subdivided into several clinical subtypes, including Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma, these clinical subtypes commonly overlapped. Langerhans cell disease is now used as a terminology that encompasses all subtypes.^18,19 Langerhans cell disease is characterized by a proliferation of Langerhans cells with a variable mixture of other inflammatory cells. The constituent cells are large and ovoid with a distinct folded or lobulated, often kidney-shaped nucleus.²⁰ Langerhans cells usually infiltrate the upper dermis and occasionally the epidermis (Figure 3). CD1a, HLA-DR, S-100 protein, and langerin are positive in Langerhans cells.²¹

Figure 3. Langerhans cell disease showing an infiltrate of large and ovoid Langerhans cells with a distinct folded or lobulated, often kidney-shaped nucleus in the upper dermis and epidermis (H&E, original magnification ×200).

Figure 4. Multicentric reticulohistiocytosis showing a mixture of mononuclear and multinucleate histiocytes with abundant eosinophilic and finely granular cytoplasm (H&E, original magnification ×200).

Multicentric reticulohistiocytosis is characterized by a combination of papulonodular cutaneous lesions and severe arthropathy.²² An irregular mixture of mononuclear and multinucleate histiocytes showing abundant eosinophilic and finely granular cytoplasm, often with a ground-glass appearance, is seen along with lymphocytic infiltration (Figure 4).²³ A few giant cells may be seen in early lesions; older lesions more commonly have giant cells and fibrosis.

The best diagnosis is:

a. granular cell tumor
b. intradermal nevus
c. Langerhans cell disease
d. mastocytosis
e. multicentric reticulohistiocytosis

Monomorphic cell infiltrate in the upper dermis (H&E, original magnification ×100).

A closer view reveals cuboidal or spindle cells with basal hyperpigmentation (H&E, original magnification ×200).

Continue to the next page for the diagnosis >>

Mastocytosis

Mastocytosis is a clonal proliferation of mast cells in the skin and various systems of the body including the bone marrow, liver, lymph nodes, and gastrointestinal tract.^1,2 Mast cell proliferation is closely associated with germline and acquired activating KIT mutations.^3-5 Adult-onset mastocytosis is likely to involve several organs, whereas pediatric mastocytosis usually affects only the skin and is self-limiting. Patients with profound mast cell infiltration in the skin or other organs are likely to have attacks of flushing, palpitation, or diarrhea resulting from the degranulation of mast cells and release of histamine.^6,7 In a majority of patients with advanced systemic mastocytosis, mast cells are positive for the Ki-1 antigen (CD30), whereas in most patients with indolent systemic mastocytosis, only a few mast cells are positive for CD30.⁸ Recently, CD30 was reported as a new drug target in patients with CD30⁺ advanced systemic mastocytosis.⁹ Because the skin frequently is involved and easily accessible in comparison with other organs, skin biopsy often is performed to establish a diagnosis of mastocytosis. Cutaneous mastocytosis comprises urticaria pigmentosa, solitary mastocytoma, diffuse cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans; approximately 80% of all cases have urticaria pigmentosa.^10-12 In cutaneous mastocytosis, skin biopsy typically shows monomorphous mast cell infiltrate mostly in the upper third of the dermis. The density of mast cells varies according to the clinical variant. For example, a lesion of telangiectasia macularis eruptiva perstans has only a perivascular mast cell infiltrate, whereas a solitary mastocytoma has sheets of mast cells in the dermis, sometimes extending into the subcutis. A skin biopsy of the brown macule on the waist showed a number of cuboidal or spindle mast cells in the upper dermis with occasional eosinophils. These mast cells are monomorphous, and no mitotic figures, necrotic cells, or atypical cells are seen. Mast cells have metachromatic granules in the cytoplasm, which can be seen with toluidine blue or Giemsa stain. CD117 (c-kit) also is positive. Mast cells in urticaria pigmentosa easily may be mistaken for nevus cells. Hyperpigmentation of the basal layer, a characteristic feature seen in urticaria pigmentosa, also may erroneously suggest a diagnosis of a melanocytic nevus.

Granular cell tumors predominantly affect the oral cavity, but the skin also can be involved. It comprises a fascicular infiltrate of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (Figure 1).¹³ Cell membranes are not always distinct. Although the nuclei usually are small and centrally located, irregular and plump nuclei with distinct nucleoli also may be seen. The overlying epidermis tends to be hyperplastic. Granular cell tumor is considered a group of lesions of varying histogenesis. Cases in which tumors originated from a neural crest–derived peripheral nerve–related cell as well as a Schwann cell have been reported.^14,15 The origin of granular cell tumors is controversial.

Figure 1. Granular cell tumor showing fascicles of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (H&E, original magnification ×200).

Figure 2. Intradermal nevus showing nests with melanin in the uppermost area of the lesion and neurotized nevus cells in the lower part (H&E, original magnification ×100). Pseudovascular spaces are seen on the right side.

Intradermal nevus usually has nests and cords of nevus cells in the upper dermis. The uppermost melanocytes often contain a moderate amount of melanin, whereas nevus cells in the mid and lower dermis usually do not contain melanin (Figure 2). Shrinkage during tissue processing maycause clefts between nevus cells, resulting in pseudovascular spaces.¹⁶ The deeper dermis may have a neuroid appearance with spindle-shaped cells and Meissner corpuscle–like structures.¹⁷

Although Langerhans cell disease was formerly known as Langerhans cell histiocytosis and subdivided into several clinical subtypes, including Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma, these clinical subtypes commonly overlapped. Langerhans cell disease is now used as a terminology that encompasses all subtypes.^18,19 Langerhans cell disease is characterized by a proliferation of Langerhans cells with a variable mixture of other inflammatory cells. The constituent cells are large and ovoid with a distinct folded or lobulated, often kidney-shaped nucleus.²⁰ Langerhans cells usually infiltrate the upper dermis and occasionally the epidermis (Figure 3). CD1a, HLA-DR, S-100 protein, and langerin are positive in Langerhans cells.²¹

Figure 3. Langerhans cell disease showing an infiltrate of large and ovoid Langerhans cells with a distinct folded or lobulated, often kidney-shaped nucleus in the upper dermis and epidermis (H&E, original magnification ×200).

Figure 4. Multicentric reticulohistiocytosis showing a mixture of mononuclear and multinucleate histiocytes with abundant eosinophilic and finely granular cytoplasm (H&E, original magnification ×200).

Multicentric reticulohistiocytosis is characterized by a combination of papulonodular cutaneous lesions and severe arthropathy.²² An irregular mixture of mononuclear and multinucleate histiocytes showing abundant eosinophilic and finely granular cytoplasm, often with a ground-glass appearance, is seen along with lymphocytic infiltration (Figure 4).²³ A few giant cells may be seen in early lesions; older lesions more commonly have giant cells and fibrosis.

The Diagnosis: Bilateral Auricular Tophaceous Gout

Histopathologic evaluation with hematoxylin and eosin staining demonstrated clusters of abundant granular amorphous material within the subcutaneous tissue (Figure 1). The overlying epidermis and dermis were unremarkable. The granular amorphous material demonstrated numerous monosodium urate crystals under polarized light (Figure 2). At a return visit following the biopsy results, the patient reported a history of a single episode of monoarticular gouty arthritis involving the right hallux approximately 6 months after the onset of the skin lesions. With the added clinical history and the biopsy results, his serum uric acid level was obtained and was found to be elevated at 9.2 mg/dL (reference range, 3.5–8 mg/dL).

In our patient, the clinical differential diagnosis included calcium deposits, weathering nodules, and tophaceous gout. The differential diagnosis of auricular lesions is broad, and benign lesions may mimic cancerous entities such as basal cell carcinoma and squamous cell carcinoma.¹ Therefore a detailed history, thorough physical examination, and tissue sampling are key to establishing the correct diagnosis. Our patient’s history of monoarticular gouty arthritis was only elucidated after a diagnosis of bilateral auricular tophaceous gout was made based on the biopsy results.

Subcutaneous tophi represent a chronic state of hyperuricemia and tend to manifest after long-standing polyarthritis and repeated acute gout attacks.^2-5 These lesions develop in approximately 50% of gout patients and usually occur an average of 11.6 years after the onset of disease.² There is a subset of individuals that are at higher risk for developing tophi, including elderly and female patients, diuretic and chronic nonsteroidal anti-inflammatory drug users, patients with a history of cyclosporine therapy, and patients with underlying chronic renal insufficiency.^2,6,7 The most commonly affected tissues are those with poor blood supply and lower temperatures, such as the ear helix and first metacarpal joint.⁴ The auricle is the most common site of tophi on the head and neck. Tophi of the helices are generally asymptomatic and nontender; however, tophi can become large, inflamed, and ulcerated, causing pressure and discomfort.² Combination treatment with dietary modification and antihyperuricemic therapy (eg, allopurinol) has been shown to reduce the size of lesions and prevent future tophi formation. However, these results may take months, warranting excision of large and symptomatic lesions.^4,8

Our case is unusual in that the onset of the auricular lesions predated the articular gout by 6 months. Gouty tophi as the initial presentation of hyperuricemia is rare; however, tophi formation without concomitant arthritis has been reported.^2,3,7,9 Wernick et al⁷ described 6 patients presenting with tophi before the onset of inflammatory arthritis that they attributed to changes in active inflammation by age (eg, elderly patients were more commonly immunosuppressed), chronic illnesses, and anti-inflammatory medications (eg, nonsteroidal anti-inflammatory drugs). Another possible explanation for this atypical presentation is misdiagnosis caused by other forms of arthritis (eg, rheumatoid arthritis, osteoarthritis) masking acute gout episodes. It also has been reported that monosodium urate crystals can be found in synovial fluid with no inflammation and therefore no symptoms.⁷

Tophi, although rare, may be the sole clinical manifestation of underlying gouty disease. It is important to be aware of this atypical presentation to prevent misdiagnosis and provide appropriate treatment.

The Diagnosis: Bilateral Auricular Tophaceous Gout

Histopathologic evaluation with hematoxylin and eosin staining demonstrated clusters of abundant granular amorphous material within the subcutaneous tissue (Figure 1). The overlying epidermis and dermis were unremarkable. The granular amorphous material demonstrated numerous monosodium urate crystals under polarized light (Figure 2). At a return visit following the biopsy results, the patient reported a history of a single episode of monoarticular gouty arthritis involving the right hallux approximately 6 months after the onset of the skin lesions. With the added clinical history and the biopsy results, his serum uric acid level was obtained and was found to be elevated at 9.2 mg/dL (reference range, 3.5–8 mg/dL).

In our patient, the clinical differential diagnosis included calcium deposits, weathering nodules, and tophaceous gout. The differential diagnosis of auricular lesions is broad, and benign lesions may mimic cancerous entities such as basal cell carcinoma and squamous cell carcinoma.¹ Therefore a detailed history, thorough physical examination, and tissue sampling are key to establishing the correct diagnosis. Our patient’s history of monoarticular gouty arthritis was only elucidated after a diagnosis of bilateral auricular tophaceous gout was made based on the biopsy results.

Subcutaneous tophi represent a chronic state of hyperuricemia and tend to manifest after long-standing polyarthritis and repeated acute gout attacks.^2-5 These lesions develop in approximately 50% of gout patients and usually occur an average of 11.6 years after the onset of disease.² There is a subset of individuals that are at higher risk for developing tophi, including elderly and female patients, diuretic and chronic nonsteroidal anti-inflammatory drug users, patients with a history of cyclosporine therapy, and patients with underlying chronic renal insufficiency.^2,6,7 The most commonly affected tissues are those with poor blood supply and lower temperatures, such as the ear helix and first metacarpal joint.⁴ The auricle is the most common site of tophi on the head and neck. Tophi of the helices are generally asymptomatic and nontender; however, tophi can become large, inflamed, and ulcerated, causing pressure and discomfort.² Combination treatment with dietary modification and antihyperuricemic therapy (eg, allopurinol) has been shown to reduce the size of lesions and prevent future tophi formation. However, these results may take months, warranting excision of large and symptomatic lesions.^4,8

Our case is unusual in that the onset of the auricular lesions predated the articular gout by 6 months. Gouty tophi as the initial presentation of hyperuricemia is rare; however, tophi formation without concomitant arthritis has been reported.^2,3,7,9 Wernick et al⁷ described 6 patients presenting with tophi before the onset of inflammatory arthritis that they attributed to changes in active inflammation by age (eg, elderly patients were more commonly immunosuppressed), chronic illnesses, and anti-inflammatory medications (eg, nonsteroidal anti-inflammatory drugs). Another possible explanation for this atypical presentation is misdiagnosis caused by other forms of arthritis (eg, rheumatoid arthritis, osteoarthritis) masking acute gout episodes. It also has been reported that monosodium urate crystals can be found in synovial fluid with no inflammation and therefore no symptoms.⁷

Tophi, although rare, may be the sole clinical manifestation of underlying gouty disease. It is important to be aware of this atypical presentation to prevent misdiagnosis and provide appropriate treatment.

The Diagnosis: Bilateral Auricular Tophaceous Gout

Histopathologic evaluation with hematoxylin and eosin staining demonstrated clusters of abundant granular amorphous material within the subcutaneous tissue (Figure 1). The overlying epidermis and dermis were unremarkable. The granular amorphous material demonstrated numerous monosodium urate crystals under polarized light (Figure 2). At a return visit following the biopsy results, the patient reported a history of a single episode of monoarticular gouty arthritis involving the right hallux approximately 6 months after the onset of the skin lesions. With the added clinical history and the biopsy results, his serum uric acid level was obtained and was found to be elevated at 9.2 mg/dL (reference range, 3.5–8 mg/dL).

In our patient, the clinical differential diagnosis included calcium deposits, weathering nodules, and tophaceous gout. The differential diagnosis of auricular lesions is broad, and benign lesions may mimic cancerous entities such as basal cell carcinoma and squamous cell carcinoma.¹ Therefore a detailed history, thorough physical examination, and tissue sampling are key to establishing the correct diagnosis. Our patient’s history of monoarticular gouty arthritis was only elucidated after a diagnosis of bilateral auricular tophaceous gout was made based on the biopsy results.

Subcutaneous tophi represent a chronic state of hyperuricemia and tend to manifest after long-standing polyarthritis and repeated acute gout attacks.^2-5 These lesions develop in approximately 50% of gout patients and usually occur an average of 11.6 years after the onset of disease.² There is a subset of individuals that are at higher risk for developing tophi, including elderly and female patients, diuretic and chronic nonsteroidal anti-inflammatory drug users, patients with a history of cyclosporine therapy, and patients with underlying chronic renal insufficiency.^2,6,7 The most commonly affected tissues are those with poor blood supply and lower temperatures, such as the ear helix and first metacarpal joint.⁴ The auricle is the most common site of tophi on the head and neck. Tophi of the helices are generally asymptomatic and nontender; however, tophi can become large, inflamed, and ulcerated, causing pressure and discomfort.² Combination treatment with dietary modification and antihyperuricemic therapy (eg, allopurinol) has been shown to reduce the size of lesions and prevent future tophi formation. However, these results may take months, warranting excision of large and symptomatic lesions.^4,8

Our case is unusual in that the onset of the auricular lesions predated the articular gout by 6 months. Gouty tophi as the initial presentation of hyperuricemia is rare; however, tophi formation without concomitant arthritis has been reported.^2,3,7,9 Wernick et al⁷ described 6 patients presenting with tophi before the onset of inflammatory arthritis that they attributed to changes in active inflammation by age (eg, elderly patients were more commonly immunosuppressed), chronic illnesses, and anti-inflammatory medications (eg, nonsteroidal anti-inflammatory drugs). Another possible explanation for this atypical presentation is misdiagnosis caused by other forms of arthritis (eg, rheumatoid arthritis, osteoarthritis) masking acute gout episodes. It also has been reported that monosodium urate crystals can be found in synovial fluid with no inflammation and therefore no symptoms.⁷

Tophi, although rare, may be the sole clinical manifestation of underlying gouty disease. It is important to be aware of this atypical presentation to prevent misdiagnosis and provide appropriate treatment.

The Diagnosis: Acquired Acrodermatitis Enteropathica

Acquired acrodermatitis enteropathica (AAE) is a rare disorder caused by severe zinc deficiency. Although acrodermatitis enteropathica is an autosomal-recessive disorder that typically manifests in infancy, AAE also can result from poor zinc intake, impaired absorption, or accelerated losses. There are reports of AAE in patients with zinc-deficient diets,¹ eating disorders,² bariatric and other gastrointestinal surgeries,³ malabsorptive diseases,⁴ and nephrotic syndrome.⁵

Zinc plays an important role in DNA and RNA synthesis, reactive oxygen species attenuation, and energy metabolism, allowing for proper wound healing, skin differentiation, and proliferation.⁶ Zinc is found in most foods, but animal protein contains higher concentrations (Table).⁷ Approximately 85% of zinc is stored in muscles and bones, with only a small amount of accessible zinc available in the liver. Liver stores can be depleted as quickly as 1 week.⁸ Total parenteral nutrition without trace element supplementation can quickly predispose patients to AAE.

Diagnosis of this condition requires triangulation of clinical presentation, histopathology examination, and laboratory findings. Acrodermatitis enteropathica typically is characterized by dermatitis, diarrhea, and epidermal appendage findings. In its early stages, the dermatitis often manifests with angular cheilitis and paronychia.⁹ Patients then develop erythema, erosions, and occasionally vesicles or psoriasiform plaques in periorificial, perineal, and acral sites (Figure 1). Epidermal appendage effects include generalized alopecia and thinning nails with white transverse ridges. Although dermatologic and gastrointestinal manifestations are the most obvious, severe AAE may cause other symptoms, including mental slowing, hypogonadism, and impaired immune function.⁹

Histopathology of AAE skin lesions is similar to other nutritional deficiencies. Early changes are more specific to deficiency dermatitis and include cytoplasmic pallor and ballooning degeneration of keratinocytes in the stratum spinosum and granulosum.⁹ Necrolysis results in confluent keratinocyte necrosis developing into subcorneal bulla. Later in the disease course, the presentation becomes psoriasiform with keratinocyte dyskeratosis and confluent parakeratosis¹⁰ (Figure 2). Dermal edema with dilated tortuous vessels and a neutrophilic infiltrate may be present throughout disease progression.

Common laboratory abnormalities used to confirm zinc deficiency are decreased plasma zinc and alkaline phosphatase levels. Plasma zinc levels should be drawn after fasting because zinc levels decrease after food intake.⁹ Concurrent albumin levels should be drawn to correct for low levels caused by hypoalbuminemia. Acquired acrodermatitis enteropathica has been seen in patients with only mildly decreased plasma zinc levels or even zinc levels within reference range.¹¹ Alkaline phosphatase metalloenzyme synthesis requires zinc and a decreased level suggests zinc deficiency even with a plasma zinc level within reference range. Alkaline phosphatase levels usually can be ascertained in a matter of hours, while the zinc levels take much longer to result.

Acquired acrodermatitis enteropathica is treated with oral elemental zinc supplementation at 1 to 2 mg/kg daily.¹² Diarrhea typically resolves within 24 hours, but skin lesions heal in 1 to 2 weeks or longer. Although there is no consensus on when to discontinue zinc replacement therapy, therapy generally is not lifelong. Once the patient is zinc replete and the inciting factor has resolved, patients can discontinue supplementation without risk for recurrence.

Trace elements had not been added to our patient’s total parenteral nutrition prior to admission. Basic nutrition laboratory results and zinc levels returned markedly low: 14 μg/dL (reference range, 60–120 μg/dL). Alkaline phosphatase, a zinc-dependent protein, also was low at 12 U/L (reference range, 40–150 U/L). We added trace elements and vitamins and began empiric zinc replacement with 440 mg oral zinc sulfate daily (100 mg elemental zinc). Cephalexin was prescribed for impetiginized skin lesions. The patient noted skin improvement after 3 days on zinc replacement therapy.

The Diagnosis: Acquired Acrodermatitis Enteropathica

Acquired acrodermatitis enteropathica (AAE) is a rare disorder caused by severe zinc deficiency. Although acrodermatitis enteropathica is an autosomal-recessive disorder that typically manifests in infancy, AAE also can result from poor zinc intake, impaired absorption, or accelerated losses. There are reports of AAE in patients with zinc-deficient diets,¹ eating disorders,² bariatric and other gastrointestinal surgeries,³ malabsorptive diseases,⁴ and nephrotic syndrome.⁵

Zinc plays an important role in DNA and RNA synthesis, reactive oxygen species attenuation, and energy metabolism, allowing for proper wound healing, skin differentiation, and proliferation.⁶ Zinc is found in most foods, but animal protein contains higher concentrations (Table).⁷ Approximately 85% of zinc is stored in muscles and bones, with only a small amount of accessible zinc available in the liver. Liver stores can be depleted as quickly as 1 week.⁸ Total parenteral nutrition without trace element supplementation can quickly predispose patients to AAE.

Diagnosis of this condition requires triangulation of clinical presentation, histopathology examination, and laboratory findings. Acrodermatitis enteropathica typically is characterized by dermatitis, diarrhea, and epidermal appendage findings. In its early stages, the dermatitis often manifests with angular cheilitis and paronychia.⁹ Patients then develop erythema, erosions, and occasionally vesicles or psoriasiform plaques in periorificial, perineal, and acral sites (Figure 1). Epidermal appendage effects include generalized alopecia and thinning nails with white transverse ridges. Although dermatologic and gastrointestinal manifestations are the most obvious, severe AAE may cause other symptoms, including mental slowing, hypogonadism, and impaired immune function.⁹

Histopathology of AAE skin lesions is similar to other nutritional deficiencies. Early changes are more specific to deficiency dermatitis and include cytoplasmic pallor and ballooning degeneration of keratinocytes in the stratum spinosum and granulosum.⁹ Necrolysis results in confluent keratinocyte necrosis developing into subcorneal bulla. Later in the disease course, the presentation becomes psoriasiform with keratinocyte dyskeratosis and confluent parakeratosis¹⁰ (Figure 2). Dermal edema with dilated tortuous vessels and a neutrophilic infiltrate may be present throughout disease progression.

Common laboratory abnormalities used to confirm zinc deficiency are decreased plasma zinc and alkaline phosphatase levels. Plasma zinc levels should be drawn after fasting because zinc levels decrease after food intake.⁹ Concurrent albumin levels should be drawn to correct for low levels caused by hypoalbuminemia. Acquired acrodermatitis enteropathica has been seen in patients with only mildly decreased plasma zinc levels or even zinc levels within reference range.¹¹ Alkaline phosphatase metalloenzyme synthesis requires zinc and a decreased level suggests zinc deficiency even with a plasma zinc level within reference range. Alkaline phosphatase levels usually can be ascertained in a matter of hours, while the zinc levels take much longer to result.

Acquired acrodermatitis enteropathica is treated with oral elemental zinc supplementation at 1 to 2 mg/kg daily.¹² Diarrhea typically resolves within 24 hours, but skin lesions heal in 1 to 2 weeks or longer. Although there is no consensus on when to discontinue zinc replacement therapy, therapy generally is not lifelong. Once the patient is zinc replete and the inciting factor has resolved, patients can discontinue supplementation without risk for recurrence.

Trace elements had not been added to our patient’s total parenteral nutrition prior to admission. Basic nutrition laboratory results and zinc levels returned markedly low: 14 μg/dL (reference range, 60–120 μg/dL). Alkaline phosphatase, a zinc-dependent protein, also was low at 12 U/L (reference range, 40–150 U/L). We added trace elements and vitamins and began empiric zinc replacement with 440 mg oral zinc sulfate daily (100 mg elemental zinc). Cephalexin was prescribed for impetiginized skin lesions. The patient noted skin improvement after 3 days on zinc replacement therapy.

The Diagnosis: Acquired Acrodermatitis Enteropathica

Acquired acrodermatitis enteropathica (AAE) is a rare disorder caused by severe zinc deficiency. Although acrodermatitis enteropathica is an autosomal-recessive disorder that typically manifests in infancy, AAE also can result from poor zinc intake, impaired absorption, or accelerated losses. There are reports of AAE in patients with zinc-deficient diets,¹ eating disorders,² bariatric and other gastrointestinal surgeries,³ malabsorptive diseases,⁴ and nephrotic syndrome.⁵

Zinc plays an important role in DNA and RNA synthesis, reactive oxygen species attenuation, and energy metabolism, allowing for proper wound healing, skin differentiation, and proliferation.⁶ Zinc is found in most foods, but animal protein contains higher concentrations (Table).⁷ Approximately 85% of zinc is stored in muscles and bones, with only a small amount of accessible zinc available in the liver. Liver stores can be depleted as quickly as 1 week.⁸ Total parenteral nutrition without trace element supplementation can quickly predispose patients to AAE.

Diagnosis of this condition requires triangulation of clinical presentation, histopathology examination, and laboratory findings. Acrodermatitis enteropathica typically is characterized by dermatitis, diarrhea, and epidermal appendage findings. In its early stages, the dermatitis often manifests with angular cheilitis and paronychia.⁹ Patients then develop erythema, erosions, and occasionally vesicles or psoriasiform plaques in periorificial, perineal, and acral sites (Figure 1). Epidermal appendage effects include generalized alopecia and thinning nails with white transverse ridges. Although dermatologic and gastrointestinal manifestations are the most obvious, severe AAE may cause other symptoms, including mental slowing, hypogonadism, and impaired immune function.⁹

Histopathology of AAE skin lesions is similar to other nutritional deficiencies. Early changes are more specific to deficiency dermatitis and include cytoplasmic pallor and ballooning degeneration of keratinocytes in the stratum spinosum and granulosum.⁹ Necrolysis results in confluent keratinocyte necrosis developing into subcorneal bulla. Later in the disease course, the presentation becomes psoriasiform with keratinocyte dyskeratosis and confluent parakeratosis¹⁰ (Figure 2). Dermal edema with dilated tortuous vessels and a neutrophilic infiltrate may be present throughout disease progression.

Common laboratory abnormalities used to confirm zinc deficiency are decreased plasma zinc and alkaline phosphatase levels. Plasma zinc levels should be drawn after fasting because zinc levels decrease after food intake.⁹ Concurrent albumin levels should be drawn to correct for low levels caused by hypoalbuminemia. Acquired acrodermatitis enteropathica has been seen in patients with only mildly decreased plasma zinc levels or even zinc levels within reference range.¹¹ Alkaline phosphatase metalloenzyme synthesis requires zinc and a decreased level suggests zinc deficiency even with a plasma zinc level within reference range. Alkaline phosphatase levels usually can be ascertained in a matter of hours, while the zinc levels take much longer to result.

Acquired acrodermatitis enteropathica is treated with oral elemental zinc supplementation at 1 to 2 mg/kg daily.¹² Diarrhea typically resolves within 24 hours, but skin lesions heal in 1 to 2 weeks or longer. Although there is no consensus on when to discontinue zinc replacement therapy, therapy generally is not lifelong. Once the patient is zinc replete and the inciting factor has resolved, patients can discontinue supplementation without risk for recurrence.

Trace elements had not been added to our patient’s total parenteral nutrition prior to admission. Basic nutrition laboratory results and zinc levels returned markedly low: 14 μg/dL (reference range, 60–120 μg/dL). Alkaline phosphatase, a zinc-dependent protein, also was low at 12 U/L (reference range, 40–150 U/L). We added trace elements and vitamins and began empiric zinc replacement with 440 mg oral zinc sulfate daily (100 mg elemental zinc). Cephalexin was prescribed for impetiginized skin lesions. The patient noted skin improvement after 3 days on zinc replacement therapy.

Lichen striatus (LS) is a benign, uncommon, self-limited, linear inflammatory skin disorder that primarily affects children up to 15 years of age, most commonly around 2 to 3 years of age, and is seen more frequently in girls.¹ It presents with a sudden eruption of asymptomatic small, flat-topped, lichenoid, scaly papules in a linear array on a single extremity. The lesions may be erythematous, flesh colored, or hypopigmented.^1,2 Multiple lesions appear over days to weeks and coalesce into linear plaques in a continuous or interrupted pattern along the lines of Blaschko, indicating possible somatic mosaicism.¹ Although typically asymptomatic, it may be pruritic. Most cases spontaneously resolve within 1 year.³ Recurrences are unusual. Digital involvement may result in onycholysis, longitudinal ridging, splitting, and nail loss.¹ The underlying cause of LS may be an abnormal immunologic reaction or genetic predisposition that is precipitated by some trigger such as a viral infection, trauma, hypersensitivity reaction, vaccine, seasonal variation, medication, or pregnancy.^1,2 An association with atopy has been described. Treatment is not necessary but options include topical steroids, topical retinoids, and topical calcineurin inhibitors.²

Histologically, findings in LS are somewhat variable but typically show a combination of spongiotic and lichenoid interface dermatitis with a perivascular and periadnexal lymphocytic infiltrate (Figure 1). Epidermal changes include intercellular and intracellular edema, focal spongiosis, lymphocytic exocytosis, parakeratosis, patchy hyperkeratosis, and keratinocyte necrosis (Figure 2A).^1,3 The epidermis is normal or slightly acanthotic, and dyskeratotic keratinocytes can be found in the granular and horny layers or at the dermoepidermal junction.² The lymphohistiocytic infiltrate in the superficial and deep dermis surrounds vascular plexuses and cutaneous adnexa such as eccrine glands and hair follicles.¹ Perivascular lymphoid aggregates and eccrine coil involvement are particularly distinctive of LS (Figure 2B).⁴ Pigment incontinence also may be seen.

Another condition that distributes linearly along the lines of Blaschko is linear epidermolytic hyperkeratosis (EHK). Similar to LS, histology shows hyperkeratosis, focal parakeratosis, and acanthosis of the epidermis.⁵ However, EHK shows epidermolysis, acantholysis, and perinuclear vacuolization in spinous and granular layers (Figure 3).⁵ The lack of perivascular and periadnexal inflammation also can help differentiate EHK from LS.

Linear lichen planus (LLP), similar to LS, histologically shows a lichenoid lymphocytic bandlike infiltrate obscuring the dermoepidermal junction, vacuolization of the basal cell layer, and pigment incontinence.^1,2 Although LS and LLP can have histologic overlap, the absence of adnexal or perieccrine lymphocytic inflammation can help distinguish the two.³ The histopathologic changes of intercellular edema or mild spongiosis, exocytosis, and parakeratosis present in LS also are typically absent in LLP. Linear lichen planus characteristically consists of wedge-shaped hypergranulosis and irregular acanthosis with saw-toothed rete ridges (Figure 4).² In addition, lobular eosinophilic deposits known as cytoid or Civatte bodies representing degenerated keratinocytes can be visualized at the dermoepidermal junction in LLP.² Immunofluorescence will highlight Civatte bodies with IgM, IgG, and C3, also helping to differentiate these 2 conditions.¹

Linear porokeratosis can be mistaken for the linear lesion of LS. Both entities may reveal perivascular lymphocytes in the dermis, and porokeratosis can be lichenoid in the central portion of the lesion.⁶ However, porokeratosis is unique in that it contains a cornoid lamella, characterized by a thin column of tightly packed parakeratotic cells extending from an invagination of the epidermis through the adjacent stratum corneum (Figure 5).⁶ Beneath the cornoid lamella, the granular layer is either absent or markedly attenuated, and pyknotic keratinocytes with perinuclear edema are present in the spinous layer.⁶ The epidermis in the central portion of the porokeratotic lesion may be normal, hyperplastic, or atrophic with effacement of rete ridges.

Similar to LS, linear psoriasis follows lines of Blaschko clinically. However, it is distinguished by its characteristic psoriatic epidermal changes as well as its lack of lichenoid or perieccrine inflammation.³ Typical findings in linear psoriasis include hyperkeratosis, confluent parakeratosis with entrapped neutrophilic microabscesses, acanthosis with regular elongation of rete ridges, intraepidermal neutrophils, thinned suprapapillary plates, dilated capillaries in the tips of the dermal papillae, and a chronic dermal inflammatory infiltrate (Figure 6).⁴

Lichen striatus (LS) is a benign, uncommon, self-limited, linear inflammatory skin disorder that primarily affects children up to 15 years of age, most commonly around 2 to 3 years of age, and is seen more frequently in girls.¹ It presents with a sudden eruption of asymptomatic small, flat-topped, lichenoid, scaly papules in a linear array on a single extremity. The lesions may be erythematous, flesh colored, or hypopigmented.^1,2 Multiple lesions appear over days to weeks and coalesce into linear plaques in a continuous or interrupted pattern along the lines of Blaschko, indicating possible somatic mosaicism.¹ Although typically asymptomatic, it may be pruritic. Most cases spontaneously resolve within 1 year.³ Recurrences are unusual. Digital involvement may result in onycholysis, longitudinal ridging, splitting, and nail loss.¹ The underlying cause of LS may be an abnormal immunologic reaction or genetic predisposition that is precipitated by some trigger such as a viral infection, trauma, hypersensitivity reaction, vaccine, seasonal variation, medication, or pregnancy.^1,2 An association with atopy has been described. Treatment is not necessary but options include topical steroids, topical retinoids, and topical calcineurin inhibitors.²

Histologically, findings in LS are somewhat variable but typically show a combination of spongiotic and lichenoid interface dermatitis with a perivascular and periadnexal lymphocytic infiltrate (Figure 1). Epidermal changes include intercellular and intracellular edema, focal spongiosis, lymphocytic exocytosis, parakeratosis, patchy hyperkeratosis, and keratinocyte necrosis (Figure 2A).^1,3 The epidermis is normal or slightly acanthotic, and dyskeratotic keratinocytes can be found in the granular and horny layers or at the dermoepidermal junction.² The lymphohistiocytic infiltrate in the superficial and deep dermis surrounds vascular plexuses and cutaneous adnexa such as eccrine glands and hair follicles.¹ Perivascular lymphoid aggregates and eccrine coil involvement are particularly distinctive of LS (Figure 2B).⁴ Pigment incontinence also may be seen.

Another condition that distributes linearly along the lines of Blaschko is linear epidermolytic hyperkeratosis (EHK). Similar to LS, histology shows hyperkeratosis, focal parakeratosis, and acanthosis of the epidermis.⁵ However, EHK shows epidermolysis, acantholysis, and perinuclear vacuolization in spinous and granular layers (Figure 3).⁵ The lack of perivascular and periadnexal inflammation also can help differentiate EHK from LS.

Linear lichen planus (LLP), similar to LS, histologically shows a lichenoid lymphocytic bandlike infiltrate obscuring the dermoepidermal junction, vacuolization of the basal cell layer, and pigment incontinence.^1,2 Although LS and LLP can have histologic overlap, the absence of adnexal or perieccrine lymphocytic inflammation can help distinguish the two.³ The histopathologic changes of intercellular edema or mild spongiosis, exocytosis, and parakeratosis present in LS also are typically absent in LLP. Linear lichen planus characteristically consists of wedge-shaped hypergranulosis and irregular acanthosis with saw-toothed rete ridges (Figure 4).² In addition, lobular eosinophilic deposits known as cytoid or Civatte bodies representing degenerated keratinocytes can be visualized at the dermoepidermal junction in LLP.² Immunofluorescence will highlight Civatte bodies with IgM, IgG, and C3, also helping to differentiate these 2 conditions.¹

Linear porokeratosis can be mistaken for the linear lesion of LS. Both entities may reveal perivascular lymphocytes in the dermis, and porokeratosis can be lichenoid in the central portion of the lesion.⁶ However, porokeratosis is unique in that it contains a cornoid lamella, characterized by a thin column of tightly packed parakeratotic cells extending from an invagination of the epidermis through the adjacent stratum corneum (Figure 5).⁶ Beneath the cornoid lamella, the granular layer is either absent or markedly attenuated, and pyknotic keratinocytes with perinuclear edema are present in the spinous layer.⁶ The epidermis in the central portion of the porokeratotic lesion may be normal, hyperplastic, or atrophic with effacement of rete ridges.

Similar to LS, linear psoriasis follows lines of Blaschko clinically. However, it is distinguished by its characteristic psoriatic epidermal changes as well as its lack of lichenoid or perieccrine inflammation.³ Typical findings in linear psoriasis include hyperkeratosis, confluent parakeratosis with entrapped neutrophilic microabscesses, acanthosis with regular elongation of rete ridges, intraepidermal neutrophils, thinned suprapapillary plates, dilated capillaries in the tips of the dermal papillae, and a chronic dermal inflammatory infiltrate (Figure 6).⁴

Lichen striatus (LS) is a benign, uncommon, self-limited, linear inflammatory skin disorder that primarily affects children up to 15 years of age, most commonly around 2 to 3 years of age, and is seen more frequently in girls.¹ It presents with a sudden eruption of asymptomatic small, flat-topped, lichenoid, scaly papules in a linear array on a single extremity. The lesions may be erythematous, flesh colored, or hypopigmented.^1,2 Multiple lesions appear over days to weeks and coalesce into linear plaques in a continuous or interrupted pattern along the lines of Blaschko, indicating possible somatic mosaicism.¹ Although typically asymptomatic, it may be pruritic. Most cases spontaneously resolve within 1 year.³ Recurrences are unusual. Digital involvement may result in onycholysis, longitudinal ridging, splitting, and nail loss.¹ The underlying cause of LS may be an abnormal immunologic reaction or genetic predisposition that is precipitated by some trigger such as a viral infection, trauma, hypersensitivity reaction, vaccine, seasonal variation, medication, or pregnancy.^1,2 An association with atopy has been described. Treatment is not necessary but options include topical steroids, topical retinoids, and topical calcineurin inhibitors.²

Histologically, findings in LS are somewhat variable but typically show a combination of spongiotic and lichenoid interface dermatitis with a perivascular and periadnexal lymphocytic infiltrate (Figure 1). Epidermal changes include intercellular and intracellular edema, focal spongiosis, lymphocytic exocytosis, parakeratosis, patchy hyperkeratosis, and keratinocyte necrosis (Figure 2A).^1,3 The epidermis is normal or slightly acanthotic, and dyskeratotic keratinocytes can be found in the granular and horny layers or at the dermoepidermal junction.² The lymphohistiocytic infiltrate in the superficial and deep dermis surrounds vascular plexuses and cutaneous adnexa such as eccrine glands and hair follicles.¹ Perivascular lymphoid aggregates and eccrine coil involvement are particularly distinctive of LS (Figure 2B).⁴ Pigment incontinence also may be seen.

Another condition that distributes linearly along the lines of Blaschko is linear epidermolytic hyperkeratosis (EHK). Similar to LS, histology shows hyperkeratosis, focal parakeratosis, and acanthosis of the epidermis.⁵ However, EHK shows epidermolysis, acantholysis, and perinuclear vacuolization in spinous and granular layers (Figure 3).⁵ The lack of perivascular and periadnexal inflammation also can help differentiate EHK from LS.

Linear lichen planus (LLP), similar to LS, histologically shows a lichenoid lymphocytic bandlike infiltrate obscuring the dermoepidermal junction, vacuolization of the basal cell layer, and pigment incontinence.^1,2 Although LS and LLP can have histologic overlap, the absence of adnexal or perieccrine lymphocytic inflammation can help distinguish the two.³ The histopathologic changes of intercellular edema or mild spongiosis, exocytosis, and parakeratosis present in LS also are typically absent in LLP. Linear lichen planus characteristically consists of wedge-shaped hypergranulosis and irregular acanthosis with saw-toothed rete ridges (Figure 4).² In addition, lobular eosinophilic deposits known as cytoid or Civatte bodies representing degenerated keratinocytes can be visualized at the dermoepidermal junction in LLP.² Immunofluorescence will highlight Civatte bodies with IgM, IgG, and C3, also helping to differentiate these 2 conditions.¹

Linear porokeratosis can be mistaken for the linear lesion of LS. Both entities may reveal perivascular lymphocytes in the dermis, and porokeratosis can be lichenoid in the central portion of the lesion.⁶ However, porokeratosis is unique in that it contains a cornoid lamella, characterized by a thin column of tightly packed parakeratotic cells extending from an invagination of the epidermis through the adjacent stratum corneum (Figure 5).⁶ Beneath the cornoid lamella, the granular layer is either absent or markedly attenuated, and pyknotic keratinocytes with perinuclear edema are present in the spinous layer.⁶ The epidermis in the central portion of the porokeratotic lesion may be normal, hyperplastic, or atrophic with effacement of rete ridges.

Similar to LS, linear psoriasis follows lines of Blaschko clinically. However, it is distinguished by its characteristic psoriatic epidermal changes as well as its lack of lichenoid or perieccrine inflammation.³ Typical findings in linear psoriasis include hyperkeratosis, confluent parakeratosis with entrapped neutrophilic microabscesses, acanthosis with regular elongation of rete ridges, intraepidermal neutrophils, thinned suprapapillary plates, dilated capillaries in the tips of the dermal papillae, and a chronic dermal inflammatory infiltrate (Figure 6).⁴

To the Editor:

A 42-year-old woman with Crohn disease of 10 years’ duration presented to the clinic with a chief concern of nonpruritic pustular lesions on the bilateral arms. Physical examination revealed several pustules on the arms with secondary excoriation. She also had a warm tender nodule on the left upper shin and subungual hemorrhages under the fingernails (Figure 1). The patient had previously undergone infliximab therapy, which was discontinued 10 months prior to presentation in anticipation of a partial colectomy and temporary ileostomy that was performed 8 months prior to presentation. She recently had developed bilateral, radiating, sharp lower extremity pain extending from the feet to the hips over the last 2 weeks and swelling of the bilateral legs that impaired her ability to ambulate. Additionally, she had recently traveled to Colorado and a Lyme disease workup was initiated at an outside hospital in Colorado; however, the results were pending. The outside hospital also performed a spinal tap that was negative. At our clinic, biopsies were performed on the shin nodule and a right palmar pustule (Figure 2). There was clinical suspicion of erythema nodosum and subcorneal pustular dermatosis or a vesiculopustular skin manifestation of the patient’s Crohn disease. The patient was switched from generic doxycycline to a brand name variant 150 mg every night at bedtime for 2 weeks. She subsequently was admitted to the inpatient rheumatology service for a complete systemic workup.

The punch biopsy of the left upper shin demonstrated operative hemorrhage and periadnexal lymphocytic inflammation without evidence of fungal or bacterial elements by Gram or Gomori methenamine-silver stain. Clinically, the diagnosis was most likely erythema nodosum, though insufficient hypodermis was present to make the diagnosis with pathology. The shave biopsy of the right medial palm was nondiagnostic but showed a transected pustule with no bacterial or fungal elements by Gram or Gomori methenamine-silver stain (Figure 3). Given the clinical context, the likely pathologic diagnosis was vesiculopustular Crohn disease.

Our patient was started on an empiric steroid trial with rapid improvement of the arthralgia and rash. The presumed diagnosis was a Crohn disease flare and the patient was discharged on an 8-week steroid taper. Three weeks later at a follow-up appointment, the patient’s skin lesions had nearly resolved. The swelling of the legs and feet had substantially decreased, but the joint pain, primarily in the ankles, persisted.

Routine laboratory studies showed a hemoglobin level of 11.6 g/dL (reference range, 12–15 g/dL), white blood cell count of 9.1 K/μL (reference range, 4.5–11.0 K/μL), C-reactive protein level of 20.15 mg/dL (reference range, <1.0 mg/dL), and an antinuclear antibody titer of 160 (<80). Serology for Lyme disease was negative. Serum chemistries were all within reference range and an echocardiogram was normal.

Up to one-third of patients with inflammatory bowel disease (IBD) experience extraintestinal manifestations of their condition. Of these patients, nearly one-third will develop cutaneous manifestations.¹ The most common skin diseases associated with IBD are pyoderma gangrenosum and erythema nodosum.² The differential diagnoses considered in this unique case included early pyoderma gangrenosum, subcorneal pustular dermatosis (Sneddon-Wilkinson disease), and vesiculopustular Crohn disease. Vesiculopustular Crohn disease is a rare component of IBD and also can be present in bowel-associated dermatosis-arthritis syndrome (BADAS). In BADAS, symptoms often include arthritis and systemic symptoms such as fever and malaise. The skin manifestations typically involve the arms and trunk. It often is seen after intestinal bypass surgery but also can be present in patients with gastrointestinal diseases such as IBD.³ Due to its early association with bypass surgery, BADAS previously was referred to as bowel bypass syndrome but has since been seen in relation to other intestinal surgeries and IBD.⁴ Patients with BADAS often present with episodes of fever, fatigue, and malaise, in addition to arthralgia and cutaneous eruptions. Cases of BADAS related to IBD instead of bypass surgery often can be less severe in nature. Unlike many of these previously reported cases, our patient’s joint pain primarily was in the knees and ankles, whereas typical cases of BADAS cause upper extremity (ie, shoulder, elbow) arthralgia. Our patient occasionally experienced upper extremity pain, but it was less frequent and less severe than the knee and ankle pain. The vesiculopustular lesions in BADAS usually begin as 3- to 10-mm painful macules that then develop into aseptic pustular lesions. These manifestations arise on the upper arms and chest or trunk and can be accompanied by erythema nodosum on the legs.⁴

It has been hypothesized that BADAS occurs as an immune reaction to bacterial overgrowth in the bowel from IBD, infection, or surgery. The reaction is in response to a bacterial antigen and manifests cutaneously.⁵ This same pathogenesis is thought to cause various other manifestations of Crohn disease such as erythema nodosum. Bacteria that incite this immune response include Bacteroides fragilis, Escherichia coli, and Streptococcus.

Resolution of both vesiculopustular Crohn disease and of BADAS often occurs with treatment of the underlying IBD but also can be improved with steroids and antibiotics. However, response to antibiotics often is variable.^5,6 The mainstay for treatment remains steroids and management of underlying bowel disease.

Bowel-associated dermatosis-arthritis syndrome often is overlooked when compiling differential diagnoses for neutrophilic dermatoses but should be considered in patients with bowel disease or recent surgery. Because the syndrome can be recurrent, early diagnosis can help to prevent and treat relapsing courses of BADAS.

To the Editor:

A 42-year-old woman with Crohn disease of 10 years’ duration presented to the clinic with a chief concern of nonpruritic pustular lesions on the bilateral arms. Physical examination revealed several pustules on the arms with secondary excoriation. She also had a warm tender nodule on the left upper shin and subungual hemorrhages under the fingernails (Figure 1). The patient had previously undergone infliximab therapy, which was discontinued 10 months prior to presentation in anticipation of a partial colectomy and temporary ileostomy that was performed 8 months prior to presentation. She recently had developed bilateral, radiating, sharp lower extremity pain extending from the feet to the hips over the last 2 weeks and swelling of the bilateral legs that impaired her ability to ambulate. Additionally, she had recently traveled to Colorado and a Lyme disease workup was initiated at an outside hospital in Colorado; however, the results were pending. The outside hospital also performed a spinal tap that was negative. At our clinic, biopsies were performed on the shin nodule and a right palmar pustule (Figure 2). There was clinical suspicion of erythema nodosum and subcorneal pustular dermatosis or a vesiculopustular skin manifestation of the patient’s Crohn disease. The patient was switched from generic doxycycline to a brand name variant 150 mg every night at bedtime for 2 weeks. She subsequently was admitted to the inpatient rheumatology service for a complete systemic workup.

The punch biopsy of the left upper shin demonstrated operative hemorrhage and periadnexal lymphocytic inflammation without evidence of fungal or bacterial elements by Gram or Gomori methenamine-silver stain. Clinically, the diagnosis was most likely erythema nodosum, though insufficient hypodermis was present to make the diagnosis with pathology. The shave biopsy of the right medial palm was nondiagnostic but showed a transected pustule with no bacterial or fungal elements by Gram or Gomori methenamine-silver stain (Figure 3). Given the clinical context, the likely pathologic diagnosis was vesiculopustular Crohn disease.

Our patient was started on an empiric steroid trial with rapid improvement of the arthralgia and rash. The presumed diagnosis was a Crohn disease flare and the patient was discharged on an 8-week steroid taper. Three weeks later at a follow-up appointment, the patient’s skin lesions had nearly resolved. The swelling of the legs and feet had substantially decreased, but the joint pain, primarily in the ankles, persisted.

Routine laboratory studies showed a hemoglobin level of 11.6 g/dL (reference range, 12–15 g/dL), white blood cell count of 9.1 K/μL (reference range, 4.5–11.0 K/μL), C-reactive protein level of 20.15 mg/dL (reference range, <1.0 mg/dL), and an antinuclear antibody titer of 160 (<80). Serology for Lyme disease was negative. Serum chemistries were all within reference range and an echocardiogram was normal.

Up to one-third of patients with inflammatory bowel disease (IBD) experience extraintestinal manifestations of their condition. Of these patients, nearly one-third will develop cutaneous manifestations.¹ The most common skin diseases associated with IBD are pyoderma gangrenosum and erythema nodosum.² The differential diagnoses considered in this unique case included early pyoderma gangrenosum, subcorneal pustular dermatosis (Sneddon-Wilkinson disease), and vesiculopustular Crohn disease. Vesiculopustular Crohn disease is a rare component of IBD and also can be present in bowel-associated dermatosis-arthritis syndrome (BADAS). In BADAS, symptoms often include arthritis and systemic symptoms such as fever and malaise. The skin manifestations typically involve the arms and trunk. It often is seen after intestinal bypass surgery but also can be present in patients with gastrointestinal diseases such as IBD.³ Due to its early association with bypass surgery, BADAS previously was referred to as bowel bypass syndrome but has since been seen in relation to other intestinal surgeries and IBD.⁴ Patients with BADAS often present with episodes of fever, fatigue, and malaise, in addition to arthralgia and cutaneous eruptions. Cases of BADAS related to IBD instead of bypass surgery often can be less severe in nature. Unlike many of these previously reported cases, our patient’s joint pain primarily was in the knees and ankles, whereas typical cases of BADAS cause upper extremity (ie, shoulder, elbow) arthralgia. Our patient occasionally experienced upper extremity pain, but it was less frequent and less severe than the knee and ankle pain. The vesiculopustular lesions in BADAS usually begin as 3- to 10-mm painful macules that then develop into aseptic pustular lesions. These manifestations arise on the upper arms and chest or trunk and can be accompanied by erythema nodosum on the legs.⁴

It has been hypothesized that BADAS occurs as an immune reaction to bacterial overgrowth in the bowel from IBD, infection, or surgery. The reaction is in response to a bacterial antigen and manifests cutaneously.⁵ This same pathogenesis is thought to cause various other manifestations of Crohn disease such as erythema nodosum. Bacteria that incite this immune response include Bacteroides fragilis, Escherichia coli, and Streptococcus.

Resolution of both vesiculopustular Crohn disease and of BADAS often occurs with treatment of the underlying IBD but also can be improved with steroids and antibiotics. However, response to antibiotics often is variable.^5,6 The mainstay for treatment remains steroids and management of underlying bowel disease.

Bowel-associated dermatosis-arthritis syndrome often is overlooked when compiling differential diagnoses for neutrophilic dermatoses but should be considered in patients with bowel disease or recent surgery. Because the syndrome can be recurrent, early diagnosis can help to prevent and treat relapsing courses of BADAS.

To the Editor:

A 42-year-old woman with Crohn disease of 10 years’ duration presented to the clinic with a chief concern of nonpruritic pustular lesions on the bilateral arms. Physical examination revealed several pustules on the arms with secondary excoriation. She also had a warm tender nodule on the left upper shin and subungual hemorrhages under the fingernails (Figure 1). The patient had previously undergone infliximab therapy, which was discontinued 10 months prior to presentation in anticipation of a partial colectomy and temporary ileostomy that was performed 8 months prior to presentation. She recently had developed bilateral, radiating, sharp lower extremity pain extending from the feet to the hips over the last 2 weeks and swelling of the bilateral legs that impaired her ability to ambulate. Additionally, she had recently traveled to Colorado and a Lyme disease workup was initiated at an outside hospital in Colorado; however, the results were pending. The outside hospital also performed a spinal tap that was negative. At our clinic, biopsies were performed on the shin nodule and a right palmar pustule (Figure 2). There was clinical suspicion of erythema nodosum and subcorneal pustular dermatosis or a vesiculopustular skin manifestation of the patient’s Crohn disease. The patient was switched from generic doxycycline to a brand name variant 150 mg every night at bedtime for 2 weeks. She subsequently was admitted to the inpatient rheumatology service for a complete systemic workup.

The punch biopsy of the left upper shin demonstrated operative hemorrhage and periadnexal lymphocytic inflammation without evidence of fungal or bacterial elements by Gram or Gomori methenamine-silver stain. Clinically, the diagnosis was most likely erythema nodosum, though insufficient hypodermis was present to make the diagnosis with pathology. The shave biopsy of the right medial palm was nondiagnostic but showed a transected pustule with no bacterial or fungal elements by Gram or Gomori methenamine-silver stain (Figure 3). Given the clinical context, the likely pathologic diagnosis was vesiculopustular Crohn disease.

Our patient was started on an empiric steroid trial with rapid improvement of the arthralgia and rash. The presumed diagnosis was a Crohn disease flare and the patient was discharged on an 8-week steroid taper. Three weeks later at a follow-up appointment, the patient’s skin lesions had nearly resolved. The swelling of the legs and feet had substantially decreased, but the joint pain, primarily in the ankles, persisted.

Routine laboratory studies showed a hemoglobin level of 11.6 g/dL (reference range, 12–15 g/dL), white blood cell count of 9.1 K/μL (reference range, 4.5–11.0 K/μL), C-reactive protein level of 20.15 mg/dL (reference range, <1.0 mg/dL), and an antinuclear antibody titer of 160 (<80). Serology for Lyme disease was negative. Serum chemistries were all within reference range and an echocardiogram was normal.

Up to one-third of patients with inflammatory bowel disease (IBD) experience extraintestinal manifestations of their condition. Of these patients, nearly one-third will develop cutaneous manifestations.¹ The most common skin diseases associated with IBD are pyoderma gangrenosum and erythema nodosum.² The differential diagnoses considered in this unique case included early pyoderma gangrenosum, subcorneal pustular dermatosis (Sneddon-Wilkinson disease), and vesiculopustular Crohn disease. Vesiculopustular Crohn disease is a rare component of IBD and also can be present in bowel-associated dermatosis-arthritis syndrome (BADAS). In BADAS, symptoms often include arthritis and systemic symptoms such as fever and malaise. The skin manifestations typically involve the arms and trunk. It often is seen after intestinal bypass surgery but also can be present in patients with gastrointestinal diseases such as IBD.³ Due to its early association with bypass surgery, BADAS previously was referred to as bowel bypass syndrome but has since been seen in relation to other intestinal surgeries and IBD.⁴ Patients with BADAS often present with episodes of fever, fatigue, and malaise, in addition to arthralgia and cutaneous eruptions. Cases of BADAS related to IBD instead of bypass surgery often can be less severe in nature. Unlike many of these previously reported cases, our patient’s joint pain primarily was in the knees and ankles, whereas typical cases of BADAS cause upper extremity (ie, shoulder, elbow) arthralgia. Our patient occasionally experienced upper extremity pain, but it was less frequent and less severe than the knee and ankle pain. The vesiculopustular lesions in BADAS usually begin as 3- to 10-mm painful macules that then develop into aseptic pustular lesions. These manifestations arise on the upper arms and chest or trunk and can be accompanied by erythema nodosum on the legs.⁴

It has been hypothesized that BADAS occurs as an immune reaction to bacterial overgrowth in the bowel from IBD, infection, or surgery. The reaction is in response to a bacterial antigen and manifests cutaneously.⁵ This same pathogenesis is thought to cause various other manifestations of Crohn disease such as erythema nodosum. Bacteria that incite this immune response include Bacteroides fragilis, Escherichia coli, and Streptococcus.

Resolution of both vesiculopustular Crohn disease and of BADAS often occurs with treatment of the underlying IBD but also can be improved with steroids and antibiotics. However, response to antibiotics often is variable.^5,6 The mainstay for treatment remains steroids and management of underlying bowel disease.

Bowel-associated dermatosis-arthritis syndrome often is overlooked when compiling differential diagnoses for neutrophilic dermatoses but should be considered in patients with bowel disease or recent surgery. Because the syndrome can be recurrent, early diagnosis can help to prevent and treat relapsing courses of BADAS.

The Diagnosis: Mycosis Fungoides

Physical examination revealed erythematous polycyclic and arcuate plaques with fine overlying scale on the right arm and shoulder (Figure 1). Mild wrinkling and telangiectasias were noted on the skin surrounding the lesions. Laboratory tests showed normal values for antinuclear antibodies, anti–Sjögren syndrome–related antigen A, and anti–Sjögren syndrome–related antigen B.

A skin biopsy of a plaque on the right upper arm showed enlarged pleomorphic lymphocytes arranged along the basal layer and in focal collections within the epidermis (Figure 2). Within the dermis were wiry bundles of collagen, a sparse superficial and patchy infiltrate of lymphocytes, and scattered large mononuclear cells (Figure 3). Immunoperoxidase staining revealed large intraepidermal lymphocytes positive for CD4 (Figure 4A) and CD5. Notably, these lymphocytes also stained positive for CD30 (Figure 4B). Staining for CD8, CD1a, CD56, and anaplastic lymphoma kinase was negative, with aberrant loss of CD3. The morphology and pattern of immunoreactivity supported the diagnosis of mycosis fungoides (MF).

Mycosis fungoides is the most common form of cutaneous T-cell lymphoma.¹ Its progression is classified in 3 stages: (1) early (patch) stage, (2) plaque stage, and (3) tumor stage. Conclusive diagnosis of early stage MF often is difficult due to its clinical features that are similar to more common benign dermatoses (eg, atopic dermatitis, psoriasis, lichen planus), leading to shortcomings in determining prognosis and selecting an appropriate treatment regimen. With this diagnositic difficulty in mind, guidelines have been created to aid in the diagnosis of early stage MF.²

Clinical features consistent with early stage MF include multiple erythematous, well-demarcated lesions with varying shapes that typically are greater than 5 cm in diameter.² Lesions usually are flat or thinly elevated and may exhibit slight scaling. As was noted in our patient, poikiloderma of the surrounding skin is fairly specific for early stage MF, as it is not a feature associated with common clinical mimics of MF (eg, atopic dermatitis, psoriasis, lichen planus). The distribution of skin lesions in non–sun-exposed areas is common. The eruption is persistent, though it may wax and wane in severity.²
 

Histopathologic examination is necessary to confirm a diagnosis of MF. Typically, early stage MF is marked by enlarged T lymphocytes within the epidermis as well as the papillary and superficial reticular dermis. Cerebriform nuclei are a key finding in the diagnosis of MF. Lymphocytes frequently are arranged linearly along the basal layer of the epidermis. Within the epidermis, clusters of atypical lymphocytes (Pautrier microabscesses) without spongiosis are uncommon but are a characteristic finding of MF if present.¹ Papillary dermal fibrosis also may be evident.²
 

Figure 4. Large intraepidermal lymphocytes were highlighted on CD4 (A) and CD30 immunostaining (B)(original magnification ×200 and ×200).

Immunostaining typically reveals positivity for CD3 and CD4, as well as for lymphocyte antigens CD2 and CD5.¹ CD30 positivity in early stage MF rarely has been reported in the literature.^3,4 Such cases appear histologically similarly to CD30‒negative cases in other respects. One study showed that the presence of CD30-positive lymphocytes does not alter the clinical course of MF.³ Another study found that, while epidermal CD30-postive lymphocytes had no prognostic relevance, an increased percentage of dermal CD30-positive cells was linked to a higher stage at diagnosis and worse overall prognosis.⁵ Pathogenesis underlying CD30 positivity in early MF is unknown. It is important to note that CD30-positive cells commonly are seen in lymphomatoid papulosis and anaplastic large cell lymphoma, as well as a variety of nonneoplastic conditions.^3,6,7

The Diagnosis: Mycosis Fungoides

Physical examination revealed erythematous polycyclic and arcuate plaques with fine overlying scale on the right arm and shoulder (Figure 1). Mild wrinkling and telangiectasias were noted on the skin surrounding the lesions. Laboratory tests showed normal values for antinuclear antibodies, anti–Sjögren syndrome–related antigen A, and anti–Sjögren syndrome–related antigen B.

A skin biopsy of a plaque on the right upper arm showed enlarged pleomorphic lymphocytes arranged along the basal layer and in focal collections within the epidermis (Figure 2). Within the dermis were wiry bundles of collagen, a sparse superficial and patchy infiltrate of lymphocytes, and scattered large mononuclear cells (Figure 3). Immunoperoxidase staining revealed large intraepidermal lymphocytes positive for CD4 (Figure 4A) and CD5. Notably, these lymphocytes also stained positive for CD30 (Figure 4B). Staining for CD8, CD1a, CD56, and anaplastic lymphoma kinase was negative, with aberrant loss of CD3. The morphology and pattern of immunoreactivity supported the diagnosis of mycosis fungoides (MF).

Mycosis fungoides is the most common form of cutaneous T-cell lymphoma.¹ Its progression is classified in 3 stages: (1) early (patch) stage, (2) plaque stage, and (3) tumor stage. Conclusive diagnosis of early stage MF often is difficult due to its clinical features that are similar to more common benign dermatoses (eg, atopic dermatitis, psoriasis, lichen planus), leading to shortcomings in determining prognosis and selecting an appropriate treatment regimen. With this diagnositic difficulty in mind, guidelines have been created to aid in the diagnosis of early stage MF.²

Clinical features consistent with early stage MF include multiple erythematous, well-demarcated lesions with varying shapes that typically are greater than 5 cm in diameter.² Lesions usually are flat or thinly elevated and may exhibit slight scaling. As was noted in our patient, poikiloderma of the surrounding skin is fairly specific for early stage MF, as it is not a feature associated with common clinical mimics of MF (eg, atopic dermatitis, psoriasis, lichen planus). The distribution of skin lesions in non–sun-exposed areas is common. The eruption is persistent, though it may wax and wane in severity.²
 

Histopathologic examination is necessary to confirm a diagnosis of MF. Typically, early stage MF is marked by enlarged T lymphocytes within the epidermis as well as the papillary and superficial reticular dermis. Cerebriform nuclei are a key finding in the diagnosis of MF. Lymphocytes frequently are arranged linearly along the basal layer of the epidermis. Within the epidermis, clusters of atypical lymphocytes (Pautrier microabscesses) without spongiosis are uncommon but are a characteristic finding of MF if present.¹ Papillary dermal fibrosis also may be evident.²
 

Figure 4. Large intraepidermal lymphocytes were highlighted on CD4 (A) and CD30 immunostaining (B)(original magnification ×200 and ×200).

Immunostaining typically reveals positivity for CD3 and CD4, as well as for lymphocyte antigens CD2 and CD5.¹ CD30 positivity in early stage MF rarely has been reported in the literature.^3,4 Such cases appear histologically similarly to CD30‒negative cases in other respects. One study showed that the presence of CD30-positive lymphocytes does not alter the clinical course of MF.³ Another study found that, while epidermal CD30-postive lymphocytes had no prognostic relevance, an increased percentage of dermal CD30-positive cells was linked to a higher stage at diagnosis and worse overall prognosis.⁵ Pathogenesis underlying CD30 positivity in early MF is unknown. It is important to note that CD30-positive cells commonly are seen in lymphomatoid papulosis and anaplastic large cell lymphoma, as well as a variety of nonneoplastic conditions.^3,6,7

The Diagnosis: Mycosis Fungoides

Physical examination revealed erythematous polycyclic and arcuate plaques with fine overlying scale on the right arm and shoulder (Figure 1). Mild wrinkling and telangiectasias were noted on the skin surrounding the lesions. Laboratory tests showed normal values for antinuclear antibodies, anti–Sjögren syndrome–related antigen A, and anti–Sjögren syndrome–related antigen B.

A skin biopsy of a plaque on the right upper arm showed enlarged pleomorphic lymphocytes arranged along the basal layer and in focal collections within the epidermis (Figure 2). Within the dermis were wiry bundles of collagen, a sparse superficial and patchy infiltrate of lymphocytes, and scattered large mononuclear cells (Figure 3). Immunoperoxidase staining revealed large intraepidermal lymphocytes positive for CD4 (Figure 4A) and CD5. Notably, these lymphocytes also stained positive for CD30 (Figure 4B). Staining for CD8, CD1a, CD56, and anaplastic lymphoma kinase was negative, with aberrant loss of CD3. The morphology and pattern of immunoreactivity supported the diagnosis of mycosis fungoides (MF).

Mycosis fungoides is the most common form of cutaneous T-cell lymphoma.¹ Its progression is classified in 3 stages: (1) early (patch) stage, (2) plaque stage, and (3) tumor stage. Conclusive diagnosis of early stage MF often is difficult due to its clinical features that are similar to more common benign dermatoses (eg, atopic dermatitis, psoriasis, lichen planus), leading to shortcomings in determining prognosis and selecting an appropriate treatment regimen. With this diagnositic difficulty in mind, guidelines have been created to aid in the diagnosis of early stage MF.²

Clinical features consistent with early stage MF include multiple erythematous, well-demarcated lesions with varying shapes that typically are greater than 5 cm in diameter.² Lesions usually are flat or thinly elevated and may exhibit slight scaling. As was noted in our patient, poikiloderma of the surrounding skin is fairly specific for early stage MF, as it is not a feature associated with common clinical mimics of MF (eg, atopic dermatitis, psoriasis, lichen planus). The distribution of skin lesions in non–sun-exposed areas is common. The eruption is persistent, though it may wax and wane in severity.²
 

Histopathologic examination is necessary to confirm a diagnosis of MF. Typically, early stage MF is marked by enlarged T lymphocytes within the epidermis as well as the papillary and superficial reticular dermis. Cerebriform nuclei are a key finding in the diagnosis of MF. Lymphocytes frequently are arranged linearly along the basal layer of the epidermis. Within the epidermis, clusters of atypical lymphocytes (Pautrier microabscesses) without spongiosis are uncommon but are a characteristic finding of MF if present.¹ Papillary dermal fibrosis also may be evident.²
 

Figure 4. Large intraepidermal lymphocytes were highlighted on CD4 (A) and CD30 immunostaining (B)(original magnification ×200 and ×200).

Immunostaining typically reveals positivity for CD3 and CD4, as well as for lymphocyte antigens CD2 and CD5.¹ CD30 positivity in early stage MF rarely has been reported in the literature.^3,4 Such cases appear histologically similarly to CD30‒negative cases in other respects. One study showed that the presence of CD30-positive lymphocytes does not alter the clinical course of MF.³ Another study found that, while epidermal CD30-postive lymphocytes had no prognostic relevance, an increased percentage of dermal CD30-positive cells was linked to a higher stage at diagnosis and worse overall prognosis.⁵ Pathogenesis underlying CD30 positivity in early MF is unknown. It is important to note that CD30-positive cells commonly are seen in lymphomatoid papulosis and anaplastic large cell lymphoma, as well as a variety of nonneoplastic conditions.^3,6,7

Syphilis often is referred to as the “great imitator” due to the protean presentations of secondary-stage disease, the most common of which are skin manifestations.¹ Secondary syphilis typically begins 3 to 10 weeks after initial exposure due to systemic dissemination of Treponema pallidum, and although presentations can vary widely, the classic presentation includes nonspecific generalized symptoms (eg, fever, malaise, lymphadenopathy), variable skin findings (eg, nonpruritic papulosquamous eruption), and mucosal ulcerations or plaques.¹ Early and accurate diagnosis of syphilis is critical to avoid the morbidity associated with advanced disease.

The classic histopathologic appearance of secondary syphilis is characterized by psoriasiform epidermal changes; a dermal inflammatory infiltrate of lymphocytes, histiocytes, and plasma cells in a lichenoid and/or superficial and deep perivascular distribution (Figure 1); and endothelial swelling of dermal blood vessels.¹ The presence of plasma cells in the infiltrate (Figure 2) is particularly useful for differentiating secondary syphilis from other clinicopathological mimickers, but this finding is not always present. Silver-based histochemical stains (eg, Warthin-Starry silver stain) can be used to high-light T pallidum organisms; however, histochemical staining is plagued by low diagnostic sensitivity for identifying the causative organism, making immunohistochemical and/or serologic testing the preferred method for confirming the diagnosis.¹

Arthropod assault is characterized by a superficial and deep perivascular lymphocytic inflammatory infiltrate with a variable number of polymorphonuclear cells.² Overlying spongiosis or focal epidermal necrosis and increased eosinophils are typical of arthropod assault (Figure 3).² The infiltrate seen following insect bites is classically described as wedge-shaped, although recent literature has disputed the sensitivity of this finding, identifying adnexal structure involvement as an alternative sensitive marker for identifying insect bites.²

Chronic cutaneous lupus erythematosus demonstrates a spectrum of histopathologic changes depending on the age of the lesion biopsied; however, characteristic histopathologic features typically include variable epidermal atrophy or acanthosis with basal layer vacuolar degeneration, basement membrane thickening, follicular plugging, superficial and deep perivascular and periappendageal lymphocytic inflammation, and dermal mucin deposition (Figure 4).⁴

Fixed drug eruption histopathologically presents as an interface tissue reaction–associated single-cell necrosis to broader areas of epidermal necrosis, as well as superficial to mid-dermal lymphocytic infiltrate. Unlike secondary syphilis, a fixed drug eruption is characterized by prominent melanin pigment incontinence and eosinophils (Figure 5).⁵

Similar to secondary syphilis, pityriasis lichenoides et varioliformis acuta (PLEVA) demonstrates variable psoriasiform epidermal hyperplasia with a lichenoid and perivascular lymphocytic infiltrate. Other findings in PLEVA include parakeratosis, variable epidermal necrosis, and prominent exocytosis of lymphocytes. Unlike typical secondary syphilis, PLEVA often is associated with lymphocytic vasculitis, consisting of the invasion of vessel walls by lymphocytes with extravasation of erythrocytes and an absence of conspicuous plasma cells (Figure 6).⁶

Syphilis often is referred to as the “great imitator” due to the protean presentations of secondary-stage disease, the most common of which are skin manifestations.¹ Secondary syphilis typically begins 3 to 10 weeks after initial exposure due to systemic dissemination of Treponema pallidum, and although presentations can vary widely, the classic presentation includes nonspecific generalized symptoms (eg, fever, malaise, lymphadenopathy), variable skin findings (eg, nonpruritic papulosquamous eruption), and mucosal ulcerations or plaques.¹ Early and accurate diagnosis of syphilis is critical to avoid the morbidity associated with advanced disease.

The classic histopathologic appearance of secondary syphilis is characterized by psoriasiform epidermal changes; a dermal inflammatory infiltrate of lymphocytes, histiocytes, and plasma cells in a lichenoid and/or superficial and deep perivascular distribution (Figure 1); and endothelial swelling of dermal blood vessels.¹ The presence of plasma cells in the infiltrate (Figure 2) is particularly useful for differentiating secondary syphilis from other clinicopathological mimickers, but this finding is not always present. Silver-based histochemical stains (eg, Warthin-Starry silver stain) can be used to high-light T pallidum organisms; however, histochemical staining is plagued by low diagnostic sensitivity for identifying the causative organism, making immunohistochemical and/or serologic testing the preferred method for confirming the diagnosis.¹

Arthropod assault is characterized by a superficial and deep perivascular lymphocytic inflammatory infiltrate with a variable number of polymorphonuclear cells.² Overlying spongiosis or focal epidermal necrosis and increased eosinophils are typical of arthropod assault (Figure 3).² The infiltrate seen following insect bites is classically described as wedge-shaped, although recent literature has disputed the sensitivity of this finding, identifying adnexal structure involvement as an alternative sensitive marker for identifying insect bites.²

Chronic cutaneous lupus erythematosus demonstrates a spectrum of histopathologic changes depending on the age of the lesion biopsied; however, characteristic histopathologic features typically include variable epidermal atrophy or acanthosis with basal layer vacuolar degeneration, basement membrane thickening, follicular plugging, superficial and deep perivascular and periappendageal lymphocytic inflammation, and dermal mucin deposition (Figure 4).⁴

Fixed drug eruption histopathologically presents as an interface tissue reaction–associated single-cell necrosis to broader areas of epidermal necrosis, as well as superficial to mid-dermal lymphocytic infiltrate. Unlike secondary syphilis, a fixed drug eruption is characterized by prominent melanin pigment incontinence and eosinophils (Figure 5).⁵

Similar to secondary syphilis, pityriasis lichenoides et varioliformis acuta (PLEVA) demonstrates variable psoriasiform epidermal hyperplasia with a lichenoid and perivascular lymphocytic infiltrate. Other findings in PLEVA include parakeratosis, variable epidermal necrosis, and prominent exocytosis of lymphocytes. Unlike typical secondary syphilis, PLEVA often is associated with lymphocytic vasculitis, consisting of the invasion of vessel walls by lymphocytes with extravasation of erythrocytes and an absence of conspicuous plasma cells (Figure 6).⁶

Syphilis often is referred to as the “great imitator” due to the protean presentations of secondary-stage disease, the most common of which are skin manifestations.¹ Secondary syphilis typically begins 3 to 10 weeks after initial exposure due to systemic dissemination of Treponema pallidum, and although presentations can vary widely, the classic presentation includes nonspecific generalized symptoms (eg, fever, malaise, lymphadenopathy), variable skin findings (eg, nonpruritic papulosquamous eruption), and mucosal ulcerations or plaques.¹ Early and accurate diagnosis of syphilis is critical to avoid the morbidity associated with advanced disease.

The classic histopathologic appearance of secondary syphilis is characterized by psoriasiform epidermal changes; a dermal inflammatory infiltrate of lymphocytes, histiocytes, and plasma cells in a lichenoid and/or superficial and deep perivascular distribution (Figure 1); and endothelial swelling of dermal blood vessels.¹ The presence of plasma cells in the infiltrate (Figure 2) is particularly useful for differentiating secondary syphilis from other clinicopathological mimickers, but this finding is not always present. Silver-based histochemical stains (eg, Warthin-Starry silver stain) can be used to high-light T pallidum organisms; however, histochemical staining is plagued by low diagnostic sensitivity for identifying the causative organism, making immunohistochemical and/or serologic testing the preferred method for confirming the diagnosis.¹

Arthropod assault is characterized by a superficial and deep perivascular lymphocytic inflammatory infiltrate with a variable number of polymorphonuclear cells.² Overlying spongiosis or focal epidermal necrosis and increased eosinophils are typical of arthropod assault (Figure 3).² The infiltrate seen following insect bites is classically described as wedge-shaped, although recent literature has disputed the sensitivity of this finding, identifying adnexal structure involvement as an alternative sensitive marker for identifying insect bites.²

Chronic cutaneous lupus erythematosus demonstrates a spectrum of histopathologic changes depending on the age of the lesion biopsied; however, characteristic histopathologic features typically include variable epidermal atrophy or acanthosis with basal layer vacuolar degeneration, basement membrane thickening, follicular plugging, superficial and deep perivascular and periappendageal lymphocytic inflammation, and dermal mucin deposition (Figure 4).⁴

Fixed drug eruption histopathologically presents as an interface tissue reaction–associated single-cell necrosis to broader areas of epidermal necrosis, as well as superficial to mid-dermal lymphocytic infiltrate. Unlike secondary syphilis, a fixed drug eruption is characterized by prominent melanin pigment incontinence and eosinophils (Figure 5).⁵

Similar to secondary syphilis, pityriasis lichenoides et varioliformis acuta (PLEVA) demonstrates variable psoriasiform epidermal hyperplasia with a lichenoid and perivascular lymphocytic infiltrate. Other findings in PLEVA include parakeratosis, variable epidermal necrosis, and prominent exocytosis of lymphocytes. Unlike typical secondary syphilis, PLEVA often is associated with lymphocytic vasculitis, consisting of the invasion of vessel walls by lymphocytes with extravasation of erythrocytes and an absence of conspicuous plasma cells (Figure 6).⁶