Dermatopathology

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

To the Editor:

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

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

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

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

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

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

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

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

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

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

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

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

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

To the Editor:

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

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

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

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

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

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

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

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

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

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

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

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

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

To the Editor:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The Diagnosis: Verrucous Carcinoma

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

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

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

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

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

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

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

The Diagnosis: Verrucous Carcinoma

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

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

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

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

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

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

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

The Diagnosis: Verrucous Carcinoma

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Cutaneous North American blastomycosis is a deep fungal infection caused by Blastomyces dermatitidis, a thermally dimorphic fungus that is endemic to the Great Lakes region as well as the Mississippi and Ohio River valleys where it thrives in moist acidic soil enriched with organic material.^1,2 In humans, the annual incidence rate is estimated to be 0.6 cases per million,³ though it may be as high as 42 cases per 100,000 in endemic areas.⁴ Infection typically results from the inhalation of conidia and manifests as either acute or chronic pneumonia.⁵ Most patients with acute disease present with nonspecific flulike symptoms and a nonproductive cough.

Dissemination occurs in approximately 25% of cases,⁶ most commonly affecting the skin. Other potential sites of dissemination include bone, the genitourinary tract, and the central nervous system. Cutaneous lesions, which may be either verrucous or ulcerative plaques, often occur on or around orifices contiguous to the respiratory tract.⁷ Verrucous lesions tend to have an irregular shape with well-defined borders and surface crusting. Ulcerative lesions have heaped-up borders and often have an exudative base.⁸ The differential diagnosis of cutaneous North American blastomycosis lesions includes squamous cell carcinoma, giant keratoacanthoma, verrucae, basal cell carcinoma, scrofuloderma, lupus vulgaris, nocardiosis, syphilis, bromoderma, iododerma, granuloma inguinale, tuberculosis verrucosa cutis, mycetoma, and actinomycosis.^7,8

Although periorificial cutaneous manifestations of disseminated blastomycosis are common, perianal lesions are rare. The differential diagnosis of  perianal verrucous plaques includes condyloma acuminatum, squamous cell carcinoma, adenocarcinoma, Buschke-Löwenstein tumor, actinomycosis, and localized fungal infections such as blastomycosis.⁹

Case Report

A 57-year-old man presented with a palpable perianal mass that produced small amounts of blood in his underwear and on toilet paper. The patient reported no history of hemorrhoids, anoreceptive intercourse, or sexually transmitted disease. Four months prior to presentation, he had a prolonged upper respiratory tract illness with a subjective fever and productive cough of 2 months’ duration. The patient described himself as an avid outdoorsman who worked at a summer resort and spent a great deal of time in the forests of central Wisconsin last autumn. Physical examination revealed a well-demarcated, firm, moist plaque with a verrucous surface that measured 3.5×2.7 cm and extended from the anal verge to the perianal skin (Figure 1).

Figure 1. A well-demarcated, firm, moist plaque with a verrucous surface extended from the anal verge to the perianal skin.

Potassium hydroxide preparation of a biopsy specimen (Figure 2), a punch biopsy of the lesion (Figure 3), and Gomori methenamine-silver staining (Figure 4) revealed scattered yeast spores, some demonstrating broad-based budding, with pseudoepitheliomatous hyperplasia, dermal neutrophils, and intraepithelial microabscesses. The patient’s urine was positive for Blastomyces antigen (1.04 ng/mL). Chest radiography demonstrated a localized infiltrate in the right hilum with possible mass effect. Computed tomography showed a consolidative opacity measuring 4.0×3.4 cm in the upper lobe of the right lung (Figure 5).

Figure 2. A biopsy specimen prepared with potassium hydroxide showed broad-based, figure eight–shaped budding yeast spores above the arrowhead (original magnification ×600).

Figure 3. A punch biopsy of the lesion revealed scattered yeast spores, some demonstrating broad-based budding, with pseudoepitheliomatous hyperplasia and microabscesses (H&E, original magnification ×400).

The patient was diagnosed with cutaneous North American blastomycosis and prescribed a 6-month course of oral itraconazole 200 mg twice daily. At his 3-month follow-up visit, the perianal plaque hadalmost completely resolved (Figure 6). However, because the patient had increasing lower extremity edema, subjective hearing loss, and abnormal liver function tests, itraconazole treatment was discontinued and replaced with oral fluconazole 400 mg daily for the next 3 months. The right hilar mass had visibly improved on follow-up chest radiography 2 months after the patient started antifungal therapy with itraconazole and had resolved within another 3 months of treatment.

Figure 4. Gomori methenamine-silver stain demonstrated broad-based budding yeast (original magnification ×400).

Figure 5. Computed tomography revealed a consolidative opacity measuring 4.0×3.4 cm in the upper lobe of the right lung.

Comment

Cutaneous blastomycosis results most often from the hematogenous spread of B dermatitidis from the lungs and rarely from direct inoculation.^5,10 Skin lesions tend to occur on exposed areas, such as the face, scalp, hands, wrists, feet, and ankles.^7,11-13 Dissemination to the perianal skin is rare, though it has been reported in 2 other patients; both patients, similar to our patient, had evidence of pulmonary involvement at some point in their clinical course.^9,14

Figure 6. The perianal plaque had almost completely resolved after 3 months of oral itraconazole therapy.

Diagnosis is based on identification of  B dermatitidis by microscopy or culture. Potassium hydroxide preparation of biopsy specimens typically shows broad-based budding yeast.¹³ Characteristic findings of histopathologic studies include pseudo-epitheliomatous hyperplasia, intraepidermal abscesses, and a dermal infiltrate of polymorphonuclear  leukocytes.¹⁵ On fungal culture, B dermatitidis is  slow growing and may require a 2- to 4-week incubation period. Serologic tests are available, but sensitivity is low, at 9%, 28%, and 77% for complement fixation, immunodiffusion, and enzyme immunoassay, respectively.¹⁶

Conclusion

North American blastomycosis should be considered in patients who have verrucous or ulcerative perianal lesions and have lived in or traveled to endemic regions, especially if they have recent or ongoing pulmonary symptoms. Potassium hydroxide preparation and fungal staining of biopsy specimens can aid in diagnosis.

Acknowledgment

The authors thank the Marshfield Clinic Research Foundation’s Office of Scientific Writing and Publication (Marshfield, Wisconsin) for editorial assistance in the preparation of  this manuscript.

Cutaneous North American blastomycosis is a deep fungal infection caused by Blastomyces dermatitidis, a thermally dimorphic fungus that is endemic to the Great Lakes region as well as the Mississippi and Ohio River valleys where it thrives in moist acidic soil enriched with organic material.^1,2 In humans, the annual incidence rate is estimated to be 0.6 cases per million,³ though it may be as high as 42 cases per 100,000 in endemic areas.⁴ Infection typically results from the inhalation of conidia and manifests as either acute or chronic pneumonia.⁵ Most patients with acute disease present with nonspecific flulike symptoms and a nonproductive cough.

Dissemination occurs in approximately 25% of cases,⁶ most commonly affecting the skin. Other potential sites of dissemination include bone, the genitourinary tract, and the central nervous system. Cutaneous lesions, which may be either verrucous or ulcerative plaques, often occur on or around orifices contiguous to the respiratory tract.⁷ Verrucous lesions tend to have an irregular shape with well-defined borders and surface crusting. Ulcerative lesions have heaped-up borders and often have an exudative base.⁸ The differential diagnosis of cutaneous North American blastomycosis lesions includes squamous cell carcinoma, giant keratoacanthoma, verrucae, basal cell carcinoma, scrofuloderma, lupus vulgaris, nocardiosis, syphilis, bromoderma, iododerma, granuloma inguinale, tuberculosis verrucosa cutis, mycetoma, and actinomycosis.^7,8

Although periorificial cutaneous manifestations of disseminated blastomycosis are common, perianal lesions are rare. The differential diagnosis of  perianal verrucous plaques includes condyloma acuminatum, squamous cell carcinoma, adenocarcinoma, Buschke-Löwenstein tumor, actinomycosis, and localized fungal infections such as blastomycosis.⁹

Case Report

A 57-year-old man presented with a palpable perianal mass that produced small amounts of blood in his underwear and on toilet paper. The patient reported no history of hemorrhoids, anoreceptive intercourse, or sexually transmitted disease. Four months prior to presentation, he had a prolonged upper respiratory tract illness with a subjective fever and productive cough of 2 months’ duration. The patient described himself as an avid outdoorsman who worked at a summer resort and spent a great deal of time in the forests of central Wisconsin last autumn. Physical examination revealed a well-demarcated, firm, moist plaque with a verrucous surface that measured 3.5×2.7 cm and extended from the anal verge to the perianal skin (Figure 1).

Figure 1. A well-demarcated, firm, moist plaque with a verrucous surface extended from the anal verge to the perianal skin.

Potassium hydroxide preparation of a biopsy specimen (Figure 2), a punch biopsy of the lesion (Figure 3), and Gomori methenamine-silver staining (Figure 4) revealed scattered yeast spores, some demonstrating broad-based budding, with pseudoepitheliomatous hyperplasia, dermal neutrophils, and intraepithelial microabscesses. The patient’s urine was positive for Blastomyces antigen (1.04 ng/mL). Chest radiography demonstrated a localized infiltrate in the right hilum with possible mass effect. Computed tomography showed a consolidative opacity measuring 4.0×3.4 cm in the upper lobe of the right lung (Figure 5).

Figure 2. A biopsy specimen prepared with potassium hydroxide showed broad-based, figure eight–shaped budding yeast spores above the arrowhead (original magnification ×600).

Figure 3. A punch biopsy of the lesion revealed scattered yeast spores, some demonstrating broad-based budding, with pseudoepitheliomatous hyperplasia and microabscesses (H&E, original magnification ×400).

The patient was diagnosed with cutaneous North American blastomycosis and prescribed a 6-month course of oral itraconazole 200 mg twice daily. At his 3-month follow-up visit, the perianal plaque hadalmost completely resolved (Figure 6). However, because the patient had increasing lower extremity edema, subjective hearing loss, and abnormal liver function tests, itraconazole treatment was discontinued and replaced with oral fluconazole 400 mg daily for the next 3 months. The right hilar mass had visibly improved on follow-up chest radiography 2 months after the patient started antifungal therapy with itraconazole and had resolved within another 3 months of treatment.

Figure 4. Gomori methenamine-silver stain demonstrated broad-based budding yeast (original magnification ×400).

Figure 5. Computed tomography revealed a consolidative opacity measuring 4.0×3.4 cm in the upper lobe of the right lung.

Comment

Cutaneous blastomycosis results most often from the hematogenous spread of B dermatitidis from the lungs and rarely from direct inoculation.^5,10 Skin lesions tend to occur on exposed areas, such as the face, scalp, hands, wrists, feet, and ankles.^7,11-13 Dissemination to the perianal skin is rare, though it has been reported in 2 other patients; both patients, similar to our patient, had evidence of pulmonary involvement at some point in their clinical course.^9,14

Figure 6. The perianal plaque had almost completely resolved after 3 months of oral itraconazole therapy.

Diagnosis is based on identification of  B dermatitidis by microscopy or culture. Potassium hydroxide preparation of biopsy specimens typically shows broad-based budding yeast.¹³ Characteristic findings of histopathologic studies include pseudo-epitheliomatous hyperplasia, intraepidermal abscesses, and a dermal infiltrate of polymorphonuclear  leukocytes.¹⁵ On fungal culture, B dermatitidis is  slow growing and may require a 2- to 4-week incubation period. Serologic tests are available, but sensitivity is low, at 9%, 28%, and 77% for complement fixation, immunodiffusion, and enzyme immunoassay, respectively.¹⁶

Conclusion

North American blastomycosis should be considered in patients who have verrucous or ulcerative perianal lesions and have lived in or traveled to endemic regions, especially if they have recent or ongoing pulmonary symptoms. Potassium hydroxide preparation and fungal staining of biopsy specimens can aid in diagnosis.

Acknowledgment

The authors thank the Marshfield Clinic Research Foundation’s Office of Scientific Writing and Publication (Marshfield, Wisconsin) for editorial assistance in the preparation of  this manuscript.

Cutaneous North American blastomycosis is a deep fungal infection caused by Blastomyces dermatitidis, a thermally dimorphic fungus that is endemic to the Great Lakes region as well as the Mississippi and Ohio River valleys where it thrives in moist acidic soil enriched with organic material.^1,2 In humans, the annual incidence rate is estimated to be 0.6 cases per million,³ though it may be as high as 42 cases per 100,000 in endemic areas.⁴ Infection typically results from the inhalation of conidia and manifests as either acute or chronic pneumonia.⁵ Most patients with acute disease present with nonspecific flulike symptoms and a nonproductive cough.

Dissemination occurs in approximately 25% of cases,⁶ most commonly affecting the skin. Other potential sites of dissemination include bone, the genitourinary tract, and the central nervous system. Cutaneous lesions, which may be either verrucous or ulcerative plaques, often occur on or around orifices contiguous to the respiratory tract.⁷ Verrucous lesions tend to have an irregular shape with well-defined borders and surface crusting. Ulcerative lesions have heaped-up borders and often have an exudative base.⁸ The differential diagnosis of cutaneous North American blastomycosis lesions includes squamous cell carcinoma, giant keratoacanthoma, verrucae, basal cell carcinoma, scrofuloderma, lupus vulgaris, nocardiosis, syphilis, bromoderma, iododerma, granuloma inguinale, tuberculosis verrucosa cutis, mycetoma, and actinomycosis.^7,8

Although periorificial cutaneous manifestations of disseminated blastomycosis are common, perianal lesions are rare. The differential diagnosis of  perianal verrucous plaques includes condyloma acuminatum, squamous cell carcinoma, adenocarcinoma, Buschke-Löwenstein tumor, actinomycosis, and localized fungal infections such as blastomycosis.⁹

Case Report

A 57-year-old man presented with a palpable perianal mass that produced small amounts of blood in his underwear and on toilet paper. The patient reported no history of hemorrhoids, anoreceptive intercourse, or sexually transmitted disease. Four months prior to presentation, he had a prolonged upper respiratory tract illness with a subjective fever and productive cough of 2 months’ duration. The patient described himself as an avid outdoorsman who worked at a summer resort and spent a great deal of time in the forests of central Wisconsin last autumn. Physical examination revealed a well-demarcated, firm, moist plaque with a verrucous surface that measured 3.5×2.7 cm and extended from the anal verge to the perianal skin (Figure 1).

Figure 1. A well-demarcated, firm, moist plaque with a verrucous surface extended from the anal verge to the perianal skin.

Potassium hydroxide preparation of a biopsy specimen (Figure 2), a punch biopsy of the lesion (Figure 3), and Gomori methenamine-silver staining (Figure 4) revealed scattered yeast spores, some demonstrating broad-based budding, with pseudoepitheliomatous hyperplasia, dermal neutrophils, and intraepithelial microabscesses. The patient’s urine was positive for Blastomyces antigen (1.04 ng/mL). Chest radiography demonstrated a localized infiltrate in the right hilum with possible mass effect. Computed tomography showed a consolidative opacity measuring 4.0×3.4 cm in the upper lobe of the right lung (Figure 5).

Figure 2. A biopsy specimen prepared with potassium hydroxide showed broad-based, figure eight–shaped budding yeast spores above the arrowhead (original magnification ×600).

Figure 3. A punch biopsy of the lesion revealed scattered yeast spores, some demonstrating broad-based budding, with pseudoepitheliomatous hyperplasia and microabscesses (H&E, original magnification ×400).

The patient was diagnosed with cutaneous North American blastomycosis and prescribed a 6-month course of oral itraconazole 200 mg twice daily. At his 3-month follow-up visit, the perianal plaque hadalmost completely resolved (Figure 6). However, because the patient had increasing lower extremity edema, subjective hearing loss, and abnormal liver function tests, itraconazole treatment was discontinued and replaced with oral fluconazole 400 mg daily for the next 3 months. The right hilar mass had visibly improved on follow-up chest radiography 2 months after the patient started antifungal therapy with itraconazole and had resolved within another 3 months of treatment.

Figure 4. Gomori methenamine-silver stain demonstrated broad-based budding yeast (original magnification ×400).

Figure 5. Computed tomography revealed a consolidative opacity measuring 4.0×3.4 cm in the upper lobe of the right lung.

Comment

Cutaneous blastomycosis results most often from the hematogenous spread of B dermatitidis from the lungs and rarely from direct inoculation.^5,10 Skin lesions tend to occur on exposed areas, such as the face, scalp, hands, wrists, feet, and ankles.^7,11-13 Dissemination to the perianal skin is rare, though it has been reported in 2 other patients; both patients, similar to our patient, had evidence of pulmonary involvement at some point in their clinical course.^9,14

Figure 6. The perianal plaque had almost completely resolved after 3 months of oral itraconazole therapy.

Diagnosis is based on identification of  B dermatitidis by microscopy or culture. Potassium hydroxide preparation of biopsy specimens typically shows broad-based budding yeast.¹³ Characteristic findings of histopathologic studies include pseudo-epitheliomatous hyperplasia, intraepidermal abscesses, and a dermal infiltrate of polymorphonuclear  leukocytes.¹⁵ On fungal culture, B dermatitidis is  slow growing and may require a 2- to 4-week incubation period. Serologic tests are available, but sensitivity is low, at 9%, 28%, and 77% for complement fixation, immunodiffusion, and enzyme immunoassay, respectively.¹⁶

Conclusion

North American blastomycosis should be considered in patients who have verrucous or ulcerative perianal lesions and have lived in or traveled to endemic regions, especially if they have recent or ongoing pulmonary symptoms. Potassium hydroxide preparation and fungal staining of biopsy specimens can aid in diagnosis.

Acknowledgment

The authors thank the Marshfield Clinic Research Foundation’s Office of Scientific Writing and Publication (Marshfield, Wisconsin) for editorial assistance in the preparation of  this manuscript.

To the Editor:

Sweet syndrome is a neutrophilic dermatosis that typically presents as an acute onset of multiple, painful, sharply demarcated, small (measuring a few centimeters), raised, red plaques that occasionally present with superimposed pustules, vesicles, or bullae on the face, neck, upper chest, back, and extremities. Patients are often febrile and may have mucosal and systemic involvement.¹ Although 71% of cases are idiopathic, others are associated with malignancy; autoimmune disorders; infections; pregnancy; and rarely medications, especially all-trans-retinoic acid, granulocyte colony-stimulating factor, vaccines, and antibiotics.^1,2 We present a case of Sweet syndrome induced by trimethoprim-sulfamethoxazole (TMP-SMX) with an unusual clinical presentation.

A 71-year-old man with a medical history of nonmelanoma skin cancer initiated a course of  TMP-SMX for a wound infection of the lower leg following Mohs micrographic surgery. Eight days later, he developed a painful eruption preceded by 1 day of fever, malaise, blurry vision, and myalgia. Trimethoprim-sulfamethoxazole was discontinued. Physical examination revealed ill-defined, discrete and coalescing, 1- to 6-mm edematous erythematous papules studded with pustules involving the scalp, face, neck, back (Figure 1), and extremities. The patient also had conjunctival erythema and an elevated temperature (38.3°C). Laboratory workup revealed an elevated white blood cell count (11,300/mL [reference range, 4500–11,000/µL]), blood urea nitrogen level (33 mg/µL [reference range, 7–20 mg/dL]),  and creatinine level (2.00 mg/dL [reference range,  0.6–1.2 mg/dL]). Liver function tests were normal. A biopsy demonstrated marked papillary dermal edema with a dense, bandlike, superficial dermal neutrophilic infiltrate (Figure 2). A few neutrophils were present in the epidermis with formation of minute intraepidermal pustules. The patient was diagnosed with Sweet syndrome and treated with intravenous methylprednisolone 60 mg 3 times daily (1.5 mg/kg body weight) tapered over 17 days and triamcinolone acetonide ointment 0.1% twice daily. His fever and leukocytosis resolved within 1 day and the eruption improved within 2 days with residual desquamation that cleared by 3 weeks.

Figure 1. Ill-defined, discrete and coalescing, 1- to 6-mm erythematous papules studded with pustules on the back.

Figure 2. Marked papillary dermal edema, a dense superficial dermal neutrophilic infiltrate, and neutrophil exocytosis with formation of minute intraepidermal pustules (H&E, original magnification ×200).

Morphologically, our case resembled acute generalized exanthematous pustulosis (AGEP), which presents with edematous erythema studded with pustules.³ Although fever and leukocytosis are often present in both AGEP and Sweet syndrome, our patient’s pain, malaise, and myalgia favored Sweet syndrome, as did his conjunctivitis, which is unusual in AGEP.^1,3 Histologically, our case was characteristic for Sweet syndrome, which presents with marked papillary dermal edema and a dense neutrophilic dermal infiltrate with neutrophil exocytosis and spongiform pustules in 21% of cases.¹ Acute generalized exanthematous pustulosis, characterized by spongiform pustules and a perivascular neutrophilic infiltrate, does not exhibit the dense dermal neutrophilic infiltrate of Sweet syndrome.³  Mecca et al⁴ also reported a case displaying overlapping features of Sweet syndrome and AGEP. The patient presented with photodistributed papules and pinpoint pustules on an erythematous base favoring a diagnosis of AGEP with histologic findings compatible with Sweet syndrome. The authors suggested a clinicopathologic continuum may exist among drug-related neutrophilic dermatoses.⁴

In conclusion, we present a case of TMP-SMX–induced Sweet syndrome that morphologically resembled AGEP. It is important to recognize that Sweet syndrome may present in this unusual manner, as it may have notable internal involvement, and responds rapidly to systemic steroids, whereas AGEP has minimal systemic involvement and clears spontaneously.

To the Editor:

Sweet syndrome is a neutrophilic dermatosis that typically presents as an acute onset of multiple, painful, sharply demarcated, small (measuring a few centimeters), raised, red plaques that occasionally present with superimposed pustules, vesicles, or bullae on the face, neck, upper chest, back, and extremities. Patients are often febrile and may have mucosal and systemic involvement.¹ Although 71% of cases are idiopathic, others are associated with malignancy; autoimmune disorders; infections; pregnancy; and rarely medications, especially all-trans-retinoic acid, granulocyte colony-stimulating factor, vaccines, and antibiotics.^1,2 We present a case of Sweet syndrome induced by trimethoprim-sulfamethoxazole (TMP-SMX) with an unusual clinical presentation.

A 71-year-old man with a medical history of nonmelanoma skin cancer initiated a course of  TMP-SMX for a wound infection of the lower leg following Mohs micrographic surgery. Eight days later, he developed a painful eruption preceded by 1 day of fever, malaise, blurry vision, and myalgia. Trimethoprim-sulfamethoxazole was discontinued. Physical examination revealed ill-defined, discrete and coalescing, 1- to 6-mm edematous erythematous papules studded with pustules involving the scalp, face, neck, back (Figure 1), and extremities. The patient also had conjunctival erythema and an elevated temperature (38.3°C). Laboratory workup revealed an elevated white blood cell count (11,300/mL [reference range, 4500–11,000/µL]), blood urea nitrogen level (33 mg/µL [reference range, 7–20 mg/dL]),  and creatinine level (2.00 mg/dL [reference range,  0.6–1.2 mg/dL]). Liver function tests were normal. A biopsy demonstrated marked papillary dermal edema with a dense, bandlike, superficial dermal neutrophilic infiltrate (Figure 2). A few neutrophils were present in the epidermis with formation of minute intraepidermal pustules. The patient was diagnosed with Sweet syndrome and treated with intravenous methylprednisolone 60 mg 3 times daily (1.5 mg/kg body weight) tapered over 17 days and triamcinolone acetonide ointment 0.1% twice daily. His fever and leukocytosis resolved within 1 day and the eruption improved within 2 days with residual desquamation that cleared by 3 weeks.

Figure 1. Ill-defined, discrete and coalescing, 1- to 6-mm erythematous papules studded with pustules on the back.

Figure 2. Marked papillary dermal edema, a dense superficial dermal neutrophilic infiltrate, and neutrophil exocytosis with formation of minute intraepidermal pustules (H&E, original magnification ×200).

Morphologically, our case resembled acute generalized exanthematous pustulosis (AGEP), which presents with edematous erythema studded with pustules.³ Although fever and leukocytosis are often present in both AGEP and Sweet syndrome, our patient’s pain, malaise, and myalgia favored Sweet syndrome, as did his conjunctivitis, which is unusual in AGEP.^1,3 Histologically, our case was characteristic for Sweet syndrome, which presents with marked papillary dermal edema and a dense neutrophilic dermal infiltrate with neutrophil exocytosis and spongiform pustules in 21% of cases.¹ Acute generalized exanthematous pustulosis, characterized by spongiform pustules and a perivascular neutrophilic infiltrate, does not exhibit the dense dermal neutrophilic infiltrate of Sweet syndrome.³  Mecca et al⁴ also reported a case displaying overlapping features of Sweet syndrome and AGEP. The patient presented with photodistributed papules and pinpoint pustules on an erythematous base favoring a diagnosis of AGEP with histologic findings compatible with Sweet syndrome. The authors suggested a clinicopathologic continuum may exist among drug-related neutrophilic dermatoses.⁴

In conclusion, we present a case of TMP-SMX–induced Sweet syndrome that morphologically resembled AGEP. It is important to recognize that Sweet syndrome may present in this unusual manner, as it may have notable internal involvement, and responds rapidly to systemic steroids, whereas AGEP has minimal systemic involvement and clears spontaneously.

To the Editor:

Sweet syndrome is a neutrophilic dermatosis that typically presents as an acute onset of multiple, painful, sharply demarcated, small (measuring a few centimeters), raised, red plaques that occasionally present with superimposed pustules, vesicles, or bullae on the face, neck, upper chest, back, and extremities. Patients are often febrile and may have mucosal and systemic involvement.¹ Although 71% of cases are idiopathic, others are associated with malignancy; autoimmune disorders; infections; pregnancy; and rarely medications, especially all-trans-retinoic acid, granulocyte colony-stimulating factor, vaccines, and antibiotics.^1,2 We present a case of Sweet syndrome induced by trimethoprim-sulfamethoxazole (TMP-SMX) with an unusual clinical presentation.

A 71-year-old man with a medical history of nonmelanoma skin cancer initiated a course of  TMP-SMX for a wound infection of the lower leg following Mohs micrographic surgery. Eight days later, he developed a painful eruption preceded by 1 day of fever, malaise, blurry vision, and myalgia. Trimethoprim-sulfamethoxazole was discontinued. Physical examination revealed ill-defined, discrete and coalescing, 1- to 6-mm edematous erythematous papules studded with pustules involving the scalp, face, neck, back (Figure 1), and extremities. The patient also had conjunctival erythema and an elevated temperature (38.3°C). Laboratory workup revealed an elevated white blood cell count (11,300/mL [reference range, 4500–11,000/µL]), blood urea nitrogen level (33 mg/µL [reference range, 7–20 mg/dL]),  and creatinine level (2.00 mg/dL [reference range,  0.6–1.2 mg/dL]). Liver function tests were normal. A biopsy demonstrated marked papillary dermal edema with a dense, bandlike, superficial dermal neutrophilic infiltrate (Figure 2). A few neutrophils were present in the epidermis with formation of minute intraepidermal pustules. The patient was diagnosed with Sweet syndrome and treated with intravenous methylprednisolone 60 mg 3 times daily (1.5 mg/kg body weight) tapered over 17 days and triamcinolone acetonide ointment 0.1% twice daily. His fever and leukocytosis resolved within 1 day and the eruption improved within 2 days with residual desquamation that cleared by 3 weeks.

Figure 1. Ill-defined, discrete and coalescing, 1- to 6-mm erythematous papules studded with pustules on the back.

Figure 2. Marked papillary dermal edema, a dense superficial dermal neutrophilic infiltrate, and neutrophil exocytosis with formation of minute intraepidermal pustules (H&E, original magnification ×200).

Morphologically, our case resembled acute generalized exanthematous pustulosis (AGEP), which presents with edematous erythema studded with pustules.³ Although fever and leukocytosis are often present in both AGEP and Sweet syndrome, our patient’s pain, malaise, and myalgia favored Sweet syndrome, as did his conjunctivitis, which is unusual in AGEP.^1,3 Histologically, our case was characteristic for Sweet syndrome, which presents with marked papillary dermal edema and a dense neutrophilic dermal infiltrate with neutrophil exocytosis and spongiform pustules in 21% of cases.¹ Acute generalized exanthematous pustulosis, characterized by spongiform pustules and a perivascular neutrophilic infiltrate, does not exhibit the dense dermal neutrophilic infiltrate of Sweet syndrome.³  Mecca et al⁴ also reported a case displaying overlapping features of Sweet syndrome and AGEP. The patient presented with photodistributed papules and pinpoint pustules on an erythematous base favoring a diagnosis of AGEP with histologic findings compatible with Sweet syndrome. The authors suggested a clinicopathologic continuum may exist among drug-related neutrophilic dermatoses.⁴

In conclusion, we present a case of TMP-SMX–induced Sweet syndrome that morphologically resembled AGEP. It is important to recognize that Sweet syndrome may present in this unusual manner, as it may have notable internal involvement, and responds rapidly to systemic steroids, whereas AGEP has minimal systemic involvement and clears spontaneously.

To the Editor:

A 66-year-old man with hypertension presented with asymptomatic, edematous, swelling plaques without local heat on the bilateral auricles of 2 months’ duration (Figure 1). Topical corticosteroids and multiple oral antihistamines were prescribed without any improvement. He reported no history of trauma or use of any topical agents except topical corticosteroids. There was no sensory defect or numbness.

Figure 1. Asymptomatic, edematous, swelling and indurated plaques without local heat on the bilateral auricles (A and B).

Laboratory results revealed leukocytosis with a white blood cell count of 13,900/mL (reference range, 3500–9900/μL) and 55.8% lymphocytes (reference range, 20%–40%). Biochemistry and tumor markers data were normal. No palpable neck lymphadenopathy was found. A skin biopsy was performed on the left earlobe showing a grenz zone between the tumor infiltrate and epidermis and a dense neoplastic lymphoid proliferation with a bottom-heavy configuration in the reticular dermis (Figure 2A). These lymphoid cells were small to medium sized with indented and irregular nuclei and abundant pale cytoplasm (Figure 2B). Immunohistochemical staining showed positivity for CD20 and BCL2; stains for CD5, CD10, CD23, and BCL6 were negative. Positron emission tomography scan showed bilateral auricular infiltration and bilateral neck lymph node involvement. A bone marrow biopsy was performed during hospitalization and was positive for lymphoma involvement. On the basis of histologic and immunohistochemical findings, a diagnosis of malignant nodal marginal zone lymphoma (MZL) with cutaneous involvement was made. The patient underwent chemotherapy with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone).

Figure 2. A skin biopsy showed basket weave hyperkeratosis, a grenz zone between the tumor infiltrate and epidermis, and dense lymphoid proliferation with a bottom-heavy configuration in the reticular dermis (A)(H&E, original magnification ×40). Small- to medium-sized lymphoid cells with indented and irregular nuclei and abundant pale cytoplasm were seen (B)(H&E, original magnification ×400).

Cutaneous MZL may be a primary cutaneous condition or the result of secondary involvement from noncutaneous MZL. The histologic and immunophenotypic changes in skin lesions from secondary cutaneous MZL may be indistinguishable from those in primary cutaneous MZL. Primary cutaneous MZL may be seen in younger patients and favors the trunk and extremities, whereas MZL secondarily involves the skin, favors the head and neck regions, and is limited to older patients.¹ Histologic aspects include a dense, nodular, deep-seated infiltrate containing various proportions of small cells displaying a centrocytelike, plasmacytoid, or monocytoid appearance.² Chronic antigen stimulation is a key player in the pathogenesis and involves deregulation of the nuclear factor κb pathway. While Helicobacter pylori and Epstein-Barr virus do not seem to be implicated in primary cutaneous MZL, the role of Borrelia burgdorferi is still a matter of debate with discordant results.^3,4

Treatment may include excision, curative or adjunctive radiotherapy, topical or intralesional corticosteroids, interferon or intralesional rituximab, or systemic therapies such as chemotherapy and/or intravenous rituximab depending on disease stage and tumor burden.⁵

Cutaneous presentation of MZL as bilateral auricular swelling is unique. Because there may be considerable overlap in the clinical presentations for patients with primary and secondary cutaneous MZL, it is imperative to perform a systemic evaluation. Clinicians should be aware of possible hematologic malignancy in patients with unexplained and refractory bilateral auricular swelling.

To the Editor:

A 66-year-old man with hypertension presented with asymptomatic, edematous, swelling plaques without local heat on the bilateral auricles of 2 months’ duration (Figure 1). Topical corticosteroids and multiple oral antihistamines were prescribed without any improvement. He reported no history of trauma or use of any topical agents except topical corticosteroids. There was no sensory defect or numbness.

Figure 1. Asymptomatic, edematous, swelling and indurated plaques without local heat on the bilateral auricles (A and B).

Laboratory results revealed leukocytosis with a white blood cell count of 13,900/mL (reference range, 3500–9900/μL) and 55.8% lymphocytes (reference range, 20%–40%). Biochemistry and tumor markers data were normal. No palpable neck lymphadenopathy was found. A skin biopsy was performed on the left earlobe showing a grenz zone between the tumor infiltrate and epidermis and a dense neoplastic lymphoid proliferation with a bottom-heavy configuration in the reticular dermis (Figure 2A). These lymphoid cells were small to medium sized with indented and irregular nuclei and abundant pale cytoplasm (Figure 2B). Immunohistochemical staining showed positivity for CD20 and BCL2; stains for CD5, CD10, CD23, and BCL6 were negative. Positron emission tomography scan showed bilateral auricular infiltration and bilateral neck lymph node involvement. A bone marrow biopsy was performed during hospitalization and was positive for lymphoma involvement. On the basis of histologic and immunohistochemical findings, a diagnosis of malignant nodal marginal zone lymphoma (MZL) with cutaneous involvement was made. The patient underwent chemotherapy with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone).

Figure 2. A skin biopsy showed basket weave hyperkeratosis, a grenz zone between the tumor infiltrate and epidermis, and dense lymphoid proliferation with a bottom-heavy configuration in the reticular dermis (A)(H&E, original magnification ×40). Small- to medium-sized lymphoid cells with indented and irregular nuclei and abundant pale cytoplasm were seen (B)(H&E, original magnification ×400).

Cutaneous MZL may be a primary cutaneous condition or the result of secondary involvement from noncutaneous MZL. The histologic and immunophenotypic changes in skin lesions from secondary cutaneous MZL may be indistinguishable from those in primary cutaneous MZL. Primary cutaneous MZL may be seen in younger patients and favors the trunk and extremities, whereas MZL secondarily involves the skin, favors the head and neck regions, and is limited to older patients.¹ Histologic aspects include a dense, nodular, deep-seated infiltrate containing various proportions of small cells displaying a centrocytelike, plasmacytoid, or monocytoid appearance.² Chronic antigen stimulation is a key player in the pathogenesis and involves deregulation of the nuclear factor κb pathway. While Helicobacter pylori and Epstein-Barr virus do not seem to be implicated in primary cutaneous MZL, the role of Borrelia burgdorferi is still a matter of debate with discordant results.^3,4

Treatment may include excision, curative or adjunctive radiotherapy, topical or intralesional corticosteroids, interferon or intralesional rituximab, or systemic therapies such as chemotherapy and/or intravenous rituximab depending on disease stage and tumor burden.⁵

Cutaneous presentation of MZL as bilateral auricular swelling is unique. Because there may be considerable overlap in the clinical presentations for patients with primary and secondary cutaneous MZL, it is imperative to perform a systemic evaluation. Clinicians should be aware of possible hematologic malignancy in patients with unexplained and refractory bilateral auricular swelling.

To the Editor:

A 66-year-old man with hypertension presented with asymptomatic, edematous, swelling plaques without local heat on the bilateral auricles of 2 months’ duration (Figure 1). Topical corticosteroids and multiple oral antihistamines were prescribed without any improvement. He reported no history of trauma or use of any topical agents except topical corticosteroids. There was no sensory defect or numbness.

Figure 1. Asymptomatic, edematous, swelling and indurated plaques without local heat on the bilateral auricles (A and B).

Laboratory results revealed leukocytosis with a white blood cell count of 13,900/mL (reference range, 3500–9900/μL) and 55.8% lymphocytes (reference range, 20%–40%). Biochemistry and tumor markers data were normal. No palpable neck lymphadenopathy was found. A skin biopsy was performed on the left earlobe showing a grenz zone between the tumor infiltrate and epidermis and a dense neoplastic lymphoid proliferation with a bottom-heavy configuration in the reticular dermis (Figure 2A). These lymphoid cells were small to medium sized with indented and irregular nuclei and abundant pale cytoplasm (Figure 2B). Immunohistochemical staining showed positivity for CD20 and BCL2; stains for CD5, CD10, CD23, and BCL6 were negative. Positron emission tomography scan showed bilateral auricular infiltration and bilateral neck lymph node involvement. A bone marrow biopsy was performed during hospitalization and was positive for lymphoma involvement. On the basis of histologic and immunohistochemical findings, a diagnosis of malignant nodal marginal zone lymphoma (MZL) with cutaneous involvement was made. The patient underwent chemotherapy with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone).

Figure 2. A skin biopsy showed basket weave hyperkeratosis, a grenz zone between the tumor infiltrate and epidermis, and dense lymphoid proliferation with a bottom-heavy configuration in the reticular dermis (A)(H&E, original magnification ×40). Small- to medium-sized lymphoid cells with indented and irregular nuclei and abundant pale cytoplasm were seen (B)(H&E, original magnification ×400).

Cutaneous MZL may be a primary cutaneous condition or the result of secondary involvement from noncutaneous MZL. The histologic and immunophenotypic changes in skin lesions from secondary cutaneous MZL may be indistinguishable from those in primary cutaneous MZL. Primary cutaneous MZL may be seen in younger patients and favors the trunk and extremities, whereas MZL secondarily involves the skin, favors the head and neck regions, and is limited to older patients.¹ Histologic aspects include a dense, nodular, deep-seated infiltrate containing various proportions of small cells displaying a centrocytelike, plasmacytoid, or monocytoid appearance.² Chronic antigen stimulation is a key player in the pathogenesis and involves deregulation of the nuclear factor κb pathway. While Helicobacter pylori and Epstein-Barr virus do not seem to be implicated in primary cutaneous MZL, the role of Borrelia burgdorferi is still a matter of debate with discordant results.^3,4

Treatment may include excision, curative or adjunctive radiotherapy, topical or intralesional corticosteroids, interferon or intralesional rituximab, or systemic therapies such as chemotherapy and/or intravenous rituximab depending on disease stage and tumor burden.⁵

Cutaneous presentation of MZL as bilateral auricular swelling is unique. Because there may be considerable overlap in the clinical presentations for patients with primary and secondary cutaneous MZL, it is imperative to perform a systemic evaluation. Clinicians should be aware of possible hematologic malignancy in patients with unexplained and refractory bilateral auricular swelling.