Dermatopathology

The Diagnosis: Scrotal Calcinosis

Scrotal calcinosis is a rare benign disease that results from the deposition of calcium, magnesium, phosphate, and carbonate within the dermis and subcutaneous layer of the skin in the absence of underlying systemic disease or serum calcium and phosphorus abnormalities.^1,2 Lesions usually are asymptomatic but can be mildly painful or pruritic. They usually present in childhood or early adulthood as yellow-white firm nodules ranging in size from a few millimeters to a few centimeters that increase in size and number over time. Additionally, lesions can ulcerate and discharge a chalklike exudative material. Although benign in nature, the quality-of-life impact in patients with this condition can be substantial, specifically regarding cosmesis, which may cause patients to feel embarrassed and even avoid sexual activity. This condition rarely has been associated with infection.¹

Our patient elected to undergo surgical excision under local anesthesia, and the lesions were sent for histopathologic examination. His postoperative course was unremarkable, and he was pleased with the cosmetic result of the surgery (Figure 1). Histopathology revealed calcified deposits that appeared as intradermal basophilic nodules lacking an epithelial lining (Figure 2), consistent with the diagnosis of scrotal calcinosis.² No recurrence of the lesions was documented over the course of 18 months.

The pathogenesis of this condition is not clear. Most research supports scrotal calcinosis resulting from dystrophic calcification of epidermal inclusion cysts.³ There have been cases of scrotal calcinosis coinciding with epidermal inclusion cysts of the scrotum in varying stages of inflammation (some intact and some ruptured).² Some research also suggests dystrophic calcification of eccrine epithelial cysts and degenerated dartos muscle as the origin of scrotal calcinosis.³

The differential diagnosis for this case included calcified steatocystoma multiplex, eruptive xanthomas, nodular scabies, and epidermal inclusion cysts. Steatocystoma multiplex can be inherited in an autosomal-dominant fashion or can develop sporadically with mutations in the KRT17 gene.⁴ It is characterized by multiple sebum-filled, cystic lesions of the pilosebaceous unit that may become calcified. Calcified lesions appear as yellow, firm, irregularly shaped papules or nodules ranging from a few millimeters to centimeters in size. Cysts can develop anywhere on the body with a predilection for the chest, upper extremities, axillae, trunk, groin, and scrotum.⁴ Histologically, our patient’s lesions were not associated with the pilosebaceous unit. Additionally, our patient denied a family history of similar skin lesions, which made calcified steatocystoma multiplex an unlikely diagnosis.

Eruptive xanthomas result from localized deposition of lipids within the dermis, typically in the setting of dyslipidemia or poorly controlled diabetes mellitus. They commonly appear on the extremities or buttocks as pruritic crops of yellow-red papules or nodules that are a few millimeters in size. Although our patient has a history of hyperlipidemia, his lesions differed substantially from eruptive xanthomas in clinical presentation.

Nodular scabies is a manifestation of classic scabies that presents with intensely pruritic erythematous papules and nodules that are a few millimeters in size and commonly occur on the axillae, groin, and genitalia. Our patient’s skin lesions were not pruritic and differed in appearance from nodular scabies.

Although research indicates scrotal calcinosis may result from dystrophic calcification of epidermal inclusion cysts,² the latter present as dome-shaped, flesh-colored nodules with central pores representing the opening of hair follicles. Our patient lacked characteristic findings of epidermal inclusion cysts on histology.

The preferred treatment for scrotal calcinosis is surgical excision, which improves the aesthetic appearance, relieves itch, and removes ulcerative lesions.⁵ Additionally, surgical excision provides histological diagnostic confirmation. Recurrence with incomplete excision is possible; therefore, all lesions should be completely excised to reduce the risk for recurrence.³

The Diagnosis: Scrotal Calcinosis

Scrotal calcinosis is a rare benign disease that results from the deposition of calcium, magnesium, phosphate, and carbonate within the dermis and subcutaneous layer of the skin in the absence of underlying systemic disease or serum calcium and phosphorus abnormalities.^1,2 Lesions usually are asymptomatic but can be mildly painful or pruritic. They usually present in childhood or early adulthood as yellow-white firm nodules ranging in size from a few millimeters to a few centimeters that increase in size and number over time. Additionally, lesions can ulcerate and discharge a chalklike exudative material. Although benign in nature, the quality-of-life impact in patients with this condition can be substantial, specifically regarding cosmesis, which may cause patients to feel embarrassed and even avoid sexual activity. This condition rarely has been associated with infection.¹

Our patient elected to undergo surgical excision under local anesthesia, and the lesions were sent for histopathologic examination. His postoperative course was unremarkable, and he was pleased with the cosmetic result of the surgery (Figure 1). Histopathology revealed calcified deposits that appeared as intradermal basophilic nodules lacking an epithelial lining (Figure 2), consistent with the diagnosis of scrotal calcinosis.² No recurrence of the lesions was documented over the course of 18 months.

The pathogenesis of this condition is not clear. Most research supports scrotal calcinosis resulting from dystrophic calcification of epidermal inclusion cysts.³ There have been cases of scrotal calcinosis coinciding with epidermal inclusion cysts of the scrotum in varying stages of inflammation (some intact and some ruptured).² Some research also suggests dystrophic calcification of eccrine epithelial cysts and degenerated dartos muscle as the origin of scrotal calcinosis.³

The differential diagnosis for this case included calcified steatocystoma multiplex, eruptive xanthomas, nodular scabies, and epidermal inclusion cysts. Steatocystoma multiplex can be inherited in an autosomal-dominant fashion or can develop sporadically with mutations in the KRT17 gene.⁴ It is characterized by multiple sebum-filled, cystic lesions of the pilosebaceous unit that may become calcified. Calcified lesions appear as yellow, firm, irregularly shaped papules or nodules ranging from a few millimeters to centimeters in size. Cysts can develop anywhere on the body with a predilection for the chest, upper extremities, axillae, trunk, groin, and scrotum.⁴ Histologically, our patient’s lesions were not associated with the pilosebaceous unit. Additionally, our patient denied a family history of similar skin lesions, which made calcified steatocystoma multiplex an unlikely diagnosis.

Eruptive xanthomas result from localized deposition of lipids within the dermis, typically in the setting of dyslipidemia or poorly controlled diabetes mellitus. They commonly appear on the extremities or buttocks as pruritic crops of yellow-red papules or nodules that are a few millimeters in size. Although our patient has a history of hyperlipidemia, his lesions differed substantially from eruptive xanthomas in clinical presentation.

Nodular scabies is a manifestation of classic scabies that presents with intensely pruritic erythematous papules and nodules that are a few millimeters in size and commonly occur on the axillae, groin, and genitalia. Our patient’s skin lesions were not pruritic and differed in appearance from nodular scabies.

Although research indicates scrotal calcinosis may result from dystrophic calcification of epidermal inclusion cysts,² the latter present as dome-shaped, flesh-colored nodules with central pores representing the opening of hair follicles. Our patient lacked characteristic findings of epidermal inclusion cysts on histology.

The preferred treatment for scrotal calcinosis is surgical excision, which improves the aesthetic appearance, relieves itch, and removes ulcerative lesions.⁵ Additionally, surgical excision provides histological diagnostic confirmation. Recurrence with incomplete excision is possible; therefore, all lesions should be completely excised to reduce the risk for recurrence.³

The Diagnosis: Scrotal Calcinosis

Scrotal calcinosis is a rare benign disease that results from the deposition of calcium, magnesium, phosphate, and carbonate within the dermis and subcutaneous layer of the skin in the absence of underlying systemic disease or serum calcium and phosphorus abnormalities.^1,2 Lesions usually are asymptomatic but can be mildly painful or pruritic. They usually present in childhood or early adulthood as yellow-white firm nodules ranging in size from a few millimeters to a few centimeters that increase in size and number over time. Additionally, lesions can ulcerate and discharge a chalklike exudative material. Although benign in nature, the quality-of-life impact in patients with this condition can be substantial, specifically regarding cosmesis, which may cause patients to feel embarrassed and even avoid sexual activity. This condition rarely has been associated with infection.¹

Our patient elected to undergo surgical excision under local anesthesia, and the lesions were sent for histopathologic examination. His postoperative course was unremarkable, and he was pleased with the cosmetic result of the surgery (Figure 1). Histopathology revealed calcified deposits that appeared as intradermal basophilic nodules lacking an epithelial lining (Figure 2), consistent with the diagnosis of scrotal calcinosis.² No recurrence of the lesions was documented over the course of 18 months.

The pathogenesis of this condition is not clear. Most research supports scrotal calcinosis resulting from dystrophic calcification of epidermal inclusion cysts.³ There have been cases of scrotal calcinosis coinciding with epidermal inclusion cysts of the scrotum in varying stages of inflammation (some intact and some ruptured).² Some research also suggests dystrophic calcification of eccrine epithelial cysts and degenerated dartos muscle as the origin of scrotal calcinosis.³

The differential diagnosis for this case included calcified steatocystoma multiplex, eruptive xanthomas, nodular scabies, and epidermal inclusion cysts. Steatocystoma multiplex can be inherited in an autosomal-dominant fashion or can develop sporadically with mutations in the KRT17 gene.⁴ It is characterized by multiple sebum-filled, cystic lesions of the pilosebaceous unit that may become calcified. Calcified lesions appear as yellow, firm, irregularly shaped papules or nodules ranging from a few millimeters to centimeters in size. Cysts can develop anywhere on the body with a predilection for the chest, upper extremities, axillae, trunk, groin, and scrotum.⁴ Histologically, our patient’s lesions were not associated with the pilosebaceous unit. Additionally, our patient denied a family history of similar skin lesions, which made calcified steatocystoma multiplex an unlikely diagnosis.

Eruptive xanthomas result from localized deposition of lipids within the dermis, typically in the setting of dyslipidemia or poorly controlled diabetes mellitus. They commonly appear on the extremities or buttocks as pruritic crops of yellow-red papules or nodules that are a few millimeters in size. Although our patient has a history of hyperlipidemia, his lesions differed substantially from eruptive xanthomas in clinical presentation.

Nodular scabies is a manifestation of classic scabies that presents with intensely pruritic erythematous papules and nodules that are a few millimeters in size and commonly occur on the axillae, groin, and genitalia. Our patient’s skin lesions were not pruritic and differed in appearance from nodular scabies.

Although research indicates scrotal calcinosis may result from dystrophic calcification of epidermal inclusion cysts,² the latter present as dome-shaped, flesh-colored nodules with central pores representing the opening of hair follicles. Our patient lacked characteristic findings of epidermal inclusion cysts on histology.

The preferred treatment for scrotal calcinosis is surgical excision, which improves the aesthetic appearance, relieves itch, and removes ulcerative lesions.⁵ Additionally, surgical excision provides histological diagnostic confirmation. Recurrence with incomplete excision is possible; therefore, all lesions should be completely excised to reduce the risk for recurrence.³

The Diagnosis: Extragenital Lichen Sclerosus et Atrophicus

A punch biopsy of the lesion revealed epidermal hyperkeratosis, atrophy, follicular plugs with basal vacuolar degeneration, and homogenous dense fibrosis in the papillary dermis with a dense lymphocytic infiltrate beneath the fibrosis (Figure 1). Dermoscopic examination was remarkable for a distinctive rainbow pattern. Clinical, histopathologic, and dermoscopic findings led to the diagnosis of extragenital lichen sclerosus et atrophicus (LSEA). A potent corticosteroid cream was prescribed twice daily for 2 months, after which the lesions completely resolved. At 2-year follow-up, a relapse was not observed (Figure 2).

Lichen sclerosus et atrophicus is an inflammatory dermatosis that clinically presents as atrophic or hypertrophic plaques that may show pigmentation changes with anogenital and extragenital involvement. It is common among females and predominantly occurs in prepubescent girls and postmenopausal women. The exact etiology is unclear; however, it is hypothesized to occur secondary to autoimmunity with an underlying genetic predisposition. Local trauma, hormonal influences, and infections are other suspected etiologic factors. Genital lesions often lead to itching, pain, and dyspareunia, whereas extragenital lesions predominantly are asymptomatic. When symptomatic, itching usually is the main concern. Unlike genital LSEA, extragenital lesions are not associated with squamous cell carcinoma development. Reported dermoscopic features of LSEA are white structureless areas with scaling, comedolike openings, follicular plugs, white shiny streaks, blue-gray peppering, pigment network, and red-purple globules.¹ In our case, the dermoscopic finding of a rainbow pattern in LSEA is rare.² Although the mechanism behind this appearance unclear, it can be the result of the birefringence effect—local variations in refractive index—influenced by the direction of structures within the dermis such as collagen. In this case, there was diffuse and dense homogenous fibrosis in the superficial dermis that corresponded to dermoscopic white polygonal clods.

Extragenital LSEA commonly is located on the neck, shoulders, wrists, and upper trunk and manifests clinically as whitish papules coalescing into scarlike plaques. Of all patients who have LSEA, 20% have extragenital lesions, and most of these lesions are seen in patients who also have genital LSEA. Approximately 6% of all LSEA patients have extragenital LSEA without genital involvement.³

For experienced dermatologists, clinical symptoms and lesion characteristics usually are sufficient for diagnosis; however, a differential diagnosis of atypical lesions and isolated extragenital presentations such as morphea, lichen simplex chronicus, lichen planus, and vitiligo requires the correlation of clinical findings with histopathology and dermoscopy. Morphea, known as localized scleroderma, is an idiopathic inflammatory skin disease with sclerotic changes. It manifests as inflammatory plaques that vary in color from red to purple. If there is moderate sclerosis in the center of this plaque, the color progressively fades to white, leaving a purplish ring around the edges. Dermoscopic features of morphea are reported as areas of erythema; red-focused vessels of linear, irregular, or dotted morphology; white fibrotic beams; and pigmentary structures.² Lichen simplex chronicus is characterized by single or multiple dry and patchy skin lesions that are intensely pruritic. It commonly occurs on the neck, scalp, extremities, genital areas, and buttocks. Scratching the lesions leads to scarring, thickening of the skin, and increased frequency of itching. Histopathology of lichen simplex chronicus most frequently demonstrates a thickening of the epidermis and papillary dermis, irregularly elongated rete ridges, and fibroplasia with stellate or multinucleated fibroblasts completed by perivascular lymphocytic inflammation.⁴ Lichen planus presents with pruritic, polygonal, purple papules and/or plaques that can present in a variety of clinical forms, including atrophic and hypertrophic lichen planus.⁵ Lichen planus was an unlikely diagnosis for our patient due to the presence of patchy scarlike lesions and dermoscopic features that are well described in patients with LSEA. Lichen sclerosus et atrophicus presents with hypopigmented and/or hyperpigmented patches and plaques, distinguishing itself from vitiligo, which has flat lesions.

Topical steroids are the first-line therapeutic agents in the treatment of LSEA.6 Despite frequent use in this setting, common side effects such as localized scarring and atrophic degenerations have led to debate about their use. In our patient, the lesions resolved almost completely in 2 months, and no relapse was observed in the following 2 years. In the setting of topical steroid resistance, topical calcineurin inhibitors, UVA/UVB phototherapy, and topical tacrolimus can be used for treatment.⁶

The diagnosis of isolated extragenital LSEA may be a clinical challenge and generally requires further workup. When evaluating extragenital lesions, dermatologists should keep in mind extragenital LSEA as a differential diagnosis in the presence of a dermoscopic rainbow pattern arranged over white polygonal clods.

The Diagnosis: Extragenital Lichen Sclerosus et Atrophicus

A punch biopsy of the lesion revealed epidermal hyperkeratosis, atrophy, follicular plugs with basal vacuolar degeneration, and homogenous dense fibrosis in the papillary dermis with a dense lymphocytic infiltrate beneath the fibrosis (Figure 1). Dermoscopic examination was remarkable for a distinctive rainbow pattern. Clinical, histopathologic, and dermoscopic findings led to the diagnosis of extragenital lichen sclerosus et atrophicus (LSEA). A potent corticosteroid cream was prescribed twice daily for 2 months, after which the lesions completely resolved. At 2-year follow-up, a relapse was not observed (Figure 2).

Lichen sclerosus et atrophicus is an inflammatory dermatosis that clinically presents as atrophic or hypertrophic plaques that may show pigmentation changes with anogenital and extragenital involvement. It is common among females and predominantly occurs in prepubescent girls and postmenopausal women. The exact etiology is unclear; however, it is hypothesized to occur secondary to autoimmunity with an underlying genetic predisposition. Local trauma, hormonal influences, and infections are other suspected etiologic factors. Genital lesions often lead to itching, pain, and dyspareunia, whereas extragenital lesions predominantly are asymptomatic. When symptomatic, itching usually is the main concern. Unlike genital LSEA, extragenital lesions are not associated with squamous cell carcinoma development. Reported dermoscopic features of LSEA are white structureless areas with scaling, comedolike openings, follicular plugs, white shiny streaks, blue-gray peppering, pigment network, and red-purple globules.¹ In our case, the dermoscopic finding of a rainbow pattern in LSEA is rare.² Although the mechanism behind this appearance unclear, it can be the result of the birefringence effect—local variations in refractive index—influenced by the direction of structures within the dermis such as collagen. In this case, there was diffuse and dense homogenous fibrosis in the superficial dermis that corresponded to dermoscopic white polygonal clods.

Extragenital LSEA commonly is located on the neck, shoulders, wrists, and upper trunk and manifests clinically as whitish papules coalescing into scarlike plaques. Of all patients who have LSEA, 20% have extragenital lesions, and most of these lesions are seen in patients who also have genital LSEA. Approximately 6% of all LSEA patients have extragenital LSEA without genital involvement.³

For experienced dermatologists, clinical symptoms and lesion characteristics usually are sufficient for diagnosis; however, a differential diagnosis of atypical lesions and isolated extragenital presentations such as morphea, lichen simplex chronicus, lichen planus, and vitiligo requires the correlation of clinical findings with histopathology and dermoscopy. Morphea, known as localized scleroderma, is an idiopathic inflammatory skin disease with sclerotic changes. It manifests as inflammatory plaques that vary in color from red to purple. If there is moderate sclerosis in the center of this plaque, the color progressively fades to white, leaving a purplish ring around the edges. Dermoscopic features of morphea are reported as areas of erythema; red-focused vessels of linear, irregular, or dotted morphology; white fibrotic beams; and pigmentary structures.² Lichen simplex chronicus is characterized by single or multiple dry and patchy skin lesions that are intensely pruritic. It commonly occurs on the neck, scalp, extremities, genital areas, and buttocks. Scratching the lesions leads to scarring, thickening of the skin, and increased frequency of itching. Histopathology of lichen simplex chronicus most frequently demonstrates a thickening of the epidermis and papillary dermis, irregularly elongated rete ridges, and fibroplasia with stellate or multinucleated fibroblasts completed by perivascular lymphocytic inflammation.⁴ Lichen planus presents with pruritic, polygonal, purple papules and/or plaques that can present in a variety of clinical forms, including atrophic and hypertrophic lichen planus.⁵ Lichen planus was an unlikely diagnosis for our patient due to the presence of patchy scarlike lesions and dermoscopic features that are well described in patients with LSEA. Lichen sclerosus et atrophicus presents with hypopigmented and/or hyperpigmented patches and plaques, distinguishing itself from vitiligo, which has flat lesions.

Topical steroids are the first-line therapeutic agents in the treatment of LSEA.6 Despite frequent use in this setting, common side effects such as localized scarring and atrophic degenerations have led to debate about their use. In our patient, the lesions resolved almost completely in 2 months, and no relapse was observed in the following 2 years. In the setting of topical steroid resistance, topical calcineurin inhibitors, UVA/UVB phototherapy, and topical tacrolimus can be used for treatment.⁶

The diagnosis of isolated extragenital LSEA may be a clinical challenge and generally requires further workup. When evaluating extragenital lesions, dermatologists should keep in mind extragenital LSEA as a differential diagnosis in the presence of a dermoscopic rainbow pattern arranged over white polygonal clods.

The Diagnosis: Extragenital Lichen Sclerosus et Atrophicus

A punch biopsy of the lesion revealed epidermal hyperkeratosis, atrophy, follicular plugs with basal vacuolar degeneration, and homogenous dense fibrosis in the papillary dermis with a dense lymphocytic infiltrate beneath the fibrosis (Figure 1). Dermoscopic examination was remarkable for a distinctive rainbow pattern. Clinical, histopathologic, and dermoscopic findings led to the diagnosis of extragenital lichen sclerosus et atrophicus (LSEA). A potent corticosteroid cream was prescribed twice daily for 2 months, after which the lesions completely resolved. At 2-year follow-up, a relapse was not observed (Figure 2).

Lichen sclerosus et atrophicus is an inflammatory dermatosis that clinically presents as atrophic or hypertrophic plaques that may show pigmentation changes with anogenital and extragenital involvement. It is common among females and predominantly occurs in prepubescent girls and postmenopausal women. The exact etiology is unclear; however, it is hypothesized to occur secondary to autoimmunity with an underlying genetic predisposition. Local trauma, hormonal influences, and infections are other suspected etiologic factors. Genital lesions often lead to itching, pain, and dyspareunia, whereas extragenital lesions predominantly are asymptomatic. When symptomatic, itching usually is the main concern. Unlike genital LSEA, extragenital lesions are not associated with squamous cell carcinoma development. Reported dermoscopic features of LSEA are white structureless areas with scaling, comedolike openings, follicular plugs, white shiny streaks, blue-gray peppering, pigment network, and red-purple globules.¹ In our case, the dermoscopic finding of a rainbow pattern in LSEA is rare.² Although the mechanism behind this appearance unclear, it can be the result of the birefringence effect—local variations in refractive index—influenced by the direction of structures within the dermis such as collagen. In this case, there was diffuse and dense homogenous fibrosis in the superficial dermis that corresponded to dermoscopic white polygonal clods.

Extragenital LSEA commonly is located on the neck, shoulders, wrists, and upper trunk and manifests clinically as whitish papules coalescing into scarlike plaques. Of all patients who have LSEA, 20% have extragenital lesions, and most of these lesions are seen in patients who also have genital LSEA. Approximately 6% of all LSEA patients have extragenital LSEA without genital involvement.³

For experienced dermatologists, clinical symptoms and lesion characteristics usually are sufficient for diagnosis; however, a differential diagnosis of atypical lesions and isolated extragenital presentations such as morphea, lichen simplex chronicus, lichen planus, and vitiligo requires the correlation of clinical findings with histopathology and dermoscopy. Morphea, known as localized scleroderma, is an idiopathic inflammatory skin disease with sclerotic changes. It manifests as inflammatory plaques that vary in color from red to purple. If there is moderate sclerosis in the center of this plaque, the color progressively fades to white, leaving a purplish ring around the edges. Dermoscopic features of morphea are reported as areas of erythema; red-focused vessels of linear, irregular, or dotted morphology; white fibrotic beams; and pigmentary structures.² Lichen simplex chronicus is characterized by single or multiple dry and patchy skin lesions that are intensely pruritic. It commonly occurs on the neck, scalp, extremities, genital areas, and buttocks. Scratching the lesions leads to scarring, thickening of the skin, and increased frequency of itching. Histopathology of lichen simplex chronicus most frequently demonstrates a thickening of the epidermis and papillary dermis, irregularly elongated rete ridges, and fibroplasia with stellate or multinucleated fibroblasts completed by perivascular lymphocytic inflammation.⁴ Lichen planus presents with pruritic, polygonal, purple papules and/or plaques that can present in a variety of clinical forms, including atrophic and hypertrophic lichen planus.⁵ Lichen planus was an unlikely diagnosis for our patient due to the presence of patchy scarlike lesions and dermoscopic features that are well described in patients with LSEA. Lichen sclerosus et atrophicus presents with hypopigmented and/or hyperpigmented patches and plaques, distinguishing itself from vitiligo, which has flat lesions.

Topical steroids are the first-line therapeutic agents in the treatment of LSEA.6 Despite frequent use in this setting, common side effects such as localized scarring and atrophic degenerations have led to debate about their use. In our patient, the lesions resolved almost completely in 2 months, and no relapse was observed in the following 2 years. In the setting of topical steroid resistance, topical calcineurin inhibitors, UVA/UVB phototherapy, and topical tacrolimus can be used for treatment.⁶

The diagnosis of isolated extragenital LSEA may be a clinical challenge and generally requires further workup. When evaluating extragenital lesions, dermatologists should keep in mind extragenital LSEA as a differential diagnosis in the presence of a dermoscopic rainbow pattern arranged over white polygonal clods.

The Diagnosis: Diffuse Dermal Angiomatosis

Diffuse dermal angiomatosis (DDA) is an acquired reactive vascular proliferation in the spectrum of cutaneous reactive angioendotheliomatoses. Clinically, DDA presents as violaceous reticulated plaques, often with secondary ulceration and sometimes necrosis.1-3 Diffuse dermal angiomatosis more commonly presents in patients with a history of severe peripheral vascular disease, coagulopathies, or infection, and it frequently arises on the extremities. Diffuse dermal angiomatosis also has been shown to develop on the breasts, particularly in patients with pendulous breast tissue. Vascular proliferation in DDA is hypothesized to be from ischemia and hypoxia, leading to angiogenesis.^1-3 Diffuse dermal angiomatosis is characterized histologically by the presence of a diffuse proliferation of spindled endothelial cells distributed between the collagen bundles throughout the dermis (quiz image and Figure 1). Spindle-shaped endothelial cells exhibit a vacuolated cytoplasm. On immunohistochemistry, these dermal spindle cells classically stain positive for CD31, CD34, and erythroblast transformation specific–related gene (Erg) and stain negative for both human herpesvirus 8 (HHV-8) and factor XIIIa.

Cutaneous fibrous histiocytoma, more commonly referred to as dermatofibroma, is a common benign lesion that presents clinically as a solitary firm nodule most commonly on the extremities in areas of repetitive trauma or pressure. It classically exhibits dimpling of the overlaying skin with lateral pressure on the lesion, known as the dimple sign.⁴ Histologically, dermatofibromas share similar features to DDA and demonstrate the presence of bland-appearing spindle cells within the dermis between the collagen bundles, resulting in collagen trapping. However, a distinguishing histologic feature of a dermatofibroma in comparison to DDA is the presence of epidermal hyperplasia overlying the dermatofibroma, leading to tabled rete ridges (Figure 2). Spindle cells in dermatofibromas are fibroblasts and have a distinct immunophenotype that includes factor XIIIa positivity and negative staining for CD31, CD34, and Erg.^4,5

Dermatofibrosarcoma protuberans (DFSP) is a rare malignant soft-tissue sarcoma that clinically presents as a firm, flesh-colored, dermal plaque on the trunk, proximal extremities, head, or neck.⁵ Histologically, DFSP can be distinguished from DDA by the high density of spindle cells that are arranged in a storiform pattern, extending and infiltrating the underlying subcutaneous fat in a honeycomblike pattern (Figure 3). Spindle cells in DFSP typically show expression of CD34 but are negative for CD31, Erg, and factor XIIIa.⁵

Kaposi sarcoma (KS) is an endothelial cell–driven angioproliferative neoplasm that is associated with HHV-8 infection.⁶ The clinical presentation of KS can range from isolated pink or purple papules and patches to more extensive ulcerated plaques or nodules. Histopathology exhibits proliferation of monomorphic spindled endothelial cells within the dermis staining positive for HHV-8, Erg, CD31, and CD34, in conjunction with extravasated erythrocytes arranged within slitlike vascular spaces (Figure 4). Additionally, KS classically exhibits aberrant endothelial cell proliferation and vessel formation around preexisting vessels, which is referred to as the promontory sign (Figure 4).

Angiosarcoma is a rare and highly aggressive vascular tumor arising from endothelial cells lining the blood vessels and lymphatics.^7,8 Clinically, angiosarcoma presents as ulcerated violaceous nodules or plaques on the head, neck, or trunk. Histologic evaluation of angiosarcoma reveals a complex and poorly demarcated vascular network dissecting between collagen bundles in the dermis (Figure 5). Multilayering of endothelial cells, papillary projections extending into the vessel lumina, and mitoses frequently are seen. On immunohistochemistry, endothelial cells demonstrate prominent cellular atypia and stain positive with CD31, CD34, and Erg.

The Diagnosis: Diffuse Dermal Angiomatosis

Diffuse dermal angiomatosis (DDA) is an acquired reactive vascular proliferation in the spectrum of cutaneous reactive angioendotheliomatoses. Clinically, DDA presents as violaceous reticulated plaques, often with secondary ulceration and sometimes necrosis.1-3 Diffuse dermal angiomatosis more commonly presents in patients with a history of severe peripheral vascular disease, coagulopathies, or infection, and it frequently arises on the extremities. Diffuse dermal angiomatosis also has been shown to develop on the breasts, particularly in patients with pendulous breast tissue. Vascular proliferation in DDA is hypothesized to be from ischemia and hypoxia, leading to angiogenesis.^1-3 Diffuse dermal angiomatosis is characterized histologically by the presence of a diffuse proliferation of spindled endothelial cells distributed between the collagen bundles throughout the dermis (quiz image and Figure 1). Spindle-shaped endothelial cells exhibit a vacuolated cytoplasm. On immunohistochemistry, these dermal spindle cells classically stain positive for CD31, CD34, and erythroblast transformation specific–related gene (Erg) and stain negative for both human herpesvirus 8 (HHV-8) and factor XIIIa.

Cutaneous fibrous histiocytoma, more commonly referred to as dermatofibroma, is a common benign lesion that presents clinically as a solitary firm nodule most commonly on the extremities in areas of repetitive trauma or pressure. It classically exhibits dimpling of the overlaying skin with lateral pressure on the lesion, known as the dimple sign.⁴ Histologically, dermatofibromas share similar features to DDA and demonstrate the presence of bland-appearing spindle cells within the dermis between the collagen bundles, resulting in collagen trapping. However, a distinguishing histologic feature of a dermatofibroma in comparison to DDA is the presence of epidermal hyperplasia overlying the dermatofibroma, leading to tabled rete ridges (Figure 2). Spindle cells in dermatofibromas are fibroblasts and have a distinct immunophenotype that includes factor XIIIa positivity and negative staining for CD31, CD34, and Erg.^4,5

Dermatofibrosarcoma protuberans (DFSP) is a rare malignant soft-tissue sarcoma that clinically presents as a firm, flesh-colored, dermal plaque on the trunk, proximal extremities, head, or neck.⁵ Histologically, DFSP can be distinguished from DDA by the high density of spindle cells that are arranged in a storiform pattern, extending and infiltrating the underlying subcutaneous fat in a honeycomblike pattern (Figure 3). Spindle cells in DFSP typically show expression of CD34 but are negative for CD31, Erg, and factor XIIIa.⁵

Kaposi sarcoma (KS) is an endothelial cell–driven angioproliferative neoplasm that is associated with HHV-8 infection.⁶ The clinical presentation of KS can range from isolated pink or purple papules and patches to more extensive ulcerated plaques or nodules. Histopathology exhibits proliferation of monomorphic spindled endothelial cells within the dermis staining positive for HHV-8, Erg, CD31, and CD34, in conjunction with extravasated erythrocytes arranged within slitlike vascular spaces (Figure 4). Additionally, KS classically exhibits aberrant endothelial cell proliferation and vessel formation around preexisting vessels, which is referred to as the promontory sign (Figure 4).

Angiosarcoma is a rare and highly aggressive vascular tumor arising from endothelial cells lining the blood vessels and lymphatics.^7,8 Clinically, angiosarcoma presents as ulcerated violaceous nodules or plaques on the head, neck, or trunk. Histologic evaluation of angiosarcoma reveals a complex and poorly demarcated vascular network dissecting between collagen bundles in the dermis (Figure 5). Multilayering of endothelial cells, papillary projections extending into the vessel lumina, and mitoses frequently are seen. On immunohistochemistry, endothelial cells demonstrate prominent cellular atypia and stain positive with CD31, CD34, and Erg.

The Diagnosis: Diffuse Dermal Angiomatosis

Diffuse dermal angiomatosis (DDA) is an acquired reactive vascular proliferation in the spectrum of cutaneous reactive angioendotheliomatoses. Clinically, DDA presents as violaceous reticulated plaques, often with secondary ulceration and sometimes necrosis.1-3 Diffuse dermal angiomatosis more commonly presents in patients with a history of severe peripheral vascular disease, coagulopathies, or infection, and it frequently arises on the extremities. Diffuse dermal angiomatosis also has been shown to develop on the breasts, particularly in patients with pendulous breast tissue. Vascular proliferation in DDA is hypothesized to be from ischemia and hypoxia, leading to angiogenesis.^1-3 Diffuse dermal angiomatosis is characterized histologically by the presence of a diffuse proliferation of spindled endothelial cells distributed between the collagen bundles throughout the dermis (quiz image and Figure 1). Spindle-shaped endothelial cells exhibit a vacuolated cytoplasm. On immunohistochemistry, these dermal spindle cells classically stain positive for CD31, CD34, and erythroblast transformation specific–related gene (Erg) and stain negative for both human herpesvirus 8 (HHV-8) and factor XIIIa.

Cutaneous fibrous histiocytoma, more commonly referred to as dermatofibroma, is a common benign lesion that presents clinically as a solitary firm nodule most commonly on the extremities in areas of repetitive trauma or pressure. It classically exhibits dimpling of the overlaying skin with lateral pressure on the lesion, known as the dimple sign.⁴ Histologically, dermatofibromas share similar features to DDA and demonstrate the presence of bland-appearing spindle cells within the dermis between the collagen bundles, resulting in collagen trapping. However, a distinguishing histologic feature of a dermatofibroma in comparison to DDA is the presence of epidermal hyperplasia overlying the dermatofibroma, leading to tabled rete ridges (Figure 2). Spindle cells in dermatofibromas are fibroblasts and have a distinct immunophenotype that includes factor XIIIa positivity and negative staining for CD31, CD34, and Erg.^4,5

Dermatofibrosarcoma protuberans (DFSP) is a rare malignant soft-tissue sarcoma that clinically presents as a firm, flesh-colored, dermal plaque on the trunk, proximal extremities, head, or neck.⁵ Histologically, DFSP can be distinguished from DDA by the high density of spindle cells that are arranged in a storiform pattern, extending and infiltrating the underlying subcutaneous fat in a honeycomblike pattern (Figure 3). Spindle cells in DFSP typically show expression of CD34 but are negative for CD31, Erg, and factor XIIIa.⁵

Kaposi sarcoma (KS) is an endothelial cell–driven angioproliferative neoplasm that is associated with HHV-8 infection.⁶ The clinical presentation of KS can range from isolated pink or purple papules and patches to more extensive ulcerated plaques or nodules. Histopathology exhibits proliferation of monomorphic spindled endothelial cells within the dermis staining positive for HHV-8, Erg, CD31, and CD34, in conjunction with extravasated erythrocytes arranged within slitlike vascular spaces (Figure 4). Additionally, KS classically exhibits aberrant endothelial cell proliferation and vessel formation around preexisting vessels, which is referred to as the promontory sign (Figure 4).

Angiosarcoma is a rare and highly aggressive vascular tumor arising from endothelial cells lining the blood vessels and lymphatics.^7,8 Clinically, angiosarcoma presents as ulcerated violaceous nodules or plaques on the head, neck, or trunk. Histologic evaluation of angiosarcoma reveals a complex and poorly demarcated vascular network dissecting between collagen bundles in the dermis (Figure 5). Multilayering of endothelial cells, papillary projections extending into the vessel lumina, and mitoses frequently are seen. On immunohistochemistry, endothelial cells demonstrate prominent cellular atypia and stain positive with CD31, CD34, and Erg.

The Diagnosis: Cutaneous Metastasis

A shave biopsy of the lip revealed a diffuse cellular infiltrate filling the superficial and deep dermis (Figure 1A). Morphologically, the cells had abundant clear cytoplasm with eccentrically located, pleomorphic, hyperchromatic nuclei with occasional prominent nucleoli (Figure 1B). The cells stained positive for AE1/ AE3 on immunohistochemistry (Figure 2). A punch biopsy of the nodule in the right axillary vault revealed a morphologically similar proliferation of cells. A colonoscopy revealed a completely obstructing circumferential mass in the distal ascending colon. A biopsy of the mass confirmed invasive adenocarcinoma, supporting a diagnosis of cutaneous metastases from adenocarcinoma of the colon. The patient underwent resection of the lip tumor and started multiagent chemotherapy for his newly diagnosed stage IV adenocarcinoma of the colon. The patient died, despite therapy.

Cutaneous metastasis from solid malignancies is uncommon, as only 1.3% of them exhibit cutaneous manifestations at presentation.¹ Cutaneous metastasis from signet ring cell adenocarcinoma (SRCA) of the colon is uncommon, and cutaneous metastasis of colorectal SRCA rarely precedes the diagnosis of the primary lesion.² Among the colorectal cancers that metastasize to the skin, metastasis to the face occurs in only 0.5% of patients.³

Signet ring cell adenocarcinomas are poorly differentiated adenocarcinomas histologically characterized by the neoplastic cells’ circular to ovoid appearance with a flattened top.^4,5 This distinctive shape is from the displacement of the nucleus to the periphery of the cell due to the accumulation of intracytoplasmic mucin.⁴ Classically, malignancies are characterized as an SRCA if more than 50% of the cells have a signet ring cell morphology; if the signet ring cells comprise less than 50% of the neoplasm, the tumor is designated as an adenocarcinoma with signet ring morphology.⁴ The most common cause of cutaneous metastasis with signet ring morphology is gastric cancer, while colorectal carcinoma is less common.1 Colorectal SRCAs usually are found in the right colon or the rectum in comparison to other colonic sites.⁶

Clinically, cutaneous metastasis can present in a variety of ways. The most common presentation is nodular lesions that may coalesce to become zosteriform in configuration or lesions that mimic inflammatory dermatoses.⁷ Cutaneous metastasis is more common in breast and lung cancer, and when it occurs secondary to colorectal cancer, cutaneous metastasis rarely predates the detection of the primary neoplasm.²

The clinical appearance of metastasis is not specific and can mimic many entities⁸; therefore, a high index of suspicion must be employed when managing patients, even those without a history of internal malignancy. In our patient, the smooth nodular lesion appeared similar to a basal cell carcinoma; however, basal cell carcinomas appear more pearly, and arborizing telangiectasia often is seen.⁹ Merkel cell carcinoma is common on sundamaged skin of the head and neck but clinically appears more violaceous than the lesion seen in our patient.¹⁰ Paracoccidioidomycosis may form ulcerated papulonodules or plaques, especially around the nose and mouth. In many of these cases, lesions develop from contiguous lesions of the oral mucosa; therefore, the presence of oral lesions will help distinguish this infectious entity from cutaneous metastasis. Multiple lesions usually are identified when there is hematogenous dissemination.¹¹ Mycosis fungoides is a subtype of cutaneous T-cell lymphoma and is characterized by multiple patches, plaques, and nodules on sun-protected areas. Involvement of the head and neck is not common, except in the folliculotropic subtype, which has a separate and distinct clinical morphology.¹²

The development of signet ring morphology from an adenocarcinoma can be attributed to the activation of phosphatidylinositol 3-kinase (PI3K), which leads to downstream activation of mitogen-activated protein kinase (MAPK) and the subsequent loss of intercellular tight junctions. The mucin 4 gene, MUC4, also is upregulated by PI3K activation and possesses antiapoptotic and mitogenic effects in addition to its mucin secretory function.¹³

The neoplastic cells in SRCAs stain positive for mucicarmine, Alcian blue, and periodic acid–Schiff, which highlights the mucinous component of the cells.⁷ Immunohistochemical stains with CK7, CK20, AE1/AE3, and epithelial membrane antigen can be implemented to confirm an epithelial origin of the primary cancer.^7,13 CK20 is a low-molecular-weight cytokeratin normally expressed by Merkel cells and by the epithelium of the gastrointestinal tract and urothelium, whereas CK7 expression typically is expressed in the lungs, ovaries, endometrium, and breasts, but not in the lower gastrointestinal tract.¹⁴ Differentiating primary cutaneous adenocarcinoma from cutaneous metastasis can be accomplished with a thorough clinical history; however, p63 positivity supports a primary cutaneous lesion and may be useful in certain situations.⁷ CDX2 stains can be utilized to aid in localizing the primary neoplasm when it is unknown, and when positive, it suggests a lower gastrointestinal tract origin. However, special AT-rich sequence-binding protein 2 (SATB2) recently has been proposed as a replacement immunohistochemical marker for CDX2, as it has greater specificity for SRCA of the lower gastrointestinal tract.¹⁵ Benign entities with signet ring cell morphology are difficult to distinguish from SRCA; however, malignant lesions are more likely to demonstrate an infiltrative growth pattern, frequent mitotic figures, and apoptosis. Immunohistochemistry also can be utilized to support the diagnosis of benign proliferation with signet ring morphology, as benign lesions often will demonstrate E-cadherin positivity and negativity for p53 and Ki-67.¹³

Cutaneous metastasis usually correlates to advanced disease and generally indicates a worse prognosis.¹³ Signet ring cell morphology in both gastric and colorectal cancer portends a poor prognosis, and there is a lower overall survival in patients with these malignancies compared to cancers of the same organ with non–signet ring cell morphology.^4,8

The Diagnosis: Cutaneous Metastasis

A shave biopsy of the lip revealed a diffuse cellular infiltrate filling the superficial and deep dermis (Figure 1A). Morphologically, the cells had abundant clear cytoplasm with eccentrically located, pleomorphic, hyperchromatic nuclei with occasional prominent nucleoli (Figure 1B). The cells stained positive for AE1/ AE3 on immunohistochemistry (Figure 2). A punch biopsy of the nodule in the right axillary vault revealed a morphologically similar proliferation of cells. A colonoscopy revealed a completely obstructing circumferential mass in the distal ascending colon. A biopsy of the mass confirmed invasive adenocarcinoma, supporting a diagnosis of cutaneous metastases from adenocarcinoma of the colon. The patient underwent resection of the lip tumor and started multiagent chemotherapy for his newly diagnosed stage IV adenocarcinoma of the colon. The patient died, despite therapy.

Cutaneous metastasis from solid malignancies is uncommon, as only 1.3% of them exhibit cutaneous manifestations at presentation.¹ Cutaneous metastasis from signet ring cell adenocarcinoma (SRCA) of the colon is uncommon, and cutaneous metastasis of colorectal SRCA rarely precedes the diagnosis of the primary lesion.² Among the colorectal cancers that metastasize to the skin, metastasis to the face occurs in only 0.5% of patients.³

Signet ring cell adenocarcinomas are poorly differentiated adenocarcinomas histologically characterized by the neoplastic cells’ circular to ovoid appearance with a flattened top.^4,5 This distinctive shape is from the displacement of the nucleus to the periphery of the cell due to the accumulation of intracytoplasmic mucin.⁴ Classically, malignancies are characterized as an SRCA if more than 50% of the cells have a signet ring cell morphology; if the signet ring cells comprise less than 50% of the neoplasm, the tumor is designated as an adenocarcinoma with signet ring morphology.⁴ The most common cause of cutaneous metastasis with signet ring morphology is gastric cancer, while colorectal carcinoma is less common.1 Colorectal SRCAs usually are found in the right colon or the rectum in comparison to other colonic sites.⁶

Clinically, cutaneous metastasis can present in a variety of ways. The most common presentation is nodular lesions that may coalesce to become zosteriform in configuration or lesions that mimic inflammatory dermatoses.⁷ Cutaneous metastasis is more common in breast and lung cancer, and when it occurs secondary to colorectal cancer, cutaneous metastasis rarely predates the detection of the primary neoplasm.²

The clinical appearance of metastasis is not specific and can mimic many entities⁸; therefore, a high index of suspicion must be employed when managing patients, even those without a history of internal malignancy. In our patient, the smooth nodular lesion appeared similar to a basal cell carcinoma; however, basal cell carcinomas appear more pearly, and arborizing telangiectasia often is seen.⁹ Merkel cell carcinoma is common on sundamaged skin of the head and neck but clinically appears more violaceous than the lesion seen in our patient.¹⁰ Paracoccidioidomycosis may form ulcerated papulonodules or plaques, especially around the nose and mouth. In many of these cases, lesions develop from contiguous lesions of the oral mucosa; therefore, the presence of oral lesions will help distinguish this infectious entity from cutaneous metastasis. Multiple lesions usually are identified when there is hematogenous dissemination.¹¹ Mycosis fungoides is a subtype of cutaneous T-cell lymphoma and is characterized by multiple patches, plaques, and nodules on sun-protected areas. Involvement of the head and neck is not common, except in the folliculotropic subtype, which has a separate and distinct clinical morphology.¹²

The development of signet ring morphology from an adenocarcinoma can be attributed to the activation of phosphatidylinositol 3-kinase (PI3K), which leads to downstream activation of mitogen-activated protein kinase (MAPK) and the subsequent loss of intercellular tight junctions. The mucin 4 gene, MUC4, also is upregulated by PI3K activation and possesses antiapoptotic and mitogenic effects in addition to its mucin secretory function.¹³

The neoplastic cells in SRCAs stain positive for mucicarmine, Alcian blue, and periodic acid–Schiff, which highlights the mucinous component of the cells.⁷ Immunohistochemical stains with CK7, CK20, AE1/AE3, and epithelial membrane antigen can be implemented to confirm an epithelial origin of the primary cancer.^7,13 CK20 is a low-molecular-weight cytokeratin normally expressed by Merkel cells and by the epithelium of the gastrointestinal tract and urothelium, whereas CK7 expression typically is expressed in the lungs, ovaries, endometrium, and breasts, but not in the lower gastrointestinal tract.¹⁴ Differentiating primary cutaneous adenocarcinoma from cutaneous metastasis can be accomplished with a thorough clinical history; however, p63 positivity supports a primary cutaneous lesion and may be useful in certain situations.⁷ CDX2 stains can be utilized to aid in localizing the primary neoplasm when it is unknown, and when positive, it suggests a lower gastrointestinal tract origin. However, special AT-rich sequence-binding protein 2 (SATB2) recently has been proposed as a replacement immunohistochemical marker for CDX2, as it has greater specificity for SRCA of the lower gastrointestinal tract.¹⁵ Benign entities with signet ring cell morphology are difficult to distinguish from SRCA; however, malignant lesions are more likely to demonstrate an infiltrative growth pattern, frequent mitotic figures, and apoptosis. Immunohistochemistry also can be utilized to support the diagnosis of benign proliferation with signet ring morphology, as benign lesions often will demonstrate E-cadherin positivity and negativity for p53 and Ki-67.¹³

Cutaneous metastasis usually correlates to advanced disease and generally indicates a worse prognosis.¹³ Signet ring cell morphology in both gastric and colorectal cancer portends a poor prognosis, and there is a lower overall survival in patients with these malignancies compared to cancers of the same organ with non–signet ring cell morphology.^4,8

The Diagnosis: Cutaneous Metastasis

A shave biopsy of the lip revealed a diffuse cellular infiltrate filling the superficial and deep dermis (Figure 1A). Morphologically, the cells had abundant clear cytoplasm with eccentrically located, pleomorphic, hyperchromatic nuclei with occasional prominent nucleoli (Figure 1B). The cells stained positive for AE1/ AE3 on immunohistochemistry (Figure 2). A punch biopsy of the nodule in the right axillary vault revealed a morphologically similar proliferation of cells. A colonoscopy revealed a completely obstructing circumferential mass in the distal ascending colon. A biopsy of the mass confirmed invasive adenocarcinoma, supporting a diagnosis of cutaneous metastases from adenocarcinoma of the colon. The patient underwent resection of the lip tumor and started multiagent chemotherapy for his newly diagnosed stage IV adenocarcinoma of the colon. The patient died, despite therapy.

Cutaneous metastasis from solid malignancies is uncommon, as only 1.3% of them exhibit cutaneous manifestations at presentation.¹ Cutaneous metastasis from signet ring cell adenocarcinoma (SRCA) of the colon is uncommon, and cutaneous metastasis of colorectal SRCA rarely precedes the diagnosis of the primary lesion.² Among the colorectal cancers that metastasize to the skin, metastasis to the face occurs in only 0.5% of patients.³

Signet ring cell adenocarcinomas are poorly differentiated adenocarcinomas histologically characterized by the neoplastic cells’ circular to ovoid appearance with a flattened top.^4,5 This distinctive shape is from the displacement of the nucleus to the periphery of the cell due to the accumulation of intracytoplasmic mucin.⁴ Classically, malignancies are characterized as an SRCA if more than 50% of the cells have a signet ring cell morphology; if the signet ring cells comprise less than 50% of the neoplasm, the tumor is designated as an adenocarcinoma with signet ring morphology.⁴ The most common cause of cutaneous metastasis with signet ring morphology is gastric cancer, while colorectal carcinoma is less common.1 Colorectal SRCAs usually are found in the right colon or the rectum in comparison to other colonic sites.⁶

Clinically, cutaneous metastasis can present in a variety of ways. The most common presentation is nodular lesions that may coalesce to become zosteriform in configuration or lesions that mimic inflammatory dermatoses.⁷ Cutaneous metastasis is more common in breast and lung cancer, and when it occurs secondary to colorectal cancer, cutaneous metastasis rarely predates the detection of the primary neoplasm.²

The clinical appearance of metastasis is not specific and can mimic many entities⁸; therefore, a high index of suspicion must be employed when managing patients, even those without a history of internal malignancy. In our patient, the smooth nodular lesion appeared similar to a basal cell carcinoma; however, basal cell carcinomas appear more pearly, and arborizing telangiectasia often is seen.⁹ Merkel cell carcinoma is common on sundamaged skin of the head and neck but clinically appears more violaceous than the lesion seen in our patient.¹⁰ Paracoccidioidomycosis may form ulcerated papulonodules or plaques, especially around the nose and mouth. In many of these cases, lesions develop from contiguous lesions of the oral mucosa; therefore, the presence of oral lesions will help distinguish this infectious entity from cutaneous metastasis. Multiple lesions usually are identified when there is hematogenous dissemination.¹¹ Mycosis fungoides is a subtype of cutaneous T-cell lymphoma and is characterized by multiple patches, plaques, and nodules on sun-protected areas. Involvement of the head and neck is not common, except in the folliculotropic subtype, which has a separate and distinct clinical morphology.¹²

The development of signet ring morphology from an adenocarcinoma can be attributed to the activation of phosphatidylinositol 3-kinase (PI3K), which leads to downstream activation of mitogen-activated protein kinase (MAPK) and the subsequent loss of intercellular tight junctions. The mucin 4 gene, MUC4, also is upregulated by PI3K activation and possesses antiapoptotic and mitogenic effects in addition to its mucin secretory function.¹³

The neoplastic cells in SRCAs stain positive for mucicarmine, Alcian blue, and periodic acid–Schiff, which highlights the mucinous component of the cells.⁷ Immunohistochemical stains with CK7, CK20, AE1/AE3, and epithelial membrane antigen can be implemented to confirm an epithelial origin of the primary cancer.^7,13 CK20 is a low-molecular-weight cytokeratin normally expressed by Merkel cells and by the epithelium of the gastrointestinal tract and urothelium, whereas CK7 expression typically is expressed in the lungs, ovaries, endometrium, and breasts, but not in the lower gastrointestinal tract.¹⁴ Differentiating primary cutaneous adenocarcinoma from cutaneous metastasis can be accomplished with a thorough clinical history; however, p63 positivity supports a primary cutaneous lesion and may be useful in certain situations.⁷ CDX2 stains can be utilized to aid in localizing the primary neoplasm when it is unknown, and when positive, it suggests a lower gastrointestinal tract origin. However, special AT-rich sequence-binding protein 2 (SATB2) recently has been proposed as a replacement immunohistochemical marker for CDX2, as it has greater specificity for SRCA of the lower gastrointestinal tract.¹⁵ Benign entities with signet ring cell morphology are difficult to distinguish from SRCA; however, malignant lesions are more likely to demonstrate an infiltrative growth pattern, frequent mitotic figures, and apoptosis. Immunohistochemistry also can be utilized to support the diagnosis of benign proliferation with signet ring morphology, as benign lesions often will demonstrate E-cadherin positivity and negativity for p53 and Ki-67.¹³

Cutaneous metastasis usually correlates to advanced disease and generally indicates a worse prognosis.¹³ Signet ring cell morphology in both gastric and colorectal cancer portends a poor prognosis, and there is a lower overall survival in patients with these malignancies compared to cancers of the same organ with non–signet ring cell morphology.^4,8

The Diagnosis: Hypopigmented Mycosis Fungoides

Histopathology showed an atypical lymphoid infiltrate with expanded cytoplasm and hyperchromatic nuclei of irregular contours in the dermoepidermal junction (Figure 1). Immunohistochemical stains of atypical lymphocytes demonstrated the presence of CD3, CD8, and CD5, as well as the absence of CD7 and CD4 lymphocytes (Figure 2). The T-cell γ rearrangement showed polyclonal lymphocytes with 5% tumor cells. The histologic and clinical findings along with our patient’s medical history led to a diagnosis of stage IA (<10% body surface area involvement) hypopigmented mycosis fungoides (hMF).¹ Our patient was treated with triamcinolone cream 0.1%; she noted an improvement in her symptoms at 2-month follow-up.

Hypopigmented MF is an uncommon manifestation of MF with unknown prevalence and incidence rates. Mycosis fungoides is considered the most common subtype of cutaneous T-cell lymphoma that classically presents as a chronic, indolent, hypopigmented or depigmented macule or patch, commonly with scaling, in sunprotected areas such as the trunk and proximal arms and legs. It predominantly affects younger adults with darker skin tones and may be present in the pediatric population within the first decade of life.¹ Classically, MF affects White patients aged 55 to 60 years. Disease progression is slow, with an incidence rate of 10% of tumor or extracutaneous involvement in the early stages of disease. A lack of specificity on the clinical and histopathologic findings in the initial stage often contributes to the diagnostic delay of hMF. As seen in our patient, this disease can be misdiagnosed as tinea versicolor, postinflammatory hypopigmentation, vitiligo, pityriasis alba, subcutaneous lupus erythematosus, or Hansen disease due to prolonged hypopigmented lesions.² The clinical findings and histopathologic results including immunohistochemistry confirmed the diagnosis of hMF and ruled out pityriasis alba, postinflammatory hypopigmentation, subcutaneous lupus erythematosus, and vitiligo.

The etiology and pathophysiology of hMF are not fully understood; however, it is hypothesized that melanocyte degeneration, abnormal melanogenesis, and disturbance of melanosome transfer result from the clonal expansion of T helper memory cells. T-cell dyscrasia has been reported to evolve into hMF during etanercept therapy.³ Clinically, hMF presents as hypopigmented papulosquamous, eczematous, or erythrodermic patches, plaques, and tumors with poorly defined atrophied borders. Multiple biopsies of steroid-naive lesions are needed for the diagnosis, as the initial hMF histologic finding cannot be specific for diagnostic confirmation. Common histopathologic findings include a bandlike lymphocytic infiltrate with epidermotropism, intraepidermal nests of atypical cells, or cerebriform nuclei lymphocytes on hematoxylin and eosin staining. In comparison to classical MF epidermotropism, CD4− and CD8+ atypical cells aid in the diagnosis of hMF. Although hMF carries a good prognosis and a benign clinical course,⁴ full-body computed tomography or positron emission tomography/computed tomography as well as laboratory analysis for lactate dehydrogenase should be pursued if lymphadenopathy, systemic symptoms, or advancedstage hMF are present.

Treatment of hMF depends on the disease stage. Psoralen plus UVA and narrowband UVB can be utilized for the initial stages with a relatively fast response and remission of lesions as early as the first 2 months of treatment. In addition to phototherapy, stage IA to IIA mycosis fungoides with localized skin lesions can benefit from topical steroids, topical retinoids, imiquimod, nitrogen mustard, and carmustine. For advanced stages of mycosis fungoides, combination therapy consisting of psoralen plus UVA with an oral retinoid, interferon alfa, and systemic chemotherapy commonly are prescribed. Maintenance therapy is used for prolonging remission; however, long-term phototherapy is not recommended due to the risk for skin cancer. Unfortunately, hMF requires long-term treatment due to its waxing and waning course, and recurrence may occur after complete resolution.⁵

The Diagnosis: Hypopigmented Mycosis Fungoides

Histopathology showed an atypical lymphoid infiltrate with expanded cytoplasm and hyperchromatic nuclei of irregular contours in the dermoepidermal junction (Figure 1). Immunohistochemical stains of atypical lymphocytes demonstrated the presence of CD3, CD8, and CD5, as well as the absence of CD7 and CD4 lymphocytes (Figure 2). The T-cell γ rearrangement showed polyclonal lymphocytes with 5% tumor cells. The histologic and clinical findings along with our patient’s medical history led to a diagnosis of stage IA (<10% body surface area involvement) hypopigmented mycosis fungoides (hMF).¹ Our patient was treated with triamcinolone cream 0.1%; she noted an improvement in her symptoms at 2-month follow-up.

Hypopigmented MF is an uncommon manifestation of MF with unknown prevalence and incidence rates. Mycosis fungoides is considered the most common subtype of cutaneous T-cell lymphoma that classically presents as a chronic, indolent, hypopigmented or depigmented macule or patch, commonly with scaling, in sunprotected areas such as the trunk and proximal arms and legs. It predominantly affects younger adults with darker skin tones and may be present in the pediatric population within the first decade of life.¹ Classically, MF affects White patients aged 55 to 60 years. Disease progression is slow, with an incidence rate of 10% of tumor or extracutaneous involvement in the early stages of disease. A lack of specificity on the clinical and histopathologic findings in the initial stage often contributes to the diagnostic delay of hMF. As seen in our patient, this disease can be misdiagnosed as tinea versicolor, postinflammatory hypopigmentation, vitiligo, pityriasis alba, subcutaneous lupus erythematosus, or Hansen disease due to prolonged hypopigmented lesions.² The clinical findings and histopathologic results including immunohistochemistry confirmed the diagnosis of hMF and ruled out pityriasis alba, postinflammatory hypopigmentation, subcutaneous lupus erythematosus, and vitiligo.

The etiology and pathophysiology of hMF are not fully understood; however, it is hypothesized that melanocyte degeneration, abnormal melanogenesis, and disturbance of melanosome transfer result from the clonal expansion of T helper memory cells. T-cell dyscrasia has been reported to evolve into hMF during etanercept therapy.³ Clinically, hMF presents as hypopigmented papulosquamous, eczematous, or erythrodermic patches, plaques, and tumors with poorly defined atrophied borders. Multiple biopsies of steroid-naive lesions are needed for the diagnosis, as the initial hMF histologic finding cannot be specific for diagnostic confirmation. Common histopathologic findings include a bandlike lymphocytic infiltrate with epidermotropism, intraepidermal nests of atypical cells, or cerebriform nuclei lymphocytes on hematoxylin and eosin staining. In comparison to classical MF epidermotropism, CD4− and CD8+ atypical cells aid in the diagnosis of hMF. Although hMF carries a good prognosis and a benign clinical course,⁴ full-body computed tomography or positron emission tomography/computed tomography as well as laboratory analysis for lactate dehydrogenase should be pursued if lymphadenopathy, systemic symptoms, or advancedstage hMF are present.

Treatment of hMF depends on the disease stage. Psoralen plus UVA and narrowband UVB can be utilized for the initial stages with a relatively fast response and remission of lesions as early as the first 2 months of treatment. In addition to phototherapy, stage IA to IIA mycosis fungoides with localized skin lesions can benefit from topical steroids, topical retinoids, imiquimod, nitrogen mustard, and carmustine. For advanced stages of mycosis fungoides, combination therapy consisting of psoralen plus UVA with an oral retinoid, interferon alfa, and systemic chemotherapy commonly are prescribed. Maintenance therapy is used for prolonging remission; however, long-term phototherapy is not recommended due to the risk for skin cancer. Unfortunately, hMF requires long-term treatment due to its waxing and waning course, and recurrence may occur after complete resolution.⁵

The Diagnosis: Hypopigmented Mycosis Fungoides

Histopathology showed an atypical lymphoid infiltrate with expanded cytoplasm and hyperchromatic nuclei of irregular contours in the dermoepidermal junction (Figure 1). Immunohistochemical stains of atypical lymphocytes demonstrated the presence of CD3, CD8, and CD5, as well as the absence of CD7 and CD4 lymphocytes (Figure 2). The T-cell γ rearrangement showed polyclonal lymphocytes with 5% tumor cells. The histologic and clinical findings along with our patient’s medical history led to a diagnosis of stage IA (<10% body surface area involvement) hypopigmented mycosis fungoides (hMF).¹ Our patient was treated with triamcinolone cream 0.1%; she noted an improvement in her symptoms at 2-month follow-up.

Hypopigmented MF is an uncommon manifestation of MF with unknown prevalence and incidence rates. Mycosis fungoides is considered the most common subtype of cutaneous T-cell lymphoma that classically presents as a chronic, indolent, hypopigmented or depigmented macule or patch, commonly with scaling, in sunprotected areas such as the trunk and proximal arms and legs. It predominantly affects younger adults with darker skin tones and may be present in the pediatric population within the first decade of life.¹ Classically, MF affects White patients aged 55 to 60 years. Disease progression is slow, with an incidence rate of 10% of tumor or extracutaneous involvement in the early stages of disease. A lack of specificity on the clinical and histopathologic findings in the initial stage often contributes to the diagnostic delay of hMF. As seen in our patient, this disease can be misdiagnosed as tinea versicolor, postinflammatory hypopigmentation, vitiligo, pityriasis alba, subcutaneous lupus erythematosus, or Hansen disease due to prolonged hypopigmented lesions.² The clinical findings and histopathologic results including immunohistochemistry confirmed the diagnosis of hMF and ruled out pityriasis alba, postinflammatory hypopigmentation, subcutaneous lupus erythematosus, and vitiligo.

The etiology and pathophysiology of hMF are not fully understood; however, it is hypothesized that melanocyte degeneration, abnormal melanogenesis, and disturbance of melanosome transfer result from the clonal expansion of T helper memory cells. T-cell dyscrasia has been reported to evolve into hMF during etanercept therapy.³ Clinically, hMF presents as hypopigmented papulosquamous, eczematous, or erythrodermic patches, plaques, and tumors with poorly defined atrophied borders. Multiple biopsies of steroid-naive lesions are needed for the diagnosis, as the initial hMF histologic finding cannot be specific for diagnostic confirmation. Common histopathologic findings include a bandlike lymphocytic infiltrate with epidermotropism, intraepidermal nests of atypical cells, or cerebriform nuclei lymphocytes on hematoxylin and eosin staining. In comparison to classical MF epidermotropism, CD4− and CD8+ atypical cells aid in the diagnosis of hMF. Although hMF carries a good prognosis and a benign clinical course,⁴ full-body computed tomography or positron emission tomography/computed tomography as well as laboratory analysis for lactate dehydrogenase should be pursued if lymphadenopathy, systemic symptoms, or advancedstage hMF are present.

Treatment of hMF depends on the disease stage. Psoralen plus UVA and narrowband UVB can be utilized for the initial stages with a relatively fast response and remission of lesions as early as the first 2 months of treatment. In addition to phototherapy, stage IA to IIA mycosis fungoides with localized skin lesions can benefit from topical steroids, topical retinoids, imiquimod, nitrogen mustard, and carmustine. For advanced stages of mycosis fungoides, combination therapy consisting of psoralen plus UVA with an oral retinoid, interferon alfa, and systemic chemotherapy commonly are prescribed. Maintenance therapy is used for prolonging remission; however, long-term phototherapy is not recommended due to the risk for skin cancer. Unfortunately, hMF requires long-term treatment due to its waxing and waning course, and recurrence may occur after complete resolution.⁵

THE DIAGNOSIS: Neutrophilic Eccrine Hidradenitis

A biopsy from the left preauricular cheek demonstrated dermal neutrophilic inflammation around eccrine coils with focal necrosis (Figure). No notable diffuse dermal neutrophilic infiltrate was present, ruling out Sweet syndrome, and no notable interstitial neutrophilic infiltrate was present, making cellulitis and erysipelas less likely; panculture of tissue also was negative.^1,2 Atypical cells in the deep dermis were positive for CD163 and negative for CD117, CD34, CD123, and myeloperoxidase, consistent with a diagnosis of neutrophilic eccrine hidradenitis (NEH) and reactive histiocytes.³ Treatment with oral prednisone resulted in rapid improvement of symptoms.

Neutrophilic eccrine hidradenitis is a rare reactive neutrophilic dermatosis characterized by eccrine gland involvement. This benign and self-limited condition presents as asymmetric erythematous papules and plaques.² Among 8 granulocytopenic patients with neutrophilic dermatoses, 5 were diagnosed with NEH.⁴ Although first identified in 1982, NEH remains poorly understood.² Initial theories suggested that NEH developed due to cytotoxic substances secreted in sweat glands causing necrosis and neutrophil chemotaxis; however, chemotherapy exposure cannot be linked to every case of NEH. Neutrophilic eccrine hidradenitis can be extremely difficult to differentiate clinically from conditions such as cellulitis and Sweet syndrome.

A patient history can be helpful in identifying triggering factors. Neutrophilic eccrine hidradenitis most commonly is associated with malignant, drug-induced, or infectious triggers, while Sweet syndrome has a broad range of associations including infections, vaccines, inflammatory bowel disease, pregnancy, malignancy, and drug-induced etiologies (Table).¹ On average, NEH presents 10 days after chemotherapy induction, with 70% of cases presenting after the first chemotherapy cycle.⁵ Bacterial cellulitis or erysipelas have an infectious etiology, and patients may report symptoms such as fever, chills, or malaise. Immunosuppressed patients are at greater risk for infection; therefore, clinical signs of infection in a granulocytopenic patient should be addressed urgently.

Physical examination may have limited value in differentiating between these diagnoses, as neutrophilic dermatoses notoriously mimic infection. Cutaneous lesions can appear as pruritic or tender erythematous plaques, papules, or nodules in these conditions, though cellulitis and erysipelas tend to be unilateral and may have associated purulence or inflamed skin lymphatics. Given the potential for misdiagnosis, approaching patients with a broad differential can be helpful. In our patient, the differential diagnosis included Sweet syndrome, NEH, bacterial cellulitis, erysipelas, leukemia cutis, sarcoid, and eosinophilic cellulitis.

Leukemia cutis refers to the infiltration of neoplastic leukocytes in the skin and often occurs in patients with peripheral leukemia, most often acute myeloid leukemia or chronic lymphocytic leukemia. Patients with leukemia cutis often have a worse prognosis, as this finding signifies extramedullary spread of disease.⁶ Clinically, lesions can appear similar to those seen in our patient, though they typically are not symptomatic, can be nodular, tend to exhibit a violaceous hue, and occasionally may be hemorrhagic. Wells syndrome (also known as eosinophilic cellulitis) is an inflammatory dermatosis that presents as painful or pruritic, edematous and erythematous plaques.^7,8 A green hue on resolution is present in some cases and may help clinicians differentiate this disease from mimickers.⁷ Often, eosinophilic cellulitis is misdiagnosed as bacterial cellulitis and treated with antibiotics. The presence of systemic symptoms such as fever or arthralgia is more typical of bacterial cellulitis, erysipelas, eosinophilic cellulitis, or Sweet syndrome than of NEH.¹ Additionally, inflammatory markers (ie, C-reactive protein) and white blood cell counts tend to be elevated in bacterial cellulitis and Sweet syndrome, while leukopenia often is seen in NEH.

Histopathology is crucial in distinguishing these disease etiologies. Neutrophilic eccrine hidradenitis is diagnosed by the characteristic neutrophilic infiltrate and necrosis surrounding eccrine glands and coils. There also may be occasional intraductal abscesses and syringosquamous metaplasia of the sweat glands along with fibrosis of the adjacent dermis. In contrast, histologic sections of Sweet syndrome show numerous mature neutrophils infiltrating the dermis with marked papillary dermal edema. The histopathology of bacterial cellulitis and erysipelas is less specific, but common features include dermal edema, lymphatic dilation, and a diffuse neutrophilic infiltrate surrounding blood vessels. Pathogenic organisms may be seen on histopathology but are not required for the diagnosis of bacterial cellulitis or erysipelas.² Additionally, blood and tissue culture can assist in identification of both the source of infection and the causative organism, but cultures may not always be positive. 

Comparatively, the histopathologic features of eosinophilic cellulitis include dermal edema, eosinophilic infiltration, and flame figures that form when eosinophils degranulate and coat collagen fibers with major basic protein. Flame figures are characteristic but not pathognomonic for eosinophilic cellulitis.⁷ The histopathology of leukemia cutis varies based on the leukemia classification; generally, in acute myeloid leukemia the infiltrate is composed of neoplastic cells in the early stages of development that are positive for myeloid markers such as myeloperoxidase. Atypical and immature granulocytes within the leukocytic infiltrate differentiate this condition from the other diagnoses. Treatment may entail chemotherapy or radiotherapy, and this diagnosis generally carries the worst prognosis of all the conditions in the differential.⁶

Differentiating between these conditions is important in guiding treatment, especially in patients with febrile neutropenia. Unnecessary steroids in immunosuppressed patients can be dangerous, especially if the patient has an infection such as bacterial cellulitis. Furthermore, unwarranted antibiotic use for noninfectious conditions may expose patients to substantial side effects and not improve the condition. Neutrophilic eccrine hidradenitis typically is self-limited and treated symptomatically with systemic corticosteroids and nonsteroidal anti-inflammatory drugs.³ Sweet syndrome often requires a longer course of oral steroids. Leukemia cutis worsens as the leukemia advances, and treatment of the underlying malignancy is the most effective treatment.⁹

Early and accurate recognition of the diagnosis can prevent harmful diagnostic delay, unnecessary antibiotic use, or extended steroid taper in neutropenic patients. Appreciating the differences between these diagnoses can assist clinicians in investigating and tailoring a broad differential to specific patient presentations, which is especially critical when considering common mimickers for life-threatening conditions.

THE DIAGNOSIS: Neutrophilic Eccrine Hidradenitis

A biopsy from the left preauricular cheek demonstrated dermal neutrophilic inflammation around eccrine coils with focal necrosis (Figure). No notable diffuse dermal neutrophilic infiltrate was present, ruling out Sweet syndrome, and no notable interstitial neutrophilic infiltrate was present, making cellulitis and erysipelas less likely; panculture of tissue also was negative.^1,2 Atypical cells in the deep dermis were positive for CD163 and negative for CD117, CD34, CD123, and myeloperoxidase, consistent with a diagnosis of neutrophilic eccrine hidradenitis (NEH) and reactive histiocytes.³ Treatment with oral prednisone resulted in rapid improvement of symptoms.

Neutrophilic eccrine hidradenitis is a rare reactive neutrophilic dermatosis characterized by eccrine gland involvement. This benign and self-limited condition presents as asymmetric erythematous papules and plaques.² Among 8 granulocytopenic patients with neutrophilic dermatoses, 5 were diagnosed with NEH.⁴ Although first identified in 1982, NEH remains poorly understood.² Initial theories suggested that NEH developed due to cytotoxic substances secreted in sweat glands causing necrosis and neutrophil chemotaxis; however, chemotherapy exposure cannot be linked to every case of NEH. Neutrophilic eccrine hidradenitis can be extremely difficult to differentiate clinically from conditions such as cellulitis and Sweet syndrome.

A patient history can be helpful in identifying triggering factors. Neutrophilic eccrine hidradenitis most commonly is associated with malignant, drug-induced, or infectious triggers, while Sweet syndrome has a broad range of associations including infections, vaccines, inflammatory bowel disease, pregnancy, malignancy, and drug-induced etiologies (Table).¹ On average, NEH presents 10 days after chemotherapy induction, with 70% of cases presenting after the first chemotherapy cycle.⁵ Bacterial cellulitis or erysipelas have an infectious etiology, and patients may report symptoms such as fever, chills, or malaise. Immunosuppressed patients are at greater risk for infection; therefore, clinical signs of infection in a granulocytopenic patient should be addressed urgently.

Physical examination may have limited value in differentiating between these diagnoses, as neutrophilic dermatoses notoriously mimic infection. Cutaneous lesions can appear as pruritic or tender erythematous plaques, papules, or nodules in these conditions, though cellulitis and erysipelas tend to be unilateral and may have associated purulence or inflamed skin lymphatics. Given the potential for misdiagnosis, approaching patients with a broad differential can be helpful. In our patient, the differential diagnosis included Sweet syndrome, NEH, bacterial cellulitis, erysipelas, leukemia cutis, sarcoid, and eosinophilic cellulitis.

Leukemia cutis refers to the infiltration of neoplastic leukocytes in the skin and often occurs in patients with peripheral leukemia, most often acute myeloid leukemia or chronic lymphocytic leukemia. Patients with leukemia cutis often have a worse prognosis, as this finding signifies extramedullary spread of disease.⁶ Clinically, lesions can appear similar to those seen in our patient, though they typically are not symptomatic, can be nodular, tend to exhibit a violaceous hue, and occasionally may be hemorrhagic. Wells syndrome (also known as eosinophilic cellulitis) is an inflammatory dermatosis that presents as painful or pruritic, edematous and erythematous plaques.^7,8 A green hue on resolution is present in some cases and may help clinicians differentiate this disease from mimickers.⁷ Often, eosinophilic cellulitis is misdiagnosed as bacterial cellulitis and treated with antibiotics. The presence of systemic symptoms such as fever or arthralgia is more typical of bacterial cellulitis, erysipelas, eosinophilic cellulitis, or Sweet syndrome than of NEH.¹ Additionally, inflammatory markers (ie, C-reactive protein) and white blood cell counts tend to be elevated in bacterial cellulitis and Sweet syndrome, while leukopenia often is seen in NEH.

Histopathology is crucial in distinguishing these disease etiologies. Neutrophilic eccrine hidradenitis is diagnosed by the characteristic neutrophilic infiltrate and necrosis surrounding eccrine glands and coils. There also may be occasional intraductal abscesses and syringosquamous metaplasia of the sweat glands along with fibrosis of the adjacent dermis. In contrast, histologic sections of Sweet syndrome show numerous mature neutrophils infiltrating the dermis with marked papillary dermal edema. The histopathology of bacterial cellulitis and erysipelas is less specific, but common features include dermal edema, lymphatic dilation, and a diffuse neutrophilic infiltrate surrounding blood vessels. Pathogenic organisms may be seen on histopathology but are not required for the diagnosis of bacterial cellulitis or erysipelas.² Additionally, blood and tissue culture can assist in identification of both the source of infection and the causative organism, but cultures may not always be positive. 

Comparatively, the histopathologic features of eosinophilic cellulitis include dermal edema, eosinophilic infiltration, and flame figures that form when eosinophils degranulate and coat collagen fibers with major basic protein. Flame figures are characteristic but not pathognomonic for eosinophilic cellulitis.⁷ The histopathology of leukemia cutis varies based on the leukemia classification; generally, in acute myeloid leukemia the infiltrate is composed of neoplastic cells in the early stages of development that are positive for myeloid markers such as myeloperoxidase. Atypical and immature granulocytes within the leukocytic infiltrate differentiate this condition from the other diagnoses. Treatment may entail chemotherapy or radiotherapy, and this diagnosis generally carries the worst prognosis of all the conditions in the differential.⁶

Differentiating between these conditions is important in guiding treatment, especially in patients with febrile neutropenia. Unnecessary steroids in immunosuppressed patients can be dangerous, especially if the patient has an infection such as bacterial cellulitis. Furthermore, unwarranted antibiotic use for noninfectious conditions may expose patients to substantial side effects and not improve the condition. Neutrophilic eccrine hidradenitis typically is self-limited and treated symptomatically with systemic corticosteroids and nonsteroidal anti-inflammatory drugs.³ Sweet syndrome often requires a longer course of oral steroids. Leukemia cutis worsens as the leukemia advances, and treatment of the underlying malignancy is the most effective treatment.⁹

Early and accurate recognition of the diagnosis can prevent harmful diagnostic delay, unnecessary antibiotic use, or extended steroid taper in neutropenic patients. Appreciating the differences between these diagnoses can assist clinicians in investigating and tailoring a broad differential to specific patient presentations, which is especially critical when considering common mimickers for life-threatening conditions.

THE DIAGNOSIS: Neutrophilic Eccrine Hidradenitis

A biopsy from the left preauricular cheek demonstrated dermal neutrophilic inflammation around eccrine coils with focal necrosis (Figure). No notable diffuse dermal neutrophilic infiltrate was present, ruling out Sweet syndrome, and no notable interstitial neutrophilic infiltrate was present, making cellulitis and erysipelas less likely; panculture of tissue also was negative.^1,2 Atypical cells in the deep dermis were positive for CD163 and negative for CD117, CD34, CD123, and myeloperoxidase, consistent with a diagnosis of neutrophilic eccrine hidradenitis (NEH) and reactive histiocytes.³ Treatment with oral prednisone resulted in rapid improvement of symptoms.

Neutrophilic eccrine hidradenitis is a rare reactive neutrophilic dermatosis characterized by eccrine gland involvement. This benign and self-limited condition presents as asymmetric erythematous papules and plaques.² Among 8 granulocytopenic patients with neutrophilic dermatoses, 5 were diagnosed with NEH.⁴ Although first identified in 1982, NEH remains poorly understood.² Initial theories suggested that NEH developed due to cytotoxic substances secreted in sweat glands causing necrosis and neutrophil chemotaxis; however, chemotherapy exposure cannot be linked to every case of NEH. Neutrophilic eccrine hidradenitis can be extremely difficult to differentiate clinically from conditions such as cellulitis and Sweet syndrome.

A patient history can be helpful in identifying triggering factors. Neutrophilic eccrine hidradenitis most commonly is associated with malignant, drug-induced, or infectious triggers, while Sweet syndrome has a broad range of associations including infections, vaccines, inflammatory bowel disease, pregnancy, malignancy, and drug-induced etiologies (Table).¹ On average, NEH presents 10 days after chemotherapy induction, with 70% of cases presenting after the first chemotherapy cycle.⁵ Bacterial cellulitis or erysipelas have an infectious etiology, and patients may report symptoms such as fever, chills, or malaise. Immunosuppressed patients are at greater risk for infection; therefore, clinical signs of infection in a granulocytopenic patient should be addressed urgently.

Physical examination may have limited value in differentiating between these diagnoses, as neutrophilic dermatoses notoriously mimic infection. Cutaneous lesions can appear as pruritic or tender erythematous plaques, papules, or nodules in these conditions, though cellulitis and erysipelas tend to be unilateral and may have associated purulence or inflamed skin lymphatics. Given the potential for misdiagnosis, approaching patients with a broad differential can be helpful. In our patient, the differential diagnosis included Sweet syndrome, NEH, bacterial cellulitis, erysipelas, leukemia cutis, sarcoid, and eosinophilic cellulitis.

Leukemia cutis refers to the infiltration of neoplastic leukocytes in the skin and often occurs in patients with peripheral leukemia, most often acute myeloid leukemia or chronic lymphocytic leukemia. Patients with leukemia cutis often have a worse prognosis, as this finding signifies extramedullary spread of disease.⁶ Clinically, lesions can appear similar to those seen in our patient, though they typically are not symptomatic, can be nodular, tend to exhibit a violaceous hue, and occasionally may be hemorrhagic. Wells syndrome (also known as eosinophilic cellulitis) is an inflammatory dermatosis that presents as painful or pruritic, edematous and erythematous plaques.^7,8 A green hue on resolution is present in some cases and may help clinicians differentiate this disease from mimickers.⁷ Often, eosinophilic cellulitis is misdiagnosed as bacterial cellulitis and treated with antibiotics. The presence of systemic symptoms such as fever or arthralgia is more typical of bacterial cellulitis, erysipelas, eosinophilic cellulitis, or Sweet syndrome than of NEH.¹ Additionally, inflammatory markers (ie, C-reactive protein) and white blood cell counts tend to be elevated in bacterial cellulitis and Sweet syndrome, while leukopenia often is seen in NEH.

Histopathology is crucial in distinguishing these disease etiologies. Neutrophilic eccrine hidradenitis is diagnosed by the characteristic neutrophilic infiltrate and necrosis surrounding eccrine glands and coils. There also may be occasional intraductal abscesses and syringosquamous metaplasia of the sweat glands along with fibrosis of the adjacent dermis. In contrast, histologic sections of Sweet syndrome show numerous mature neutrophils infiltrating the dermis with marked papillary dermal edema. The histopathology of bacterial cellulitis and erysipelas is less specific, but common features include dermal edema, lymphatic dilation, and a diffuse neutrophilic infiltrate surrounding blood vessels. Pathogenic organisms may be seen on histopathology but are not required for the diagnosis of bacterial cellulitis or erysipelas.² Additionally, blood and tissue culture can assist in identification of both the source of infection and the causative organism, but cultures may not always be positive. 

Comparatively, the histopathologic features of eosinophilic cellulitis include dermal edema, eosinophilic infiltration, and flame figures that form when eosinophils degranulate and coat collagen fibers with major basic protein. Flame figures are characteristic but not pathognomonic for eosinophilic cellulitis.⁷ The histopathology of leukemia cutis varies based on the leukemia classification; generally, in acute myeloid leukemia the infiltrate is composed of neoplastic cells in the early stages of development that are positive for myeloid markers such as myeloperoxidase. Atypical and immature granulocytes within the leukocytic infiltrate differentiate this condition from the other diagnoses. Treatment may entail chemotherapy or radiotherapy, and this diagnosis generally carries the worst prognosis of all the conditions in the differential.⁶

Differentiating between these conditions is important in guiding treatment, especially in patients with febrile neutropenia. Unnecessary steroids in immunosuppressed patients can be dangerous, especially if the patient has an infection such as bacterial cellulitis. Furthermore, unwarranted antibiotic use for noninfectious conditions may expose patients to substantial side effects and not improve the condition. Neutrophilic eccrine hidradenitis typically is self-limited and treated symptomatically with systemic corticosteroids and nonsteroidal anti-inflammatory drugs.³ Sweet syndrome often requires a longer course of oral steroids. Leukemia cutis worsens as the leukemia advances, and treatment of the underlying malignancy is the most effective treatment.⁹

Early and accurate recognition of the diagnosis can prevent harmful diagnostic delay, unnecessary antibiotic use, or extended steroid taper in neutropenic patients. Appreciating the differences between these diagnoses can assist clinicians in investigating and tailoring a broad differential to specific patient presentations, which is especially critical when considering common mimickers for life-threatening conditions.

The Diagnosis: Dominant Dystrophic Epidermolysis Bullosa

Blisters in a neonate may be caused by infectious, traumatic, autoimmune, or congenital etiologies. Biopsy findings correlated with clinical findings usually can establish a prompt diagnosis when the clinical diagnosis is uncertain. Direct immunofluorescence (DIF) as well as indirect immunofluorescence studies are useful when autoimmune blistering disease or congenital or heritable disorders of skin fragility are in the differential diagnosis. Many genetic abnormalities of skin fragility are associated with marked morbidity and mortality, and prompt diagnosis is essential to provide proper care. Our patient’s parents had no history of skin disorders, and there was no known family history of blistering disease or traumatic birth. A heritable disorder of skin fragility was still a top consideration because of the extensive blistering in the absence of any other symptoms.

Although dystrophic epidermolysis bullosa (DEB) is an uncommon cause of skin fragility in neonates, our patient’s presentation was typical because of the extensive blistering and increased fragility of the skin at pressure points. Dystrophic epidermolysis bullosa has both dominant and recessive presentations that span a spectrum from mild and focal skin blistering to extensive blistering with esophageal involvement.¹ Early diagnosis and treatment can mitigate potential failure to thrive or premature death. Inherited mutations in the type VII collagen gene, COL7A1, are causative.² Dominant DEB may be associated with dental caries, swallowing problems secondary to esophageal scarring, and constipation, as well as dystrophic or absent nails. Immunomapping studies of the skin often reveal type VII collagen cytoplasmic granules in the epidermis and weaker reaction in the roof of the subepidermal separation (quiz image).³ Abnormalities in type VII collagen impact the production of anchoring fibrils. Blister cleavage occurs in the sublamina densa with type VII collagen staining evident on the blister roof (quiz image).⁴ Patients with severe generalized recessive DEB may have barely detectable type VII collagen. In our patient, the cytoplasmic staining and weak staining in the epidermal roof of the separation confirmed the clinical impression of dominant DEB.

Autoimmune blistering disease should be considered in the histologic differential diagnosis, but it usually is associated with obvious disease in the mother. Direct immunofluorescence of pemphigoid gestationis reveals linear deposition of C3 at the basement membrane zone, which also can be associated with IgG (Figure 1). Neonates receiving passive transfer of antibodies may develop annular erythema, vesicles, and even dyshidroticlike changes on the soles.⁵

Suction blisters are subepithelial.^6,7 When they occur in the neonatal period, they often are localized and are thought to be the result of vigorous sucking in utero.⁶ They quickly resolve without treatment and do not reveal abnormalities on DIF. If immunomapping is done for type VII collagen, it will be located at the floor of the suction blister (Figure 2).

Bullous pemphigoid is associated with deposition of linear IgG along the dermoepidermal junction—IgG4 is most common—and/or C3 (Figure 3). Direct immunofluorescence on split-skin biopsy reveals IgG on the epidermal side of the blister in bullous pemphigoid in contrast to epidermolysis bullosa acquisita, where the immune deposits are found on the dermal side of the split.^8,9 Linear IgA bullous disease is associated with IgA deposition (Figure 4).^10,11 Secretory IgA derived from breast milk can be causative.¹¹ Neonatal linear IgA bullous disease is a serious condition associated with marked mucosal involvement that can eventuate in respiratory compromise. Prompt recognition is important; breastfeeding must be stopped and supportive therapy must be provided.

Other types of vesicular or pustular eruptions in the newborn usually are easily diagnosed by their typical clinical presentation without biopsy. Erythema toxicum neonatorum usually presents within 1 to 2 days of birth. It is self-limited and often resembles acne, but it also occurs on the trunk and extremities. Transient neonatal pustular melanosis may be present at birth and predominantly is seen in newborns with skin of color. Lesions easily rupture and usually resolve within 1 to 2 days. Infectious causes of blistering often can be identified on clinical examination and confirmed by culture. Herpes simplex virus infection is associated with characteristic multinucleated giant cells as well as steel grey nuclei evident on routine histologic evaluation. Bullous impetigo reveals superficial acantholysis and will have negative findings on DIF.¹²

When a neonate presents with widespread blistering, both genetic disorders of skin fragility as well as passive transfer of antibodies from maternal autoimmune disease need to be considered. Direct immunofluorescence and indirect immunofluorescence immunomapping findings can be useful in clarifying the diagnosis when heritable disorders of skin fragility or autoimmune blistering diseases are a clinical consideration.

The Diagnosis: Dominant Dystrophic Epidermolysis Bullosa

Blisters in a neonate may be caused by infectious, traumatic, autoimmune, or congenital etiologies. Biopsy findings correlated with clinical findings usually can establish a prompt diagnosis when the clinical diagnosis is uncertain. Direct immunofluorescence (DIF) as well as indirect immunofluorescence studies are useful when autoimmune blistering disease or congenital or heritable disorders of skin fragility are in the differential diagnosis. Many genetic abnormalities of skin fragility are associated with marked morbidity and mortality, and prompt diagnosis is essential to provide proper care. Our patient’s parents had no history of skin disorders, and there was no known family history of blistering disease or traumatic birth. A heritable disorder of skin fragility was still a top consideration because of the extensive blistering in the absence of any other symptoms.

Although dystrophic epidermolysis bullosa (DEB) is an uncommon cause of skin fragility in neonates, our patient’s presentation was typical because of the extensive blistering and increased fragility of the skin at pressure points. Dystrophic epidermolysis bullosa has both dominant and recessive presentations that span a spectrum from mild and focal skin blistering to extensive blistering with esophageal involvement.¹ Early diagnosis and treatment can mitigate potential failure to thrive or premature death. Inherited mutations in the type VII collagen gene, COL7A1, are causative.² Dominant DEB may be associated with dental caries, swallowing problems secondary to esophageal scarring, and constipation, as well as dystrophic or absent nails. Immunomapping studies of the skin often reveal type VII collagen cytoplasmic granules in the epidermis and weaker reaction in the roof of the subepidermal separation (quiz image).³ Abnormalities in type VII collagen impact the production of anchoring fibrils. Blister cleavage occurs in the sublamina densa with type VII collagen staining evident on the blister roof (quiz image).⁴ Patients with severe generalized recessive DEB may have barely detectable type VII collagen. In our patient, the cytoplasmic staining and weak staining in the epidermal roof of the separation confirmed the clinical impression of dominant DEB.

Autoimmune blistering disease should be considered in the histologic differential diagnosis, but it usually is associated with obvious disease in the mother. Direct immunofluorescence of pemphigoid gestationis reveals linear deposition of C3 at the basement membrane zone, which also can be associated with IgG (Figure 1). Neonates receiving passive transfer of antibodies may develop annular erythema, vesicles, and even dyshidroticlike changes on the soles.⁵

Suction blisters are subepithelial.^6,7 When they occur in the neonatal period, they often are localized and are thought to be the result of vigorous sucking in utero.⁶ They quickly resolve without treatment and do not reveal abnormalities on DIF. If immunomapping is done for type VII collagen, it will be located at the floor of the suction blister (Figure 2).

Bullous pemphigoid is associated with deposition of linear IgG along the dermoepidermal junction—IgG4 is most common—and/or C3 (Figure 3). Direct immunofluorescence on split-skin biopsy reveals IgG on the epidermal side of the blister in bullous pemphigoid in contrast to epidermolysis bullosa acquisita, where the immune deposits are found on the dermal side of the split.^8,9 Linear IgA bullous disease is associated with IgA deposition (Figure 4).^10,11 Secretory IgA derived from breast milk can be causative.¹¹ Neonatal linear IgA bullous disease is a serious condition associated with marked mucosal involvement that can eventuate in respiratory compromise. Prompt recognition is important; breastfeeding must be stopped and supportive therapy must be provided.

Other types of vesicular or pustular eruptions in the newborn usually are easily diagnosed by their typical clinical presentation without biopsy. Erythema toxicum neonatorum usually presents within 1 to 2 days of birth. It is self-limited and often resembles acne, but it also occurs on the trunk and extremities. Transient neonatal pustular melanosis may be present at birth and predominantly is seen in newborns with skin of color. Lesions easily rupture and usually resolve within 1 to 2 days. Infectious causes of blistering often can be identified on clinical examination and confirmed by culture. Herpes simplex virus infection is associated with characteristic multinucleated giant cells as well as steel grey nuclei evident on routine histologic evaluation. Bullous impetigo reveals superficial acantholysis and will have negative findings on DIF.¹²

When a neonate presents with widespread blistering, both genetic disorders of skin fragility as well as passive transfer of antibodies from maternal autoimmune disease need to be considered. Direct immunofluorescence and indirect immunofluorescence immunomapping findings can be useful in clarifying the diagnosis when heritable disorders of skin fragility or autoimmune blistering diseases are a clinical consideration.

The Diagnosis: Dominant Dystrophic Epidermolysis Bullosa

Blisters in a neonate may be caused by infectious, traumatic, autoimmune, or congenital etiologies. Biopsy findings correlated with clinical findings usually can establish a prompt diagnosis when the clinical diagnosis is uncertain. Direct immunofluorescence (DIF) as well as indirect immunofluorescence studies are useful when autoimmune blistering disease or congenital or heritable disorders of skin fragility are in the differential diagnosis. Many genetic abnormalities of skin fragility are associated with marked morbidity and mortality, and prompt diagnosis is essential to provide proper care. Our patient’s parents had no history of skin disorders, and there was no known family history of blistering disease or traumatic birth. A heritable disorder of skin fragility was still a top consideration because of the extensive blistering in the absence of any other symptoms.

Although dystrophic epidermolysis bullosa (DEB) is an uncommon cause of skin fragility in neonates, our patient’s presentation was typical because of the extensive blistering and increased fragility of the skin at pressure points. Dystrophic epidermolysis bullosa has both dominant and recessive presentations that span a spectrum from mild and focal skin blistering to extensive blistering with esophageal involvement.¹ Early diagnosis and treatment can mitigate potential failure to thrive or premature death. Inherited mutations in the type VII collagen gene, COL7A1, are causative.² Dominant DEB may be associated with dental caries, swallowing problems secondary to esophageal scarring, and constipation, as well as dystrophic or absent nails. Immunomapping studies of the skin often reveal type VII collagen cytoplasmic granules in the epidermis and weaker reaction in the roof of the subepidermal separation (quiz image).³ Abnormalities in type VII collagen impact the production of anchoring fibrils. Blister cleavage occurs in the sublamina densa with type VII collagen staining evident on the blister roof (quiz image).⁴ Patients with severe generalized recessive DEB may have barely detectable type VII collagen. In our patient, the cytoplasmic staining and weak staining in the epidermal roof of the separation confirmed the clinical impression of dominant DEB.

Autoimmune blistering disease should be considered in the histologic differential diagnosis, but it usually is associated with obvious disease in the mother. Direct immunofluorescence of pemphigoid gestationis reveals linear deposition of C3 at the basement membrane zone, which also can be associated with IgG (Figure 1). Neonates receiving passive transfer of antibodies may develop annular erythema, vesicles, and even dyshidroticlike changes on the soles.⁵

Suction blisters are subepithelial.^6,7 When they occur in the neonatal period, they often are localized and are thought to be the result of vigorous sucking in utero.⁶ They quickly resolve without treatment and do not reveal abnormalities on DIF. If immunomapping is done for type VII collagen, it will be located at the floor of the suction blister (Figure 2).

Bullous pemphigoid is associated with deposition of linear IgG along the dermoepidermal junction—IgG4 is most common—and/or C3 (Figure 3). Direct immunofluorescence on split-skin biopsy reveals IgG on the epidermal side of the blister in bullous pemphigoid in contrast to epidermolysis bullosa acquisita, where the immune deposits are found on the dermal side of the split.^8,9 Linear IgA bullous disease is associated with IgA deposition (Figure 4).^10,11 Secretory IgA derived from breast milk can be causative.¹¹ Neonatal linear IgA bullous disease is a serious condition associated with marked mucosal involvement that can eventuate in respiratory compromise. Prompt recognition is important; breastfeeding must be stopped and supportive therapy must be provided.

Other types of vesicular or pustular eruptions in the newborn usually are easily diagnosed by their typical clinical presentation without biopsy. Erythema toxicum neonatorum usually presents within 1 to 2 days of birth. It is self-limited and often resembles acne, but it also occurs on the trunk and extremities. Transient neonatal pustular melanosis may be present at birth and predominantly is seen in newborns with skin of color. Lesions easily rupture and usually resolve within 1 to 2 days. Infectious causes of blistering often can be identified on clinical examination and confirmed by culture. Herpes simplex virus infection is associated with characteristic multinucleated giant cells as well as steel grey nuclei evident on routine histologic evaluation. Bullous impetigo reveals superficial acantholysis and will have negative findings on DIF.¹²

When a neonate presents with widespread blistering, both genetic disorders of skin fragility as well as passive transfer of antibodies from maternal autoimmune disease need to be considered. Direct immunofluorescence and indirect immunofluorescence immunomapping findings can be useful in clarifying the diagnosis when heritable disorders of skin fragility or autoimmune blistering diseases are a clinical consideration.

Practice Gap

Nail art can skew the results of optical coherence tomography (OCT), a noninvasive imaging technology that is used to visualize nail morphology in diseases such as psoriatic arthritis and onychomycosis, with a penetration depth of 2 mm and high-resolution images.¹ Few studies have evaluated the effects of nail art on OCT. Saleah and colleagues¹ found that clear, semitransparent, and red nail polishes do not interfere with visualization of the nail plate, whereas nontransparent gel polish and art stones obscure the image. They did not comment on the effect of glitter nail art in their study, though they did test 1 nail that contained glitter.¹ Monpeurt et al² compared matte and glossy nail polishes. They found that matte polish was readily identifiable from the nail plate, whereas glossy polish presented a greater number of artifacts.²

The Solution

We looked at 3 glitter nail polishes—gold, pink, and silver—that were scanned by OCT to assess the effect of the polish on the resulting image. We determined that glitter particles completely obscured the nail bed and nail plate, regardless of color (Figure 1). Glossy clear polish imparted a distinct film on the top of the nail plate that did not obscure the nail plate or the nail bed (Figure 2).

We conclude that glitter nail polish contains numerous reflective solid particles that interfere with OCT imaging of the nail plate and nail bed. As a result, we recommend removal of nail art to properly assess nail pathology. Because removal may need to be conducted by a nail technician, the treating clinician should inform the patient ahead of time to come to the appointment with bare (ie, unpolished) nails.

Practice Implications

Bringing awareness to the necessity of removing nail art prior to OCT imaging is crucial because many patients partake in its application, and removal may require the involvement of a professional nail technician. If a patient can be made aware that they should remove all nail art in advance, they will be better prepared for an OCT imaging session. Such a protocol increases efficiency, decreases diagnostic delay, and reduces cost associated with multiple office visits.

Practice Gap

Nail art can skew the results of optical coherence tomography (OCT), a noninvasive imaging technology that is used to visualize nail morphology in diseases such as psoriatic arthritis and onychomycosis, with a penetration depth of 2 mm and high-resolution images.¹ Few studies have evaluated the effects of nail art on OCT. Saleah and colleagues¹ found that clear, semitransparent, and red nail polishes do not interfere with visualization of the nail plate, whereas nontransparent gel polish and art stones obscure the image. They did not comment on the effect of glitter nail art in their study, though they did test 1 nail that contained glitter.¹ Monpeurt et al² compared matte and glossy nail polishes. They found that matte polish was readily identifiable from the nail plate, whereas glossy polish presented a greater number of artifacts.²

The Solution

We looked at 3 glitter nail polishes—gold, pink, and silver—that were scanned by OCT to assess the effect of the polish on the resulting image. We determined that glitter particles completely obscured the nail bed and nail plate, regardless of color (Figure 1). Glossy clear polish imparted a distinct film on the top of the nail plate that did not obscure the nail plate or the nail bed (Figure 2).

We conclude that glitter nail polish contains numerous reflective solid particles that interfere with OCT imaging of the nail plate and nail bed. As a result, we recommend removal of nail art to properly assess nail pathology. Because removal may need to be conducted by a nail technician, the treating clinician should inform the patient ahead of time to come to the appointment with bare (ie, unpolished) nails.

Practice Implications

Bringing awareness to the necessity of removing nail art prior to OCT imaging is crucial because many patients partake in its application, and removal may require the involvement of a professional nail technician. If a patient can be made aware that they should remove all nail art in advance, they will be better prepared for an OCT imaging session. Such a protocol increases efficiency, decreases diagnostic delay, and reduces cost associated with multiple office visits.

Practice Gap

Nail art can skew the results of optical coherence tomography (OCT), a noninvasive imaging technology that is used to visualize nail morphology in diseases such as psoriatic arthritis and onychomycosis, with a penetration depth of 2 mm and high-resolution images.¹ Few studies have evaluated the effects of nail art on OCT. Saleah and colleagues¹ found that clear, semitransparent, and red nail polishes do not interfere with visualization of the nail plate, whereas nontransparent gel polish and art stones obscure the image. They did not comment on the effect of glitter nail art in their study, though they did test 1 nail that contained glitter.¹ Monpeurt et al² compared matte and glossy nail polishes. They found that matte polish was readily identifiable from the nail plate, whereas glossy polish presented a greater number of artifacts.²

The Solution

We looked at 3 glitter nail polishes—gold, pink, and silver—that were scanned by OCT to assess the effect of the polish on the resulting image. We determined that glitter particles completely obscured the nail bed and nail plate, regardless of color (Figure 1). Glossy clear polish imparted a distinct film on the top of the nail plate that did not obscure the nail plate or the nail bed (Figure 2).

We conclude that glitter nail polish contains numerous reflective solid particles that interfere with OCT imaging of the nail plate and nail bed. As a result, we recommend removal of nail art to properly assess nail pathology. Because removal may need to be conducted by a nail technician, the treating clinician should inform the patient ahead of time to come to the appointment with bare (ie, unpolished) nails.

Practice Implications

Bringing awareness to the necessity of removing nail art prior to OCT imaging is crucial because many patients partake in its application, and removal may require the involvement of a professional nail technician. If a patient can be made aware that they should remove all nail art in advance, they will be better prepared for an OCT imaging session. Such a protocol increases efficiency, decreases diagnostic delay, and reduces cost associated with multiple office visits.

The Diagnosis: Poroma

Histopathology showed an endophytic expansion of the epidermis by bland, uniform, basaloid epithelial cells with focal ductal differentiation and an abrupt transition with surrounding epidermal keratinocytes (Figure), consistent with a diagnosis of poroma. The patient elected to monitor the lesion rather than to have it excised.

Eccrine poroma, used interchangeably with the term poroma, is a rare benign adnexal tumor of the eccrine sweat glands resulting from proliferation of the acrosyringium.^1,2 It often occurs on the palms or soles, though it also can arise anywhere sweat glands are present.¹ Eccrine poromas often appear in middle-aged individuals as singular, well-circumscribed, red-brown papules or nodules.³ A characteristic feature is a shallow, cup-shaped depression within the larger papule or nodule.¹

Because the condition is benign and often asymptomatic, it can be safely monitored for progression.¹ However, if the lesion is symptomatic or located in a sensitive area, complete excision is curative.⁴ Eccrine poromas can recur, making close monitoring following excision important.⁵ The development of bleeding, itching, or pain in a previously asymptomatic lesion may indicate possible malignant transformation, which occurs in only 18% of cases.⁶

The differential diagnosis includes basal cell carcinoma, circumscribed acral hypokeratosis, Kaposi sarcoma, and pyogenic granuloma. Basal cell carcinoma is the most common type of skin cancer.⁷ In rare cases it has been shown to present on the palms or soles as a slowgrowing, reddish-pink papule or plaque with central ulceration. It typically is asymptomatic. Histopathology shows dermal nests of basaloid cells with peripheral palisading, stromal mucin, and peritumoral clefts. Treatment is surgical excision.⁷

Circumscribed acral hypokeratosis presents on the palms or soles as a solitary, shallow, well-defined lesion with a flat base and raised border.⁸ It often is red-pink in color and most frequently occurs in middle-aged women. Although the cause of the condition is unknown, it is thought to be the result of trauma or human papillomavirus infection.8 Biopsy results characteristically show hypokeratosis demarcated by a sharp and frayed cutoff from uninvolved acral skin with discrete hypogranulosis, dilated blood vessels in the papillary dermis, and slightly thickened collagen fibers in the reticular dermis.⁹ Surgical excision is a potential treatment option, as topical corticosteroids, retinoids, and calcipotriene have not been shown to be effective; spontaneous resolution has been reported.⁸

Kaposi sarcoma is a vascular neoplasm that is associated with human herpesvirus 8 infection.¹⁰ It typically presents on mucocutaneous sites and the lower extremities. Palmar involvement has been reported in rare cases, occurring as a solitary, well-demarcated, violaceous macule or patch that may be painful.^10-12 Characteristic histopathologic features include a proliferation in the dermis of slitlike vascular spaces and spindle cell proliferation.¹³ Treatment options include cryosurgery; pulsed dye laser; and topical, intralesional, or systemic chemotherapy agents, depending on the stage of the patient’s disease. Antiretroviral therapy is indicated for patients with Kaposi sarcoma secondary to AIDS.¹⁴

Pyogenic granuloma presents as a solitary red-brown or bluish-black papule or nodule that bleeds easily when manipulated.¹⁵ It commonly occurs following trauma, typically on the fingers, feet, and lips.⁶ Although benign, potential complications include ulceration and blood loss. Pyogenic granulomas can be treated via curettage and cautery, excision, cryosurgery, or pulsed dye laser.¹⁵

The Diagnosis: Poroma

Histopathology showed an endophytic expansion of the epidermis by bland, uniform, basaloid epithelial cells with focal ductal differentiation and an abrupt transition with surrounding epidermal keratinocytes (Figure), consistent with a diagnosis of poroma. The patient elected to monitor the lesion rather than to have it excised.

Eccrine poroma, used interchangeably with the term poroma, is a rare benign adnexal tumor of the eccrine sweat glands resulting from proliferation of the acrosyringium.^1,2 It often occurs on the palms or soles, though it also can arise anywhere sweat glands are present.¹ Eccrine poromas often appear in middle-aged individuals as singular, well-circumscribed, red-brown papules or nodules.³ A characteristic feature is a shallow, cup-shaped depression within the larger papule or nodule.¹

Because the condition is benign and often asymptomatic, it can be safely monitored for progression.¹ However, if the lesion is symptomatic or located in a sensitive area, complete excision is curative.⁴ Eccrine poromas can recur, making close monitoring following excision important.⁵ The development of bleeding, itching, or pain in a previously asymptomatic lesion may indicate possible malignant transformation, which occurs in only 18% of cases.⁶

The differential diagnosis includes basal cell carcinoma, circumscribed acral hypokeratosis, Kaposi sarcoma, and pyogenic granuloma. Basal cell carcinoma is the most common type of skin cancer.⁷ In rare cases it has been shown to present on the palms or soles as a slowgrowing, reddish-pink papule or plaque with central ulceration. It typically is asymptomatic. Histopathology shows dermal nests of basaloid cells with peripheral palisading, stromal mucin, and peritumoral clefts. Treatment is surgical excision.⁷

Circumscribed acral hypokeratosis presents on the palms or soles as a solitary, shallow, well-defined lesion with a flat base and raised border.⁸ It often is red-pink in color and most frequently occurs in middle-aged women. Although the cause of the condition is unknown, it is thought to be the result of trauma or human papillomavirus infection.8 Biopsy results characteristically show hypokeratosis demarcated by a sharp and frayed cutoff from uninvolved acral skin with discrete hypogranulosis, dilated blood vessels in the papillary dermis, and slightly thickened collagen fibers in the reticular dermis.⁹ Surgical excision is a potential treatment option, as topical corticosteroids, retinoids, and calcipotriene have not been shown to be effective; spontaneous resolution has been reported.⁸

Kaposi sarcoma is a vascular neoplasm that is associated with human herpesvirus 8 infection.¹⁰ It typically presents on mucocutaneous sites and the lower extremities. Palmar involvement has been reported in rare cases, occurring as a solitary, well-demarcated, violaceous macule or patch that may be painful.^10-12 Characteristic histopathologic features include a proliferation in the dermis of slitlike vascular spaces and spindle cell proliferation.¹³ Treatment options include cryosurgery; pulsed dye laser; and topical, intralesional, or systemic chemotherapy agents, depending on the stage of the patient’s disease. Antiretroviral therapy is indicated for patients with Kaposi sarcoma secondary to AIDS.¹⁴

Pyogenic granuloma presents as a solitary red-brown or bluish-black papule or nodule that bleeds easily when manipulated.¹⁵ It commonly occurs following trauma, typically on the fingers, feet, and lips.⁶ Although benign, potential complications include ulceration and blood loss. Pyogenic granulomas can be treated via curettage and cautery, excision, cryosurgery, or pulsed dye laser.¹⁵

The Diagnosis: Poroma

Histopathology showed an endophytic expansion of the epidermis by bland, uniform, basaloid epithelial cells with focal ductal differentiation and an abrupt transition with surrounding epidermal keratinocytes (Figure), consistent with a diagnosis of poroma. The patient elected to monitor the lesion rather than to have it excised.

Eccrine poroma, used interchangeably with the term poroma, is a rare benign adnexal tumor of the eccrine sweat glands resulting from proliferation of the acrosyringium.^1,2 It often occurs on the palms or soles, though it also can arise anywhere sweat glands are present.¹ Eccrine poromas often appear in middle-aged individuals as singular, well-circumscribed, red-brown papules or nodules.³ A characteristic feature is a shallow, cup-shaped depression within the larger papule or nodule.¹

Because the condition is benign and often asymptomatic, it can be safely monitored for progression.¹ However, if the lesion is symptomatic or located in a sensitive area, complete excision is curative.⁴ Eccrine poromas can recur, making close monitoring following excision important.⁵ The development of bleeding, itching, or pain in a previously asymptomatic lesion may indicate possible malignant transformation, which occurs in only 18% of cases.⁶

The differential diagnosis includes basal cell carcinoma, circumscribed acral hypokeratosis, Kaposi sarcoma, and pyogenic granuloma. Basal cell carcinoma is the most common type of skin cancer.⁷ In rare cases it has been shown to present on the palms or soles as a slowgrowing, reddish-pink papule or plaque with central ulceration. It typically is asymptomatic. Histopathology shows dermal nests of basaloid cells with peripheral palisading, stromal mucin, and peritumoral clefts. Treatment is surgical excision.⁷

Circumscribed acral hypokeratosis presents on the palms or soles as a solitary, shallow, well-defined lesion with a flat base and raised border.⁸ It often is red-pink in color and most frequently occurs in middle-aged women. Although the cause of the condition is unknown, it is thought to be the result of trauma or human papillomavirus infection.8 Biopsy results characteristically show hypokeratosis demarcated by a sharp and frayed cutoff from uninvolved acral skin with discrete hypogranulosis, dilated blood vessels in the papillary dermis, and slightly thickened collagen fibers in the reticular dermis.⁹ Surgical excision is a potential treatment option, as topical corticosteroids, retinoids, and calcipotriene have not been shown to be effective; spontaneous resolution has been reported.⁸

Kaposi sarcoma is a vascular neoplasm that is associated with human herpesvirus 8 infection.¹⁰ It typically presents on mucocutaneous sites and the lower extremities. Palmar involvement has been reported in rare cases, occurring as a solitary, well-demarcated, violaceous macule or patch that may be painful.^10-12 Characteristic histopathologic features include a proliferation in the dermis of slitlike vascular spaces and spindle cell proliferation.¹³ Treatment options include cryosurgery; pulsed dye laser; and topical, intralesional, or systemic chemotherapy agents, depending on the stage of the patient’s disease. Antiretroviral therapy is indicated for patients with Kaposi sarcoma secondary to AIDS.¹⁴

Pyogenic granuloma presents as a solitary red-brown or bluish-black papule or nodule that bleeds easily when manipulated.¹⁵ It commonly occurs following trauma, typically on the fingers, feet, and lips.⁶ Although benign, potential complications include ulceration and blood loss. Pyogenic granulomas can be treated via curettage and cautery, excision, cryosurgery, or pulsed dye laser.¹⁵

Scabies is caused by cutaneous ectoparasitic infection by the mite Sarcoptes scabiei var hominis. The infection is highly contagious via direct skin-to-skin contact or indirectly through infested bedding, clothing or fomites.^1,2 Scabies occurs at all ages, in all ethnic groups, and at all socioeconomic levels.¹ Analysis by the Global Burden of Disease estimates that 200 million individuals have been infected with scabies worldwide. The World Health Organization has declared scabies a neglected tropical disease.³

Crusted scabies is a severe and rare form of scabies, with hyperinfestation of thousands to millions of mites, and more commonly is associated with immunosuppressed states, including HIV and hematologic malignancies.^1,2,4 Crusted scabies has a high mortality rate due to sepsis when left untreated.^3,5

Occasionally, iatrogenic immunosuppression contributes to the development of crusted scabies.^1,2 Iatrogenic immunosuppression leading to crusted scabies most commonly occurs secondary to immunosuppression after bone marrow or solid organ transplantation.⁶ Less often, crusted scabies is caused by iatrogenic immunosuppression from other clinical scenarios.^1,2

We describe a patient with iatrogenic immunosuppression due to azathioprine-induced myelosuppression for the treatment of granulomatosis with polyangiitis (GPA) who developed crusted scabies that clinically presented as erythroderma. Crusted scabies should be included in the differential diagnosis of erythroderma, especially in the setting of iatrogenic immunosuppression, for timely and appropriate management.

Case Report

An 84-year-old man presented with worsening pruritus, erythema, and thick yellow scale that progressed to erythroderma over the last 2 weeks. He was diagnosed with GPA 6 months prior to presentation and was treated with azathioprine 150 mg/d, prednisone 10 mg/d, and sulfamethoxazole 800 mg plus trimethoprim 160 mg twice weekly for prophylaxis against Pneumocystis jirovecii pneumonia.

Three weeks prior to presentation, the patient was hospitalized for pancytopenia attributed to azathioprine-induced myelosuppression (hemoglobin, 6.1 g/dL [reference range, 13.5–18.0 g/dL]; hematocrit, 17.5% [reference range, 42%–52%]; white blood cell count, 1.66×10³/μL [reference range, 4.0–10.5×10³/μL]; platelet count, 146×10³/μL [reference range, 150–450×10³/μL]; absolute neutrophil count, 1.29×10³/μL [reference range, 1.4–6.5×10³/μL]). He was transferred to a skilled nursing facility after discharge and referred to dermatology for evaluation of the worsening pruritic rash.

At the current presentation, the patient denied close contact with anyone who had a similar rash at home or at the skilled nursing facility. Physical examination revealed diffuse erythroderma with yellow scale on the scalp, trunk, arms, and legs (Figure 1). The palms showed scattered 2- to 3-mm pustules. The mucosal surfaces did not have lesions. A punch biopsy of a pustule from the right arm revealed focal spongiosis, parakeratosis, and acanthosis, as well as a perivascular and interstitial mixed inflammatory infiltrate with lymphocytes and eosinophils. Organisms morphologically compatible with scabies were found in the stratum corneum (Figure 2). Another punch biopsy of a pustule from the right arm was performed for direct immunofluorescence (DIF) and was negative for immunoglobulin deposition. Mineral oil preparation from pustules on the palm was positive for mites.

The patient was treated with permethrin cream 5% and oral ivermectin 200 μg/kg on day 1 and day 10. The prednisone dosage was increased from 10 mg/d to 50 mg/d and tapered over 2 weeks to treat the symptomatic rash and GPA. He remains on maintenance rituximab for GPA, without recurrence of scabies.

Comment

Pathogenesis—As an obligate parasite, S scabiei spends its entire life cycle within the host. Impregnated female mites burrow into the epidermis after mating and lay eggs daily for 1 to 2 months. Eggs hatch 2 or 3 days later. Larvae then migrate to the skin surface; burrow into the stratum corneum, where they mature into adults; and then mate on the skin surface.^1,4

Clinical Presentation and Sequelae—Typically, scabies presents 2 to 6 weeks after initial exposure with generalized and intense itching and inflammatory pruritic papules on the finger webs, wrists, elbows, axillae, buttocks, umbilicus, genitalia, and areolae.¹ Burrows are specific for scabies but may not always be present. Often, there are nonspecific secondary lesions, including excoriations, dermatitis, and impetiginization.

Complications of scabies can be severe, with initial colonization and infection of the skin resulting in impetigo and cellulitis. Systematic sequelae from local skin infection include post-streptococcal glomerulonephritis, rheumatic fever, and sepsis. Mortality from sepsis in scabies can be high.^3,5

Classic Crusted Scabies and Other Variants—Crusted scabies presents with psoriasiform hyperkeratotic plaques involving the hands and feet with potential nail involvement that can become more generalized.¹ Alterations in CD4⁺ T-cell function have been implicated in the development of crusted scabies, in which an excessive helper T cell (T_H2) response is elicited against the ectoparasite, which may help explain the intense pruritus of scabies.⁶ Occasionally, iatrogenic immunosuppression contributes to development of crusted scabies,¹ as was the case with our patient. However, it is rare for crusted scabies to present with erythroderma.⁷

Other atypical presentations of scabies include a seborrheic dermatitis–like presentation in infants, nodular lesions in the groin and axillae in more chronic scabies, and vesicles or bullous lesions.¹

Diagnosis—Identification of mites, eggs, or feces is necessary for definitive diagnosis of scabies.⁸ These materials can be obtained through skin scrapings with mineral oil and observed under light microscopy or direct dermoscopy. Multiple scrapings on many lesions should be performed because failure to identify mites can be common and does not rule out scabies. Dermoscopic examination of active lesions under low power also can be helpful, given that identification of dark brown triangular structures can correspond to visualization of the pigmented anterior section of the mite.^9-11 A skin biopsy can help identify mites, but histopathology often shows a nonspecific hypersensitivity reaction.¹² Therefore, empiric treatment often is necessary.

Differential Diagnosis—The differential diagnosis of erythroderma is broad and includes a drug eruption; Sézary syndrome; and pre-existing skin diseases, including psoriasis, atopic dermatitis, pityriasis rubra pilaris, pemphigus foliaceus, and bullous pemphigoid. Histopathology is critical to differentiate these diagnoses. Bullous pemphigoid and pemphigus foliaceus are immunobullous diseases that typically are positive for immunoglobulin deposition on DIF. In rare cases, scabies also can present with bullae and positive DIF test results.¹³

Treatment—First-line treatment of crusted scabies in the United States is permethrin cream 5%, followed by oral ivermectin 200 μg/kg.^4,5,14,15 Other scabicides include topicals such as benzyl benzoate 10% to 25%; precipitated sulfur 2% to 10%; crotamiton 10%; malathion 0.5%; and lindane 1%.⁵ The association of neurotoxicity with lindane has considerably reduced the drug’s use.¹

During treatment of scabies, it is important to isolate patients to mitigate the possibility of spread.⁴ Pruritus can persist for a few weeks after completion of therapy.⁵ Patients should be closely monitored to ensure that this symptom is secondary to skin inflammation and not incomplete treatment.

Treatment of crusted scabies may require repeated treatments to decrease the notable mite burden as well as the associated crusting and scale. Adding a keratolytic such as 5% to 10% salicylic acid in petrolatum to the treatment regimen may be useful for breaking up thick scale.⁵

Immunosuppression—With numerous immunomodulatory drugs for treating autoimmunity comes an increased risk for iatrogenic immunosuppression that may contribute to the development of crusted scabies.¹⁶ In a number of autoimmune diseases such as rheumatoid arthritis,^17-19 psoriasis,^20,21 pemphigus vulgaris,²² systemic lupus erythematosus,²³ systemic sclerosis,^22,24 bullous pemphigoid,^25,26 and dermatomyositis,²⁷ patients have developed crusted scabies secondary to treatment-related immunosuppression. These immunosuppressive therapies include systemic steroids,^22-24,26-31 methotrexate,²³ infliximab,¹⁸ adalimumab,²¹ toclizumab,¹⁹ and etanercept.²⁰ In a case of drug-induced Stevens-Johnson syndrome, the patient developed crusted scabies during long-term use of oral steroids.²²

Patients with a malignancy who are being treated with chemotherapy also can develop crusted scabies.²⁸ Crusted scabies has even been associated with long-term topical steroid^32-34 and topical calcineurin inhibitor use.¹⁶

Iatrogenic immunosuppression in our patient resulted from treatment of GPA with azathioprine, an immunosuppressive drug that acts as an antagonist of the breakdown of purines, leading to inhibition of DNA, RNA, and protein synthesis.³⁵ On occasion, azathioprine can induce immunosuppression in the form of myelosuppression and resulting pancytopenia, as was the case with our patient.

Conclusion

Although scabies is designated as a neglected tropical disease by the World Health Organization, it still causes a notable burden worldwide, regardless of the economics. Our case highlights an unusual presentation of scabies as erythroderma in the setting of iatrogenic immunosuppression from azathioprine use. Dermatologists should consider crusted scabies in the differential diagnosis of erythroderma, especially in immunocompromised patients, to avoid delays in diagnosis and treatment. Immunosuppressive therapy is an important mainstay in the treatment of many conditions, but it is important to consider that these medications can place patients at an increased risk for rare opportunistic infections. Therefore, patients receiving such treatment should be closely monitored.

Scabies is caused by cutaneous ectoparasitic infection by the mite Sarcoptes scabiei var hominis. The infection is highly contagious via direct skin-to-skin contact or indirectly through infested bedding, clothing or fomites.^1,2 Scabies occurs at all ages, in all ethnic groups, and at all socioeconomic levels.¹ Analysis by the Global Burden of Disease estimates that 200 million individuals have been infected with scabies worldwide. The World Health Organization has declared scabies a neglected tropical disease.³

Crusted scabies is a severe and rare form of scabies, with hyperinfestation of thousands to millions of mites, and more commonly is associated with immunosuppressed states, including HIV and hematologic malignancies.^1,2,4 Crusted scabies has a high mortality rate due to sepsis when left untreated.^3,5

Occasionally, iatrogenic immunosuppression contributes to the development of crusted scabies.^1,2 Iatrogenic immunosuppression leading to crusted scabies most commonly occurs secondary to immunosuppression after bone marrow or solid organ transplantation.⁶ Less often, crusted scabies is caused by iatrogenic immunosuppression from other clinical scenarios.^1,2

We describe a patient with iatrogenic immunosuppression due to azathioprine-induced myelosuppression for the treatment of granulomatosis with polyangiitis (GPA) who developed crusted scabies that clinically presented as erythroderma. Crusted scabies should be included in the differential diagnosis of erythroderma, especially in the setting of iatrogenic immunosuppression, for timely and appropriate management.

Case Report

An 84-year-old man presented with worsening pruritus, erythema, and thick yellow scale that progressed to erythroderma over the last 2 weeks. He was diagnosed with GPA 6 months prior to presentation and was treated with azathioprine 150 mg/d, prednisone 10 mg/d, and sulfamethoxazole 800 mg plus trimethoprim 160 mg twice weekly for prophylaxis against Pneumocystis jirovecii pneumonia.

Three weeks prior to presentation, the patient was hospitalized for pancytopenia attributed to azathioprine-induced myelosuppression (hemoglobin, 6.1 g/dL [reference range, 13.5–18.0 g/dL]; hematocrit, 17.5% [reference range, 42%–52%]; white blood cell count, 1.66×10³/μL [reference range, 4.0–10.5×10³/μL]; platelet count, 146×10³/μL [reference range, 150–450×10³/μL]; absolute neutrophil count, 1.29×10³/μL [reference range, 1.4–6.5×10³/μL]). He was transferred to a skilled nursing facility after discharge and referred to dermatology for evaluation of the worsening pruritic rash.

At the current presentation, the patient denied close contact with anyone who had a similar rash at home or at the skilled nursing facility. Physical examination revealed diffuse erythroderma with yellow scale on the scalp, trunk, arms, and legs (Figure 1). The palms showed scattered 2- to 3-mm pustules. The mucosal surfaces did not have lesions. A punch biopsy of a pustule from the right arm revealed focal spongiosis, parakeratosis, and acanthosis, as well as a perivascular and interstitial mixed inflammatory infiltrate with lymphocytes and eosinophils. Organisms morphologically compatible with scabies were found in the stratum corneum (Figure 2). Another punch biopsy of a pustule from the right arm was performed for direct immunofluorescence (DIF) and was negative for immunoglobulin deposition. Mineral oil preparation from pustules on the palm was positive for mites.

The patient was treated with permethrin cream 5% and oral ivermectin 200 μg/kg on day 1 and day 10. The prednisone dosage was increased from 10 mg/d to 50 mg/d and tapered over 2 weeks to treat the symptomatic rash and GPA. He remains on maintenance rituximab for GPA, without recurrence of scabies.

Comment

Pathogenesis—As an obligate parasite, S scabiei spends its entire life cycle within the host. Impregnated female mites burrow into the epidermis after mating and lay eggs daily for 1 to 2 months. Eggs hatch 2 or 3 days later. Larvae then migrate to the skin surface; burrow into the stratum corneum, where they mature into adults; and then mate on the skin surface.^1,4

Clinical Presentation and Sequelae—Typically, scabies presents 2 to 6 weeks after initial exposure with generalized and intense itching and inflammatory pruritic papules on the finger webs, wrists, elbows, axillae, buttocks, umbilicus, genitalia, and areolae.¹ Burrows are specific for scabies but may not always be present. Often, there are nonspecific secondary lesions, including excoriations, dermatitis, and impetiginization.

Complications of scabies can be severe, with initial colonization and infection of the skin resulting in impetigo and cellulitis. Systematic sequelae from local skin infection include post-streptococcal glomerulonephritis, rheumatic fever, and sepsis. Mortality from sepsis in scabies can be high.^3,5

Classic Crusted Scabies and Other Variants—Crusted scabies presents with psoriasiform hyperkeratotic plaques involving the hands and feet with potential nail involvement that can become more generalized.¹ Alterations in CD4⁺ T-cell function have been implicated in the development of crusted scabies, in which an excessive helper T cell (T_H2) response is elicited against the ectoparasite, which may help explain the intense pruritus of scabies.⁶ Occasionally, iatrogenic immunosuppression contributes to development of crusted scabies,¹ as was the case with our patient. However, it is rare for crusted scabies to present with erythroderma.⁷

Other atypical presentations of scabies include a seborrheic dermatitis–like presentation in infants, nodular lesions in the groin and axillae in more chronic scabies, and vesicles or bullous lesions.¹

Diagnosis—Identification of mites, eggs, or feces is necessary for definitive diagnosis of scabies.⁸ These materials can be obtained through skin scrapings with mineral oil and observed under light microscopy or direct dermoscopy. Multiple scrapings on many lesions should be performed because failure to identify mites can be common and does not rule out scabies. Dermoscopic examination of active lesions under low power also can be helpful, given that identification of dark brown triangular structures can correspond to visualization of the pigmented anterior section of the mite.^9-11 A skin biopsy can help identify mites, but histopathology often shows a nonspecific hypersensitivity reaction.¹² Therefore, empiric treatment often is necessary.

Differential Diagnosis—The differential diagnosis of erythroderma is broad and includes a drug eruption; Sézary syndrome; and pre-existing skin diseases, including psoriasis, atopic dermatitis, pityriasis rubra pilaris, pemphigus foliaceus, and bullous pemphigoid. Histopathology is critical to differentiate these diagnoses. Bullous pemphigoid and pemphigus foliaceus are immunobullous diseases that typically are positive for immunoglobulin deposition on DIF. In rare cases, scabies also can present with bullae and positive DIF test results.¹³

Treatment—First-line treatment of crusted scabies in the United States is permethrin cream 5%, followed by oral ivermectin 200 μg/kg.^4,5,14,15 Other scabicides include topicals such as benzyl benzoate 10% to 25%; precipitated sulfur 2% to 10%; crotamiton 10%; malathion 0.5%; and lindane 1%.⁵ The association of neurotoxicity with lindane has considerably reduced the drug’s use.¹

During treatment of scabies, it is important to isolate patients to mitigate the possibility of spread.⁴ Pruritus can persist for a few weeks after completion of therapy.⁵ Patients should be closely monitored to ensure that this symptom is secondary to skin inflammation and not incomplete treatment.

Treatment of crusted scabies may require repeated treatments to decrease the notable mite burden as well as the associated crusting and scale. Adding a keratolytic such as 5% to 10% salicylic acid in petrolatum to the treatment regimen may be useful for breaking up thick scale.⁵

Immunosuppression—With numerous immunomodulatory drugs for treating autoimmunity comes an increased risk for iatrogenic immunosuppression that may contribute to the development of crusted scabies.¹⁶ In a number of autoimmune diseases such as rheumatoid arthritis,^17-19 psoriasis,^20,21 pemphigus vulgaris,²² systemic lupus erythematosus,²³ systemic sclerosis,^22,24 bullous pemphigoid,^25,26 and dermatomyositis,²⁷ patients have developed crusted scabies secondary to treatment-related immunosuppression. These immunosuppressive therapies include systemic steroids,^22-24,26-31 methotrexate,²³ infliximab,¹⁸ adalimumab,²¹ toclizumab,¹⁹ and etanercept.²⁰ In a case of drug-induced Stevens-Johnson syndrome, the patient developed crusted scabies during long-term use of oral steroids.²²

Patients with a malignancy who are being treated with chemotherapy also can develop crusted scabies.²⁸ Crusted scabies has even been associated with long-term topical steroid^32-34 and topical calcineurin inhibitor use.¹⁶

Iatrogenic immunosuppression in our patient resulted from treatment of GPA with azathioprine, an immunosuppressive drug that acts as an antagonist of the breakdown of purines, leading to inhibition of DNA, RNA, and protein synthesis.³⁵ On occasion, azathioprine can induce immunosuppression in the form of myelosuppression and resulting pancytopenia, as was the case with our patient.

Conclusion

Although scabies is designated as a neglected tropical disease by the World Health Organization, it still causes a notable burden worldwide, regardless of the economics. Our case highlights an unusual presentation of scabies as erythroderma in the setting of iatrogenic immunosuppression from azathioprine use. Dermatologists should consider crusted scabies in the differential diagnosis of erythroderma, especially in immunocompromised patients, to avoid delays in diagnosis and treatment. Immunosuppressive therapy is an important mainstay in the treatment of many conditions, but it is important to consider that these medications can place patients at an increased risk for rare opportunistic infections. Therefore, patients receiving such treatment should be closely monitored.

Scabies is caused by cutaneous ectoparasitic infection by the mite Sarcoptes scabiei var hominis. The infection is highly contagious via direct skin-to-skin contact or indirectly through infested bedding, clothing or fomites.^1,2 Scabies occurs at all ages, in all ethnic groups, and at all socioeconomic levels.¹ Analysis by the Global Burden of Disease estimates that 200 million individuals have been infected with scabies worldwide. The World Health Organization has declared scabies a neglected tropical disease.³

Crusted scabies is a severe and rare form of scabies, with hyperinfestation of thousands to millions of mites, and more commonly is associated with immunosuppressed states, including HIV and hematologic malignancies.^1,2,4 Crusted scabies has a high mortality rate due to sepsis when left untreated.^3,5

Occasionally, iatrogenic immunosuppression contributes to the development of crusted scabies.^1,2 Iatrogenic immunosuppression leading to crusted scabies most commonly occurs secondary to immunosuppression after bone marrow or solid organ transplantation.⁶ Less often, crusted scabies is caused by iatrogenic immunosuppression from other clinical scenarios.^1,2

We describe a patient with iatrogenic immunosuppression due to azathioprine-induced myelosuppression for the treatment of granulomatosis with polyangiitis (GPA) who developed crusted scabies that clinically presented as erythroderma. Crusted scabies should be included in the differential diagnosis of erythroderma, especially in the setting of iatrogenic immunosuppression, for timely and appropriate management.

Case Report

An 84-year-old man presented with worsening pruritus, erythema, and thick yellow scale that progressed to erythroderma over the last 2 weeks. He was diagnosed with GPA 6 months prior to presentation and was treated with azathioprine 150 mg/d, prednisone 10 mg/d, and sulfamethoxazole 800 mg plus trimethoprim 160 mg twice weekly for prophylaxis against Pneumocystis jirovecii pneumonia.

Three weeks prior to presentation, the patient was hospitalized for pancytopenia attributed to azathioprine-induced myelosuppression (hemoglobin, 6.1 g/dL [reference range, 13.5–18.0 g/dL]; hematocrit, 17.5% [reference range, 42%–52%]; white blood cell count, 1.66×10³/μL [reference range, 4.0–10.5×10³/μL]; platelet count, 146×10³/μL [reference range, 150–450×10³/μL]; absolute neutrophil count, 1.29×10³/μL [reference range, 1.4–6.5×10³/μL]). He was transferred to a skilled nursing facility after discharge and referred to dermatology for evaluation of the worsening pruritic rash.

At the current presentation, the patient denied close contact with anyone who had a similar rash at home or at the skilled nursing facility. Physical examination revealed diffuse erythroderma with yellow scale on the scalp, trunk, arms, and legs (Figure 1). The palms showed scattered 2- to 3-mm pustules. The mucosal surfaces did not have lesions. A punch biopsy of a pustule from the right arm revealed focal spongiosis, parakeratosis, and acanthosis, as well as a perivascular and interstitial mixed inflammatory infiltrate with lymphocytes and eosinophils. Organisms morphologically compatible with scabies were found in the stratum corneum (Figure 2). Another punch biopsy of a pustule from the right arm was performed for direct immunofluorescence (DIF) and was negative for immunoglobulin deposition. Mineral oil preparation from pustules on the palm was positive for mites.

The patient was treated with permethrin cream 5% and oral ivermectin 200 μg/kg on day 1 and day 10. The prednisone dosage was increased from 10 mg/d to 50 mg/d and tapered over 2 weeks to treat the symptomatic rash and GPA. He remains on maintenance rituximab for GPA, without recurrence of scabies.

Comment

Pathogenesis—As an obligate parasite, S scabiei spends its entire life cycle within the host. Impregnated female mites burrow into the epidermis after mating and lay eggs daily for 1 to 2 months. Eggs hatch 2 or 3 days later. Larvae then migrate to the skin surface; burrow into the stratum corneum, where they mature into adults; and then mate on the skin surface.^1,4

Clinical Presentation and Sequelae—Typically, scabies presents 2 to 6 weeks after initial exposure with generalized and intense itching and inflammatory pruritic papules on the finger webs, wrists, elbows, axillae, buttocks, umbilicus, genitalia, and areolae.¹ Burrows are specific for scabies but may not always be present. Often, there are nonspecific secondary lesions, including excoriations, dermatitis, and impetiginization.

Complications of scabies can be severe, with initial colonization and infection of the skin resulting in impetigo and cellulitis. Systematic sequelae from local skin infection include post-streptococcal glomerulonephritis, rheumatic fever, and sepsis. Mortality from sepsis in scabies can be high.^3,5

Classic Crusted Scabies and Other Variants—Crusted scabies presents with psoriasiform hyperkeratotic plaques involving the hands and feet with potential nail involvement that can become more generalized.¹ Alterations in CD4⁺ T-cell function have been implicated in the development of crusted scabies, in which an excessive helper T cell (T_H2) response is elicited against the ectoparasite, which may help explain the intense pruritus of scabies.⁶ Occasionally, iatrogenic immunosuppression contributes to development of crusted scabies,¹ as was the case with our patient. However, it is rare for crusted scabies to present with erythroderma.⁷

Other atypical presentations of scabies include a seborrheic dermatitis–like presentation in infants, nodular lesions in the groin and axillae in more chronic scabies, and vesicles or bullous lesions.¹

Diagnosis—Identification of mites, eggs, or feces is necessary for definitive diagnosis of scabies.⁸ These materials can be obtained through skin scrapings with mineral oil and observed under light microscopy or direct dermoscopy. Multiple scrapings on many lesions should be performed because failure to identify mites can be common and does not rule out scabies. Dermoscopic examination of active lesions under low power also can be helpful, given that identification of dark brown triangular structures can correspond to visualization of the pigmented anterior section of the mite.^9-11 A skin biopsy can help identify mites, but histopathology often shows a nonspecific hypersensitivity reaction.¹² Therefore, empiric treatment often is necessary.

Differential Diagnosis—The differential diagnosis of erythroderma is broad and includes a drug eruption; Sézary syndrome; and pre-existing skin diseases, including psoriasis, atopic dermatitis, pityriasis rubra pilaris, pemphigus foliaceus, and bullous pemphigoid. Histopathology is critical to differentiate these diagnoses. Bullous pemphigoid and pemphigus foliaceus are immunobullous diseases that typically are positive for immunoglobulin deposition on DIF. In rare cases, scabies also can present with bullae and positive DIF test results.¹³

Treatment—First-line treatment of crusted scabies in the United States is permethrin cream 5%, followed by oral ivermectin 200 μg/kg.^4,5,14,15 Other scabicides include topicals such as benzyl benzoate 10% to 25%; precipitated sulfur 2% to 10%; crotamiton 10%; malathion 0.5%; and lindane 1%.⁵ The association of neurotoxicity with lindane has considerably reduced the drug’s use.¹

During treatment of scabies, it is important to isolate patients to mitigate the possibility of spread.⁴ Pruritus can persist for a few weeks after completion of therapy.⁵ Patients should be closely monitored to ensure that this symptom is secondary to skin inflammation and not incomplete treatment.

Treatment of crusted scabies may require repeated treatments to decrease the notable mite burden as well as the associated crusting and scale. Adding a keratolytic such as 5% to 10% salicylic acid in petrolatum to the treatment regimen may be useful for breaking up thick scale.⁵

Immunosuppression—With numerous immunomodulatory drugs for treating autoimmunity comes an increased risk for iatrogenic immunosuppression that may contribute to the development of crusted scabies.¹⁶ In a number of autoimmune diseases such as rheumatoid arthritis,^17-19 psoriasis,^20,21 pemphigus vulgaris,²² systemic lupus erythematosus,²³ systemic sclerosis,^22,24 bullous pemphigoid,^25,26 and dermatomyositis,²⁷ patients have developed crusted scabies secondary to treatment-related immunosuppression. These immunosuppressive therapies include systemic steroids,^22-24,26-31 methotrexate,²³ infliximab,¹⁸ adalimumab,²¹ toclizumab,¹⁹ and etanercept.²⁰ In a case of drug-induced Stevens-Johnson syndrome, the patient developed crusted scabies during long-term use of oral steroids.²²

Patients with a malignancy who are being treated with chemotherapy also can develop crusted scabies.²⁸ Crusted scabies has even been associated with long-term topical steroid^32-34 and topical calcineurin inhibitor use.¹⁶

Iatrogenic immunosuppression in our patient resulted from treatment of GPA with azathioprine, an immunosuppressive drug that acts as an antagonist of the breakdown of purines, leading to inhibition of DNA, RNA, and protein synthesis.³⁵ On occasion, azathioprine can induce immunosuppression in the form of myelosuppression and resulting pancytopenia, as was the case with our patient.

Conclusion

Although scabies is designated as a neglected tropical disease by the World Health Organization, it still causes a notable burden worldwide, regardless of the economics. Our case highlights an unusual presentation of scabies as erythroderma in the setting of iatrogenic immunosuppression from azathioprine use. Dermatologists should consider crusted scabies in the differential diagnosis of erythroderma, especially in immunocompromised patients, to avoid delays in diagnosis and treatment. Immunosuppressive therapy is an important mainstay in the treatment of many conditions, but it is important to consider that these medications can place patients at an increased risk for rare opportunistic infections. Therefore, patients receiving such treatment should be closely monitored.