Dermatopathology

The Diagnosis: Granuloma Annulare

A biopsy of a lesion on the right flank demonstrated granulomatous inflammation and interstitial mucin (Figure), characteristic of granuloma annulare (GA).^1,2 Granuloma annulare is a relatively common skin disorder with an unknown etiology. It typically presents as smooth, annular, erythematous plaques.¹ The most common variants of GA are localized, generalized, and subcutaneous. Our case demonstrated Wolf isotopic response, an unrelated skin disease that forms at the same location as a previously healed skin lesion.² It is important to be aware of this phenomenon so that it is not confused with a recurrence of herpes zoster virus (HZV).

Although relatively infrequent, GA is the most common isotopic response following HZV infections.^3-5 Other postherpetic isotopic eruptions include cutaneous malignancies, lichen planus, sarcoidosis, morphea, reactive perforating collagenosis, psoriasis, and infections, among others.^3,5,6 The time between HZV infection and GA can be variable, ranging from a few weeks to many years apart.³

Oftentimes GA will spontaneously resolve within 2 years; however, recurrence is common.^7-9 There currently are no standard treatment guidelines. The most promising treatment options include intralesional or topical glucocorticoids for localized GA as well as phototherapy or hydroxychloroquine for widespread disease.^8,10  

Annular elastolytic giant cell granuloma (also called actinic granuloma) is a rare idiopathic inflammatory skin disease. It is characterized by erythematous annular papules or plaques mainly found on sun-exposed skin, such as the backs of the hands, forearms, or face.^11,12 Therefore, based on the distribution of our patient’s lesions, annular elastolytic giant cell granuloma was an unlikely diagnosis. Furthermore, it is not a known postherpetic isotopic reaction. Annular elastolytic giant cell granuloma can appear histologically similar to GA. Differentiating histologic features include a nonpalisading granuloma as well as the absence of mucin and necrobiosis.¹²

Annular lichen planus is a long-recognized but uncommon clinical variant of lichen planus that typically presents as pruritic, purple, annular plaques on the penis, scrotum, or intertriginous areas.¹³ The violaceous coloring is more characteristic of lichen planus. Histology is helpful in differentiating from GA.

Nummular eczema presents as scattered, welldefined, pruritic, erythematous, coin-shaped, coin-sized plaques in patients with diffusely dry skin.¹⁴ The scaling and serous crusting as well as more prominent pruritus help distinguish it from GA. The appearance of nummular eczema is quite characteristic; therefore, a biopsy typically is unnecessary for diagnosis. However, a potassium hydroxide wet mount examination of a skin scraping should be performed if tinea corporis also is suspected.

Superficial erythema annulare centrifugum classically presents as an annular or arciform pruritic lesion with an advancing outer erythematous edge with an inner rim of scale that most commonly occurs on the lower extremities. ¹⁵ The presence of pruritus and trailing scale helps distinguish this lesion from GA. Histologically, there are epidermal changes of hyperplasia, spongiosis, and parakeratosis, as well as lymphohistiocytic infiltrate surrounding the superficial dermal vessels^.16

We report this case to highlight GA as the most common postherpetic isotopic response. It should be on the differential diagnosis when a patient presents with erythematous, smooth, annular plaques occurring in the distribution of a resolved case of HZV.

The Diagnosis: Granuloma Annulare

A biopsy of a lesion on the right flank demonstrated granulomatous inflammation and interstitial mucin (Figure), characteristic of granuloma annulare (GA).^1,2 Granuloma annulare is a relatively common skin disorder with an unknown etiology. It typically presents as smooth, annular, erythematous plaques.¹ The most common variants of GA are localized, generalized, and subcutaneous. Our case demonstrated Wolf isotopic response, an unrelated skin disease that forms at the same location as a previously healed skin lesion.² It is important to be aware of this phenomenon so that it is not confused with a recurrence of herpes zoster virus (HZV).

Although relatively infrequent, GA is the most common isotopic response following HZV infections.^3-5 Other postherpetic isotopic eruptions include cutaneous malignancies, lichen planus, sarcoidosis, morphea, reactive perforating collagenosis, psoriasis, and infections, among others.^3,5,6 The time between HZV infection and GA can be variable, ranging from a few weeks to many years apart.³

Oftentimes GA will spontaneously resolve within 2 years; however, recurrence is common.^7-9 There currently are no standard treatment guidelines. The most promising treatment options include intralesional or topical glucocorticoids for localized GA as well as phototherapy or hydroxychloroquine for widespread disease.^8,10  

Annular elastolytic giant cell granuloma (also called actinic granuloma) is a rare idiopathic inflammatory skin disease. It is characterized by erythematous annular papules or plaques mainly found on sun-exposed skin, such as the backs of the hands, forearms, or face.^11,12 Therefore, based on the distribution of our patient’s lesions, annular elastolytic giant cell granuloma was an unlikely diagnosis. Furthermore, it is not a known postherpetic isotopic reaction. Annular elastolytic giant cell granuloma can appear histologically similar to GA. Differentiating histologic features include a nonpalisading granuloma as well as the absence of mucin and necrobiosis.¹²

Annular lichen planus is a long-recognized but uncommon clinical variant of lichen planus that typically presents as pruritic, purple, annular plaques on the penis, scrotum, or intertriginous areas.¹³ The violaceous coloring is more characteristic of lichen planus. Histology is helpful in differentiating from GA.

Nummular eczema presents as scattered, welldefined, pruritic, erythematous, coin-shaped, coin-sized plaques in patients with diffusely dry skin.¹⁴ The scaling and serous crusting as well as more prominent pruritus help distinguish it from GA. The appearance of nummular eczema is quite characteristic; therefore, a biopsy typically is unnecessary for diagnosis. However, a potassium hydroxide wet mount examination of a skin scraping should be performed if tinea corporis also is suspected.

Superficial erythema annulare centrifugum classically presents as an annular or arciform pruritic lesion with an advancing outer erythematous edge with an inner rim of scale that most commonly occurs on the lower extremities. ¹⁵ The presence of pruritus and trailing scale helps distinguish this lesion from GA. Histologically, there are epidermal changes of hyperplasia, spongiosis, and parakeratosis, as well as lymphohistiocytic infiltrate surrounding the superficial dermal vessels^.16

We report this case to highlight GA as the most common postherpetic isotopic response. It should be on the differential diagnosis when a patient presents with erythematous, smooth, annular plaques occurring in the distribution of a resolved case of HZV.

The Diagnosis: Granuloma Annulare

A biopsy of a lesion on the right flank demonstrated granulomatous inflammation and interstitial mucin (Figure), characteristic of granuloma annulare (GA).^1,2 Granuloma annulare is a relatively common skin disorder with an unknown etiology. It typically presents as smooth, annular, erythematous plaques.¹ The most common variants of GA are localized, generalized, and subcutaneous. Our case demonstrated Wolf isotopic response, an unrelated skin disease that forms at the same location as a previously healed skin lesion.² It is important to be aware of this phenomenon so that it is not confused with a recurrence of herpes zoster virus (HZV).

Although relatively infrequent, GA is the most common isotopic response following HZV infections.^3-5 Other postherpetic isotopic eruptions include cutaneous malignancies, lichen planus, sarcoidosis, morphea, reactive perforating collagenosis, psoriasis, and infections, among others.^3,5,6 The time between HZV infection and GA can be variable, ranging from a few weeks to many years apart.³

Oftentimes GA will spontaneously resolve within 2 years; however, recurrence is common.^7-9 There currently are no standard treatment guidelines. The most promising treatment options include intralesional or topical glucocorticoids for localized GA as well as phototherapy or hydroxychloroquine for widespread disease.^8,10  

Annular elastolytic giant cell granuloma (also called actinic granuloma) is a rare idiopathic inflammatory skin disease. It is characterized by erythematous annular papules or plaques mainly found on sun-exposed skin, such as the backs of the hands, forearms, or face.^11,12 Therefore, based on the distribution of our patient’s lesions, annular elastolytic giant cell granuloma was an unlikely diagnosis. Furthermore, it is not a known postherpetic isotopic reaction. Annular elastolytic giant cell granuloma can appear histologically similar to GA. Differentiating histologic features include a nonpalisading granuloma as well as the absence of mucin and necrobiosis.¹²

Annular lichen planus is a long-recognized but uncommon clinical variant of lichen planus that typically presents as pruritic, purple, annular plaques on the penis, scrotum, or intertriginous areas.¹³ The violaceous coloring is more characteristic of lichen planus. Histology is helpful in differentiating from GA.

Nummular eczema presents as scattered, welldefined, pruritic, erythematous, coin-shaped, coin-sized plaques in patients with diffusely dry skin.¹⁴ The scaling and serous crusting as well as more prominent pruritus help distinguish it from GA. The appearance of nummular eczema is quite characteristic; therefore, a biopsy typically is unnecessary for diagnosis. However, a potassium hydroxide wet mount examination of a skin scraping should be performed if tinea corporis also is suspected.

Superficial erythema annulare centrifugum classically presents as an annular or arciform pruritic lesion with an advancing outer erythematous edge with an inner rim of scale that most commonly occurs on the lower extremities. ¹⁵ The presence of pruritus and trailing scale helps distinguish this lesion from GA. Histologically, there are epidermal changes of hyperplasia, spongiosis, and parakeratosis, as well as lymphohistiocytic infiltrate surrounding the superficial dermal vessels^.16

We report this case to highlight GA as the most common postherpetic isotopic response. It should be on the differential diagnosis when a patient presents with erythematous, smooth, annular plaques occurring in the distribution of a resolved case of HZV.

The Diagnosis: Proximal-Type Epithelioid Sarcoma

Proximal-type epithelioid sarcoma (PES) is a rare high-grade sarcoma of uncertain histogenesis that may present with a benign clinical appearance. Proximal-type epithelioid sarcoma peaks at 20 to 40 years of age and has a slight male predominance. This tumor exhibits aggressive behavior with both local recurrence and metastasis.¹ The average overall survival is poor; however, tumor size less than 5 cm and complete excision with tumor-free margin status improves the prognosis.² Proximal-type epithelioid sarcoma should not be confused with distal-type epithelioid sarcoma, which has a better prognosis and occurs in younger patients.¹ Treatment of PES is wide excision, and chemotherapy trials with tazemetostat are ongoing.³

The deceptively banal clinical appearance of PES may delay appropriate diagnosis and treatment. Proximal-type epithelioid sarcoma often grows in sheets (quiz image [top] inset) and loose nests1 but also may take on a more corded appearance mimicking myoepithelial carcinoma. The cells themselves are plump dyscohesive epithelioid cells (quiz image [top]) with large nucleoli and eosinophilic cytoplasm or hyaline globules1 (quiz image [bottom]), but cells also may be focally spindled. Myxoid stroma, hemorrhage, and necrosis often are prominent features. Epithelioid sarcomas characteristically demonstrate positive immunostaining for both epithelial and mesenchymal markers (pan-cytokeratin and vimentin),¹ with the majority having loss of expression of integrase interactor 1 (INI-1).² Histology in this case was positive for cytokeratin monoclonal antibodies CAM5.2 and OSCAR, epithelial membrane antigen, and vimentin; it showed loss of INI-1 staining (quiz image [bottom]). Negative stains included S-100, p63, cytokeratins 7 and 20, CD34, CD31, ERG, glial fibrillary acidic protein, transducin-like enhancer of split 1, CD117, myogenin, synaptophysin, chromogranin, CD10, inhibin, CD99, and estrogen receptor.

The differential diagnosis of PES includes poorly differentiated squamous cell carcinoma (Figure 1 [inset]), melanoma, myoepithelial carcinoma, and epithelioid angiosarcoma. Primary squamous cell carcinoma of the vulva presents as an endophytic or exophytic mass with raised borders. Vulvar cancer is uncommon among gynecologic malignancies, with squamous cell carcinoma being the most commonly encountered.⁴ Vulvar intraepithelial neoplasia (VIN) is increasing in incidence, while the occurrence of invasive squamous cell carcinoma remains stable.⁵ Human papillomavirus–related VIN (usual-type VIN) is less likely to progress to squamous cell carcinoma than differentiated VIN (d-VIN), a dysplasia that is unrelated to human papillomavirus that frequently harbors p53 mutations.⁴ The presence of histologic epidermal involvement can help distinguish squamous cell carcinoma from PES (Figure 1). As opposed to PES, metastatic squamous cell carcinoma is characterized by intercellular bridges and often at least focal keratinization (Figure 1). Squamous cell carcinoma demonstrates positivity with p63 and p40 immunohistochemical stains, while PES rarely stains for either.⁶

Melanoma is the second most common vulvar malignancy. Vulvar melanoma tends to occur in women of advanced age but has been reported in girls as young as 10 years old.⁷ There is some evidence that patients with lichen sclerosus may be at an increased risk for the development of vulvar melanoma.⁸ Compared to PES, primary vulvar melanoma usually demonstrates epidermal involvement as well as clinical findings of a pigmented lesion (Figure 2). A notable minority of vulvar melanomas are amelanotic.⁹ Melanoma may be distinguished from PES with a panel of melanocytic markers—human melanoma black 45, Melan-A, SRY-box transcription factor 10, S-100, and microphthalmia transcription factor—that rarely are expressed in the latter. Both PES and rhabdoid melanoma have eosinophilic and tinctorial cytoplasmic inclusions.¹⁰ Melanin pigment and more cohesive nests are helpful clues that may point to melanoma when present.

Myoepithelial carcinoma of the vulva is rare.¹¹ Myoepithelial carcinoma of soft tissue is more aggressive than its benign counterpart, with up to a 50% metastasis rate.¹² The presence of prominent corded or trabecular growth in a myxoid or hyaline background may point to the diagnosis (Figure 3). Similar to PES, myoepithelial carcinoma may lose expression of nuclear INI-1, while myoepithelial carcinoma is more likely to express S-100 and glial fibrillary acidic protein.¹³ Rearrangements of EWS RNA binding protein 1, EWSR1, have been found in half of myoepithelial neoplasms.¹²

Angiosarcomas represent 5% of cutaneous sarcomas and rarely have been reported in the vulva, primarily occurring in the setting of long-standing lymphedema and radiation.¹⁴ Angiosarcoma more often occurs on the head and neck, breasts, or extremities. Additional risk factors for the development of angiosarcoma include toxin exposure (eg, polyvinyl chloride, thorium dioxide, arsenic), anabolic steroids, and filariasis, as well as genetic disorders (eg, neurofibromatosis type 1, BRCA gene mutations, Maffucci syndrome).¹⁵ Epithelioid angiosarcoma is an infiltrative tumor composed of irregular anastomosing vascular channels with extravasated erythrocytes (Figure 4). Solid growth and necrosis may be present in more aggressive tumors. The cells themselves are pleomorphic endothelial cells with vesicular chromatin and prominent nucleoli. Epithelioid angiosarcoma may resemble carcinoma and have focal keratin expression. However, the characteristic eosinophilic cytoplasm seen in PES should not be identified in epithelioid angiosarcoma. Unlike PES, epithelioid angiosarcoma is positive for CD31 and has retained expression for INI-1. Both angiosarcoma and proximal-type epithelioid sarcoma may express vascular markers CD34 and FLI-1¹⁶; thus an expanded panel of immunohistochemical studies may be of utility.

The Diagnosis: Proximal-Type Epithelioid Sarcoma

Proximal-type epithelioid sarcoma (PES) is a rare high-grade sarcoma of uncertain histogenesis that may present with a benign clinical appearance. Proximal-type epithelioid sarcoma peaks at 20 to 40 years of age and has a slight male predominance. This tumor exhibits aggressive behavior with both local recurrence and metastasis.¹ The average overall survival is poor; however, tumor size less than 5 cm and complete excision with tumor-free margin status improves the prognosis.² Proximal-type epithelioid sarcoma should not be confused with distal-type epithelioid sarcoma, which has a better prognosis and occurs in younger patients.¹ Treatment of PES is wide excision, and chemotherapy trials with tazemetostat are ongoing.³

The deceptively banal clinical appearance of PES may delay appropriate diagnosis and treatment. Proximal-type epithelioid sarcoma often grows in sheets (quiz image [top] inset) and loose nests1 but also may take on a more corded appearance mimicking myoepithelial carcinoma. The cells themselves are plump dyscohesive epithelioid cells (quiz image [top]) with large nucleoli and eosinophilic cytoplasm or hyaline globules1 (quiz image [bottom]), but cells also may be focally spindled. Myxoid stroma, hemorrhage, and necrosis often are prominent features. Epithelioid sarcomas characteristically demonstrate positive immunostaining for both epithelial and mesenchymal markers (pan-cytokeratin and vimentin),¹ with the majority having loss of expression of integrase interactor 1 (INI-1).² Histology in this case was positive for cytokeratin monoclonal antibodies CAM5.2 and OSCAR, epithelial membrane antigen, and vimentin; it showed loss of INI-1 staining (quiz image [bottom]). Negative stains included S-100, p63, cytokeratins 7 and 20, CD34, CD31, ERG, glial fibrillary acidic protein, transducin-like enhancer of split 1, CD117, myogenin, synaptophysin, chromogranin, CD10, inhibin, CD99, and estrogen receptor.

The differential diagnosis of PES includes poorly differentiated squamous cell carcinoma (Figure 1 [inset]), melanoma, myoepithelial carcinoma, and epithelioid angiosarcoma. Primary squamous cell carcinoma of the vulva presents as an endophytic or exophytic mass with raised borders. Vulvar cancer is uncommon among gynecologic malignancies, with squamous cell carcinoma being the most commonly encountered.⁴ Vulvar intraepithelial neoplasia (VIN) is increasing in incidence, while the occurrence of invasive squamous cell carcinoma remains stable.⁵ Human papillomavirus–related VIN (usual-type VIN) is less likely to progress to squamous cell carcinoma than differentiated VIN (d-VIN), a dysplasia that is unrelated to human papillomavirus that frequently harbors p53 mutations.⁴ The presence of histologic epidermal involvement can help distinguish squamous cell carcinoma from PES (Figure 1). As opposed to PES, metastatic squamous cell carcinoma is characterized by intercellular bridges and often at least focal keratinization (Figure 1). Squamous cell carcinoma demonstrates positivity with p63 and p40 immunohistochemical stains, while PES rarely stains for either.⁶

Melanoma is the second most common vulvar malignancy. Vulvar melanoma tends to occur in women of advanced age but has been reported in girls as young as 10 years old.⁷ There is some evidence that patients with lichen sclerosus may be at an increased risk for the development of vulvar melanoma.⁸ Compared to PES, primary vulvar melanoma usually demonstrates epidermal involvement as well as clinical findings of a pigmented lesion (Figure 2). A notable minority of vulvar melanomas are amelanotic.⁹ Melanoma may be distinguished from PES with a panel of melanocytic markers—human melanoma black 45, Melan-A, SRY-box transcription factor 10, S-100, and microphthalmia transcription factor—that rarely are expressed in the latter. Both PES and rhabdoid melanoma have eosinophilic and tinctorial cytoplasmic inclusions.¹⁰ Melanin pigment and more cohesive nests are helpful clues that may point to melanoma when present.

Myoepithelial carcinoma of the vulva is rare.¹¹ Myoepithelial carcinoma of soft tissue is more aggressive than its benign counterpart, with up to a 50% metastasis rate.¹² The presence of prominent corded or trabecular growth in a myxoid or hyaline background may point to the diagnosis (Figure 3). Similar to PES, myoepithelial carcinoma may lose expression of nuclear INI-1, while myoepithelial carcinoma is more likely to express S-100 and glial fibrillary acidic protein.¹³ Rearrangements of EWS RNA binding protein 1, EWSR1, have been found in half of myoepithelial neoplasms.¹²

Angiosarcomas represent 5% of cutaneous sarcomas and rarely have been reported in the vulva, primarily occurring in the setting of long-standing lymphedema and radiation.¹⁴ Angiosarcoma more often occurs on the head and neck, breasts, or extremities. Additional risk factors for the development of angiosarcoma include toxin exposure (eg, polyvinyl chloride, thorium dioxide, arsenic), anabolic steroids, and filariasis, as well as genetic disorders (eg, neurofibromatosis type 1, BRCA gene mutations, Maffucci syndrome).¹⁵ Epithelioid angiosarcoma is an infiltrative tumor composed of irregular anastomosing vascular channels with extravasated erythrocytes (Figure 4). Solid growth and necrosis may be present in more aggressive tumors. The cells themselves are pleomorphic endothelial cells with vesicular chromatin and prominent nucleoli. Epithelioid angiosarcoma may resemble carcinoma and have focal keratin expression. However, the characteristic eosinophilic cytoplasm seen in PES should not be identified in epithelioid angiosarcoma. Unlike PES, epithelioid angiosarcoma is positive for CD31 and has retained expression for INI-1. Both angiosarcoma and proximal-type epithelioid sarcoma may express vascular markers CD34 and FLI-1¹⁶; thus an expanded panel of immunohistochemical studies may be of utility.

The Diagnosis: Proximal-Type Epithelioid Sarcoma

Proximal-type epithelioid sarcoma (PES) is a rare high-grade sarcoma of uncertain histogenesis that may present with a benign clinical appearance. Proximal-type epithelioid sarcoma peaks at 20 to 40 years of age and has a slight male predominance. This tumor exhibits aggressive behavior with both local recurrence and metastasis.¹ The average overall survival is poor; however, tumor size less than 5 cm and complete excision with tumor-free margin status improves the prognosis.² Proximal-type epithelioid sarcoma should not be confused with distal-type epithelioid sarcoma, which has a better prognosis and occurs in younger patients.¹ Treatment of PES is wide excision, and chemotherapy trials with tazemetostat are ongoing.³

The deceptively banal clinical appearance of PES may delay appropriate diagnosis and treatment. Proximal-type epithelioid sarcoma often grows in sheets (quiz image [top] inset) and loose nests1 but also may take on a more corded appearance mimicking myoepithelial carcinoma. The cells themselves are plump dyscohesive epithelioid cells (quiz image [top]) with large nucleoli and eosinophilic cytoplasm or hyaline globules1 (quiz image [bottom]), but cells also may be focally spindled. Myxoid stroma, hemorrhage, and necrosis often are prominent features. Epithelioid sarcomas characteristically demonstrate positive immunostaining for both epithelial and mesenchymal markers (pan-cytokeratin and vimentin),¹ with the majority having loss of expression of integrase interactor 1 (INI-1).² Histology in this case was positive for cytokeratin monoclonal antibodies CAM5.2 and OSCAR, epithelial membrane antigen, and vimentin; it showed loss of INI-1 staining (quiz image [bottom]). Negative stains included S-100, p63, cytokeratins 7 and 20, CD34, CD31, ERG, glial fibrillary acidic protein, transducin-like enhancer of split 1, CD117, myogenin, synaptophysin, chromogranin, CD10, inhibin, CD99, and estrogen receptor.

The differential diagnosis of PES includes poorly differentiated squamous cell carcinoma (Figure 1 [inset]), melanoma, myoepithelial carcinoma, and epithelioid angiosarcoma. Primary squamous cell carcinoma of the vulva presents as an endophytic or exophytic mass with raised borders. Vulvar cancer is uncommon among gynecologic malignancies, with squamous cell carcinoma being the most commonly encountered.⁴ Vulvar intraepithelial neoplasia (VIN) is increasing in incidence, while the occurrence of invasive squamous cell carcinoma remains stable.⁵ Human papillomavirus–related VIN (usual-type VIN) is less likely to progress to squamous cell carcinoma than differentiated VIN (d-VIN), a dysplasia that is unrelated to human papillomavirus that frequently harbors p53 mutations.⁴ The presence of histologic epidermal involvement can help distinguish squamous cell carcinoma from PES (Figure 1). As opposed to PES, metastatic squamous cell carcinoma is characterized by intercellular bridges and often at least focal keratinization (Figure 1). Squamous cell carcinoma demonstrates positivity with p63 and p40 immunohistochemical stains, while PES rarely stains for either.⁶

Melanoma is the second most common vulvar malignancy. Vulvar melanoma tends to occur in women of advanced age but has been reported in girls as young as 10 years old.⁷ There is some evidence that patients with lichen sclerosus may be at an increased risk for the development of vulvar melanoma.⁸ Compared to PES, primary vulvar melanoma usually demonstrates epidermal involvement as well as clinical findings of a pigmented lesion (Figure 2). A notable minority of vulvar melanomas are amelanotic.⁹ Melanoma may be distinguished from PES with a panel of melanocytic markers—human melanoma black 45, Melan-A, SRY-box transcription factor 10, S-100, and microphthalmia transcription factor—that rarely are expressed in the latter. Both PES and rhabdoid melanoma have eosinophilic and tinctorial cytoplasmic inclusions.¹⁰ Melanin pigment and more cohesive nests are helpful clues that may point to melanoma when present.

Myoepithelial carcinoma of the vulva is rare.¹¹ Myoepithelial carcinoma of soft tissue is more aggressive than its benign counterpart, with up to a 50% metastasis rate.¹² The presence of prominent corded or trabecular growth in a myxoid or hyaline background may point to the diagnosis (Figure 3). Similar to PES, myoepithelial carcinoma may lose expression of nuclear INI-1, while myoepithelial carcinoma is more likely to express S-100 and glial fibrillary acidic protein.¹³ Rearrangements of EWS RNA binding protein 1, EWSR1, have been found in half of myoepithelial neoplasms.¹²

Angiosarcomas represent 5% of cutaneous sarcomas and rarely have been reported in the vulva, primarily occurring in the setting of long-standing lymphedema and radiation.¹⁴ Angiosarcoma more often occurs on the head and neck, breasts, or extremities. Additional risk factors for the development of angiosarcoma include toxin exposure (eg, polyvinyl chloride, thorium dioxide, arsenic), anabolic steroids, and filariasis, as well as genetic disorders (eg, neurofibromatosis type 1, BRCA gene mutations, Maffucci syndrome).¹⁵ Epithelioid angiosarcoma is an infiltrative tumor composed of irregular anastomosing vascular channels with extravasated erythrocytes (Figure 4). Solid growth and necrosis may be present in more aggressive tumors. The cells themselves are pleomorphic endothelial cells with vesicular chromatin and prominent nucleoli. Epithelioid angiosarcoma may resemble carcinoma and have focal keratin expression. However, the characteristic eosinophilic cytoplasm seen in PES should not be identified in epithelioid angiosarcoma. Unlike PES, epithelioid angiosarcoma is positive for CD31 and has retained expression for INI-1. Both angiosarcoma and proximal-type epithelioid sarcoma may express vascular markers CD34 and FLI-1¹⁶; thus an expanded panel of immunohistochemical studies may be of utility.

Airbags are lifesaving during motor vehicle accidents (MVAs), but their deployment has been associated with skin issues such as irritant dermatitis¹; lacerations²; abrasions³; and thermal, friction, and chemical burns.^4-6 Ocular issues such as alkaline chemical keratitis⁷ and ocular alkali injuries⁸ also have been described.

Airbag deployment is triggered by rapid deceleration and impact, which ignite a sodium azide cartridge, causing the woven nylon bag to inflate with hydrocarbon gases.⁸ This leads to release of sodium hydroxide, sodium bicarbonate, and metallic oxides in an aerosolized form. If a tear in the meshwork of the airbag occurs, exposure to an even larger amount of powder containing caustic alkali chemicals can occur.⁸

We describe a patient who developed a bullous reaction to airbag contents after he was involved in an MVA in which the airbag deployed.

Case Report

A 35-year-old man with a history of type 2 diabetes mellitus and chronic hepatitis B presented to the dermatology clinic for an evaluation of new-onset blisters. The rash occurred 1 day after the patient was involved in an MVA in which he was exposed to the airbag’s contents after it burst. He had been evaluated twice in the emergency department for the skin eruption before being referred to dermatology. He noted the lesions were pruritic and painful. Prior treatments included silver sulfadiazine cream 1% and clobetasol cream 0.05%, though he discontinued using the latter because of burning with application. Physical examination revealed tense vesicles and bullae on an erythematous base on the right lower flank, forearms, and legs, with the exception of the lower right leg where a cast had been from a prior injury (Figure 1).

Two punch biopsies of the left arm were performed and sent for hematoxylin and eosin staining and direct immunofluorescence to rule out bullous diseases, such as bullous pemphigoid, linear IgA, and bullous lupus. Hematoxylin and eosin staining revealed extensive spongiosis with blister formation and a dense perivascular infiltrate in the superficial and mid dermis composed of lymphocytes with numerous scattered eosinophils (Figures 2 and 3). Direct immunofluorescence studies were negative. Treatment with oral prednisone and oral antihistamines was initiated.

At 10-day follow-up, the patient had a few residual bullae; most lesions were demonstrating various stages of healing (Figure 4). The patient’s cast had been removed, and there were no lesions in this previously covered area. At 6-week follow-up he had continued healing of the bullae and erosions as well as postinflammatory hyperpigmentation (Figure 5).

Comment

With the advent of airbags for safety purposes, these potentially lifesaving devices also have been known to cause injury.⁹ In 1998, the most commonly reported airbag injuries were ocular injuries.¹⁰ Cutaneous manifestations of airbag injury are less well known.¹¹

Two cases of airbag deployment with skin blistering have been reported in the literature based on a PubMed search of articles indexed for MEDLINE using the terms airbag blistering or airbag bullae^12,13; however, the blistering was described in the context of a burn. One case of the effects of airbag deployment residue highlights a patient arriving to the emergency department with erythema and blisters on the hands within 48 hours of airbag deployment in an MVA, and the treatment was standard burn therapy.¹² Another case report described a patient with a second-degree burn with a 12-cm blister occurring on the radial side of the hand and distal forearm following an MVA and airbag deployment, which was treated conservatively.¹³ Cases of thermal burns, chemical burns, and irritant contact dermatitis after airbag deployment have been described in the literature.^{4-6,11,12,14,15} Our patient’s distal right lower leg was covered with a cast for osteomyelitis, and no blisters had developed in this area. It is likely that the transfer of airbag contents occurred during the process of unbuckling his seatbelt, which could explain the bullae that developed on the right flank. Per the Centers for Disease Control and Prevention, individuals should quickly remove clothing and wash their body with large amounts of soap and water following exposure to sodium azide.¹⁶

In 1989, the Federal Motor Vehicle Safety Standard No. 208 (occupant crash protection) became effective, stating all cars must have vehicle crash protection.¹² Prior to 1993, it was reported that there had been no associated chemical injuries with airbag deployment. Subsequently, a 6-month retrospective study in 1993 showed that dermal injuries were found in connection with the presence of sodium hydroxide in automobile airbags.¹² By 2004, it was known that airbags could cause chemical and thermal burns in addition to traumatic injuries from deployment.¹ Since 2007, all motor vehicles have been required to have advanced airbags, which are engineered to sense the presence of passengers and determine if the airbag will deploy, and if so, how much to deploy to minimize airbag-related injury.³

The brand of car that our patient drove during the MVA is one with known airbag recalls due to safety defects; however, the year and actual model of the vehicle are not known, so specific information about the airbag in question is not available. It has been noted that some defective airbag inflators that were exposed to excess moisture during the manufacturing process could explode during deployment, causing shrapnel and airbag rupture, which has been linked to nearly 300 injuries worldwide.¹⁷

Conclusion

It is evident that the use of airbag devices reduces morbidity and mortality due to MVAs.⁹ It also had been reported that up to 96% of airbag-related injuries are relatively minor, which many would argue justifies their use.¹⁸ Furthermore, it has been reported that 99.8% of skin injuries following airbag deployment are minor.¹⁹ In the United States, it is mandated that every vehicle have functional airbags installed.⁸

This case highlights the potential for substantial airbag-induced skin reactions, specifically a bullous reaction, following airbag deployment. The persistent pruritus and lasting postinflammatory hyperpigmentation seen in this case were certainly worrisome for our patient. We also present this case to remind dermatology providers of possible treatment approaches to these skin reactions. Immediate cleansing of the affected areas of skin may help avoid such reactions.

Airbags are lifesaving during motor vehicle accidents (MVAs), but their deployment has been associated with skin issues such as irritant dermatitis¹; lacerations²; abrasions³; and thermal, friction, and chemical burns.^4-6 Ocular issues such as alkaline chemical keratitis⁷ and ocular alkali injuries⁸ also have been described.

Airbag deployment is triggered by rapid deceleration and impact, which ignite a sodium azide cartridge, causing the woven nylon bag to inflate with hydrocarbon gases.⁸ This leads to release of sodium hydroxide, sodium bicarbonate, and metallic oxides in an aerosolized form. If a tear in the meshwork of the airbag occurs, exposure to an even larger amount of powder containing caustic alkali chemicals can occur.⁸

We describe a patient who developed a bullous reaction to airbag contents after he was involved in an MVA in which the airbag deployed.

Case Report

A 35-year-old man with a history of type 2 diabetes mellitus and chronic hepatitis B presented to the dermatology clinic for an evaluation of new-onset blisters. The rash occurred 1 day after the patient was involved in an MVA in which he was exposed to the airbag’s contents after it burst. He had been evaluated twice in the emergency department for the skin eruption before being referred to dermatology. He noted the lesions were pruritic and painful. Prior treatments included silver sulfadiazine cream 1% and clobetasol cream 0.05%, though he discontinued using the latter because of burning with application. Physical examination revealed tense vesicles and bullae on an erythematous base on the right lower flank, forearms, and legs, with the exception of the lower right leg where a cast had been from a prior injury (Figure 1).

Two punch biopsies of the left arm were performed and sent for hematoxylin and eosin staining and direct immunofluorescence to rule out bullous diseases, such as bullous pemphigoid, linear IgA, and bullous lupus. Hematoxylin and eosin staining revealed extensive spongiosis with blister formation and a dense perivascular infiltrate in the superficial and mid dermis composed of lymphocytes with numerous scattered eosinophils (Figures 2 and 3). Direct immunofluorescence studies were negative. Treatment with oral prednisone and oral antihistamines was initiated.

At 10-day follow-up, the patient had a few residual bullae; most lesions were demonstrating various stages of healing (Figure 4). The patient’s cast had been removed, and there were no lesions in this previously covered area. At 6-week follow-up he had continued healing of the bullae and erosions as well as postinflammatory hyperpigmentation (Figure 5).

Comment

With the advent of airbags for safety purposes, these potentially lifesaving devices also have been known to cause injury.⁹ In 1998, the most commonly reported airbag injuries were ocular injuries.¹⁰ Cutaneous manifestations of airbag injury are less well known.¹¹

Two cases of airbag deployment with skin blistering have been reported in the literature based on a PubMed search of articles indexed for MEDLINE using the terms airbag blistering or airbag bullae^12,13; however, the blistering was described in the context of a burn. One case of the effects of airbag deployment residue highlights a patient arriving to the emergency department with erythema and blisters on the hands within 48 hours of airbag deployment in an MVA, and the treatment was standard burn therapy.¹² Another case report described a patient with a second-degree burn with a 12-cm blister occurring on the radial side of the hand and distal forearm following an MVA and airbag deployment, which was treated conservatively.¹³ Cases of thermal burns, chemical burns, and irritant contact dermatitis after airbag deployment have been described in the literature.^{4-6,11,12,14,15} Our patient’s distal right lower leg was covered with a cast for osteomyelitis, and no blisters had developed in this area. It is likely that the transfer of airbag contents occurred during the process of unbuckling his seatbelt, which could explain the bullae that developed on the right flank. Per the Centers for Disease Control and Prevention, individuals should quickly remove clothing and wash their body with large amounts of soap and water following exposure to sodium azide.¹⁶

In 1989, the Federal Motor Vehicle Safety Standard No. 208 (occupant crash protection) became effective, stating all cars must have vehicle crash protection.¹² Prior to 1993, it was reported that there had been no associated chemical injuries with airbag deployment. Subsequently, a 6-month retrospective study in 1993 showed that dermal injuries were found in connection with the presence of sodium hydroxide in automobile airbags.¹² By 2004, it was known that airbags could cause chemical and thermal burns in addition to traumatic injuries from deployment.¹ Since 2007, all motor vehicles have been required to have advanced airbags, which are engineered to sense the presence of passengers and determine if the airbag will deploy, and if so, how much to deploy to minimize airbag-related injury.³

The brand of car that our patient drove during the MVA is one with known airbag recalls due to safety defects; however, the year and actual model of the vehicle are not known, so specific information about the airbag in question is not available. It has been noted that some defective airbag inflators that were exposed to excess moisture during the manufacturing process could explode during deployment, causing shrapnel and airbag rupture, which has been linked to nearly 300 injuries worldwide.¹⁷

Conclusion

It is evident that the use of airbag devices reduces morbidity and mortality due to MVAs.⁹ It also had been reported that up to 96% of airbag-related injuries are relatively minor, which many would argue justifies their use.¹⁸ Furthermore, it has been reported that 99.8% of skin injuries following airbag deployment are minor.¹⁹ In the United States, it is mandated that every vehicle have functional airbags installed.⁸

This case highlights the potential for substantial airbag-induced skin reactions, specifically a bullous reaction, following airbag deployment. The persistent pruritus and lasting postinflammatory hyperpigmentation seen in this case were certainly worrisome for our patient. We also present this case to remind dermatology providers of possible treatment approaches to these skin reactions. Immediate cleansing of the affected areas of skin may help avoid such reactions.

Airbags are lifesaving during motor vehicle accidents (MVAs), but their deployment has been associated with skin issues such as irritant dermatitis¹; lacerations²; abrasions³; and thermal, friction, and chemical burns.^4-6 Ocular issues such as alkaline chemical keratitis⁷ and ocular alkali injuries⁸ also have been described.

Airbag deployment is triggered by rapid deceleration and impact, which ignite a sodium azide cartridge, causing the woven nylon bag to inflate with hydrocarbon gases.⁸ This leads to release of sodium hydroxide, sodium bicarbonate, and metallic oxides in an aerosolized form. If a tear in the meshwork of the airbag occurs, exposure to an even larger amount of powder containing caustic alkali chemicals can occur.⁸

We describe a patient who developed a bullous reaction to airbag contents after he was involved in an MVA in which the airbag deployed.

Case Report

A 35-year-old man with a history of type 2 diabetes mellitus and chronic hepatitis B presented to the dermatology clinic for an evaluation of new-onset blisters. The rash occurred 1 day after the patient was involved in an MVA in which he was exposed to the airbag’s contents after it burst. He had been evaluated twice in the emergency department for the skin eruption before being referred to dermatology. He noted the lesions were pruritic and painful. Prior treatments included silver sulfadiazine cream 1% and clobetasol cream 0.05%, though he discontinued using the latter because of burning with application. Physical examination revealed tense vesicles and bullae on an erythematous base on the right lower flank, forearms, and legs, with the exception of the lower right leg where a cast had been from a prior injury (Figure 1).

Two punch biopsies of the left arm were performed and sent for hematoxylin and eosin staining and direct immunofluorescence to rule out bullous diseases, such as bullous pemphigoid, linear IgA, and bullous lupus. Hematoxylin and eosin staining revealed extensive spongiosis with blister formation and a dense perivascular infiltrate in the superficial and mid dermis composed of lymphocytes with numerous scattered eosinophils (Figures 2 and 3). Direct immunofluorescence studies were negative. Treatment with oral prednisone and oral antihistamines was initiated.

At 10-day follow-up, the patient had a few residual bullae; most lesions were demonstrating various stages of healing (Figure 4). The patient’s cast had been removed, and there were no lesions in this previously covered area. At 6-week follow-up he had continued healing of the bullae and erosions as well as postinflammatory hyperpigmentation (Figure 5).

Comment

With the advent of airbags for safety purposes, these potentially lifesaving devices also have been known to cause injury.⁹ In 1998, the most commonly reported airbag injuries were ocular injuries.¹⁰ Cutaneous manifestations of airbag injury are less well known.¹¹

Two cases of airbag deployment with skin blistering have been reported in the literature based on a PubMed search of articles indexed for MEDLINE using the terms airbag blistering or airbag bullae^12,13; however, the blistering was described in the context of a burn. One case of the effects of airbag deployment residue highlights a patient arriving to the emergency department with erythema and blisters on the hands within 48 hours of airbag deployment in an MVA, and the treatment was standard burn therapy.¹² Another case report described a patient with a second-degree burn with a 12-cm blister occurring on the radial side of the hand and distal forearm following an MVA and airbag deployment, which was treated conservatively.¹³ Cases of thermal burns, chemical burns, and irritant contact dermatitis after airbag deployment have been described in the literature.^{4-6,11,12,14,15} Our patient’s distal right lower leg was covered with a cast for osteomyelitis, and no blisters had developed in this area. It is likely that the transfer of airbag contents occurred during the process of unbuckling his seatbelt, which could explain the bullae that developed on the right flank. Per the Centers for Disease Control and Prevention, individuals should quickly remove clothing and wash their body with large amounts of soap and water following exposure to sodium azide.¹⁶

In 1989, the Federal Motor Vehicle Safety Standard No. 208 (occupant crash protection) became effective, stating all cars must have vehicle crash protection.¹² Prior to 1993, it was reported that there had been no associated chemical injuries with airbag deployment. Subsequently, a 6-month retrospective study in 1993 showed that dermal injuries were found in connection with the presence of sodium hydroxide in automobile airbags.¹² By 2004, it was known that airbags could cause chemical and thermal burns in addition to traumatic injuries from deployment.¹ Since 2007, all motor vehicles have been required to have advanced airbags, which are engineered to sense the presence of passengers and determine if the airbag will deploy, and if so, how much to deploy to minimize airbag-related injury.³

The brand of car that our patient drove during the MVA is one with known airbag recalls due to safety defects; however, the year and actual model of the vehicle are not known, so specific information about the airbag in question is not available. It has been noted that some defective airbag inflators that were exposed to excess moisture during the manufacturing process could explode during deployment, causing shrapnel and airbag rupture, which has been linked to nearly 300 injuries worldwide.¹⁷

Conclusion

It is evident that the use of airbag devices reduces morbidity and mortality due to MVAs.⁹ It also had been reported that up to 96% of airbag-related injuries are relatively minor, which many would argue justifies their use.¹⁸ Furthermore, it has been reported that 99.8% of skin injuries following airbag deployment are minor.¹⁹ In the United States, it is mandated that every vehicle have functional airbags installed.⁸

This case highlights the potential for substantial airbag-induced skin reactions, specifically a bullous reaction, following airbag deployment. The persistent pruritus and lasting postinflammatory hyperpigmentation seen in this case were certainly worrisome for our patient. We also present this case to remind dermatology providers of possible treatment approaches to these skin reactions. Immediate cleansing of the affected areas of skin may help avoid such reactions.

The Diagnosis: Tufted Angioma

Histopathology revealed discrete lobules of closely packed capillaries with bland endothelial cells throughout the upper and lower dermis (Figure 1). The surrounding crescentlike vessels and lymphatics stained with D2-40 (Figure 2). These histologic findings were consistent with tufted angioma, and the patient elected for observation.

Tufted angiomas are benign vascular lesions named for the tufted appearance of capillaries on histology.¹ They commonly present in children, with a lower incidence in adults and rare cases in pregnancy.² Tufted angiomas typically present as solitary, slowly expanding, erythematous macules, plaques, or nodules on the neck or trunk ranging in size from less than 1 to 10 cm.^2-4 They can be histologically distinguished from other vascular tumors, including aggressive malignant neoplasms.¹

Tufted angiomas are identified by characteristic “cannon ball tufts” of capillaries in the dermis and subcutis at low power.^3,5 Distinct cellular lobules may be found bulging into thin-walled vascular channels at the margins of the lobules in the dermis and subcutis (Figure 3).⁴ The lobules are formed by cells with spindle-shaped nuclei.⁶ Some mitotic figures may be present, but no cellular atypia is seen.² The capillaries at the periphery appear as dilated semilunar vessels.⁴ Dilated lymphatics, which stain with D2-40, can be found at the periphery of the tufted capillaries and throughout the remaining dermis.^3,4

Tufted angiomas may arise independently in adults but also have been associated with conditions such as pregnancy. Omori et al⁷ identified an acquired tufted angioma in pregnancy that was positive for estrogen and progesterone receptors. Reports of tufted angiomas in pregnancy vary; some are multiple lesions, some regress postpartum, and some undergo successful surgical treatment.^3,5

Vascular lesions such as tufted angiomas specifically may appear in pregnancy due to a high-volume state with vasodilation and increased vascular proliferation. Although tumor angiogenesis has been linked to specific growth factors and cytokines, it has been hypothesized that the systemic hormones of pregnancy such as human chorionic gonadotropin, estradiol, and progesterone also shift the body to a more angiogenic state.⁸ In a study of cutaneous changes in pregnant women (N=905), 41% developed a vascular skin change, including spider veins, varicosities, hemangiomas, and granulomas.⁹ The most common vascular tumor in pregnancy is pyogenic granuloma. Pyogenic granulomas are small, solitary, friable papules that commonly are found on the hands, forearms, face, or in the mouth; histologically they demonstrate dilated capillaries in lobular structures accompanied by larger thick-walled vessels.^3,10,11

Tufted angiomas may mimic a variety of other conditions. Epithelioid hemangioma, considered by some to be on the same morphologic spectrum as angiolymphoid hyperplasia with eosinophilia, classically occurs in young adults on the head and in the neck region. It histologically demonstrates a lobular appearance at low power; however, these lobules are made up of vessels with histiocytoid to epithelioid endothelial cells surrounded by a prominent inflammatory infiltrate consisting of lymphocytes and eosinophils.¹²

Kaposi sarcoma may appear on the neck but most often presents as macules and patches on the extremities that may form nodules with a rubbery consistency. In tufted angiomas, the cellular nodules with dilated channels at the margins bear a resemblance to Kaposi sarcoma or kaposiform hemangioendothelioma; however, in tufted angiomas the lobules are composed of bland spindle cells and slitlike vessels at the periphery.^3,13,14 Tufted angiomas are negative for human herpesvirus 8 and typically do not have an associated inflammatory infiltrate with plasma cells.^11,15

Moreover, it is important to differentiate tufted angioma from a cutaneous manifestation of an underlying malignancy, which has been described previously in cases of breast cancer.^16,17 Our case illustrates a rare vascular tumor arising in the novel context of a pregnant patient with breast cancer. Distinguishing tufted angioma from other benign or malignant vascular tumors is necessary to avoid inappropriate therapeutic interventions.

The Diagnosis: Tufted Angioma

Histopathology revealed discrete lobules of closely packed capillaries with bland endothelial cells throughout the upper and lower dermis (Figure 1). The surrounding crescentlike vessels and lymphatics stained with D2-40 (Figure 2). These histologic findings were consistent with tufted angioma, and the patient elected for observation.

Tufted angiomas are benign vascular lesions named for the tufted appearance of capillaries on histology.¹ They commonly present in children, with a lower incidence in adults and rare cases in pregnancy.² Tufted angiomas typically present as solitary, slowly expanding, erythematous macules, plaques, or nodules on the neck or trunk ranging in size from less than 1 to 10 cm.^2-4 They can be histologically distinguished from other vascular tumors, including aggressive malignant neoplasms.¹

Tufted angiomas are identified by characteristic “cannon ball tufts” of capillaries in the dermis and subcutis at low power.^3,5 Distinct cellular lobules may be found bulging into thin-walled vascular channels at the margins of the lobules in the dermis and subcutis (Figure 3).⁴ The lobules are formed by cells with spindle-shaped nuclei.⁶ Some mitotic figures may be present, but no cellular atypia is seen.² The capillaries at the periphery appear as dilated semilunar vessels.⁴ Dilated lymphatics, which stain with D2-40, can be found at the periphery of the tufted capillaries and throughout the remaining dermis.^3,4

Tufted angiomas may arise independently in adults but also have been associated with conditions such as pregnancy. Omori et al⁷ identified an acquired tufted angioma in pregnancy that was positive for estrogen and progesterone receptors. Reports of tufted angiomas in pregnancy vary; some are multiple lesions, some regress postpartum, and some undergo successful surgical treatment.^3,5

Vascular lesions such as tufted angiomas specifically may appear in pregnancy due to a high-volume state with vasodilation and increased vascular proliferation. Although tumor angiogenesis has been linked to specific growth factors and cytokines, it has been hypothesized that the systemic hormones of pregnancy such as human chorionic gonadotropin, estradiol, and progesterone also shift the body to a more angiogenic state.⁸ In a study of cutaneous changes in pregnant women (N=905), 41% developed a vascular skin change, including spider veins, varicosities, hemangiomas, and granulomas.⁹ The most common vascular tumor in pregnancy is pyogenic granuloma. Pyogenic granulomas are small, solitary, friable papules that commonly are found on the hands, forearms, face, or in the mouth; histologically they demonstrate dilated capillaries in lobular structures accompanied by larger thick-walled vessels.^3,10,11

Tufted angiomas may mimic a variety of other conditions. Epithelioid hemangioma, considered by some to be on the same morphologic spectrum as angiolymphoid hyperplasia with eosinophilia, classically occurs in young adults on the head and in the neck region. It histologically demonstrates a lobular appearance at low power; however, these lobules are made up of vessels with histiocytoid to epithelioid endothelial cells surrounded by a prominent inflammatory infiltrate consisting of lymphocytes and eosinophils.¹²

Kaposi sarcoma may appear on the neck but most often presents as macules and patches on the extremities that may form nodules with a rubbery consistency. In tufted angiomas, the cellular nodules with dilated channels at the margins bear a resemblance to Kaposi sarcoma or kaposiform hemangioendothelioma; however, in tufted angiomas the lobules are composed of bland spindle cells and slitlike vessels at the periphery.^3,13,14 Tufted angiomas are negative for human herpesvirus 8 and typically do not have an associated inflammatory infiltrate with plasma cells.^11,15

Moreover, it is important to differentiate tufted angioma from a cutaneous manifestation of an underlying malignancy, which has been described previously in cases of breast cancer.^16,17 Our case illustrates a rare vascular tumor arising in the novel context of a pregnant patient with breast cancer. Distinguishing tufted angioma from other benign or malignant vascular tumors is necessary to avoid inappropriate therapeutic interventions.

The Diagnosis: Tufted Angioma

Histopathology revealed discrete lobules of closely packed capillaries with bland endothelial cells throughout the upper and lower dermis (Figure 1). The surrounding crescentlike vessels and lymphatics stained with D2-40 (Figure 2). These histologic findings were consistent with tufted angioma, and the patient elected for observation.

Tufted angiomas are benign vascular lesions named for the tufted appearance of capillaries on histology.¹ They commonly present in children, with a lower incidence in adults and rare cases in pregnancy.² Tufted angiomas typically present as solitary, slowly expanding, erythematous macules, plaques, or nodules on the neck or trunk ranging in size from less than 1 to 10 cm.^2-4 They can be histologically distinguished from other vascular tumors, including aggressive malignant neoplasms.¹

Tufted angiomas are identified by characteristic “cannon ball tufts” of capillaries in the dermis and subcutis at low power.^3,5 Distinct cellular lobules may be found bulging into thin-walled vascular channels at the margins of the lobules in the dermis and subcutis (Figure 3).⁴ The lobules are formed by cells with spindle-shaped nuclei.⁶ Some mitotic figures may be present, but no cellular atypia is seen.² The capillaries at the periphery appear as dilated semilunar vessels.⁴ Dilated lymphatics, which stain with D2-40, can be found at the periphery of the tufted capillaries and throughout the remaining dermis.^3,4

Tufted angiomas may arise independently in adults but also have been associated with conditions such as pregnancy. Omori et al⁷ identified an acquired tufted angioma in pregnancy that was positive for estrogen and progesterone receptors. Reports of tufted angiomas in pregnancy vary; some are multiple lesions, some regress postpartum, and some undergo successful surgical treatment.^3,5

Vascular lesions such as tufted angiomas specifically may appear in pregnancy due to a high-volume state with vasodilation and increased vascular proliferation. Although tumor angiogenesis has been linked to specific growth factors and cytokines, it has been hypothesized that the systemic hormones of pregnancy such as human chorionic gonadotropin, estradiol, and progesterone also shift the body to a more angiogenic state.⁸ In a study of cutaneous changes in pregnant women (N=905), 41% developed a vascular skin change, including spider veins, varicosities, hemangiomas, and granulomas.⁹ The most common vascular tumor in pregnancy is pyogenic granuloma. Pyogenic granulomas are small, solitary, friable papules that commonly are found on the hands, forearms, face, or in the mouth; histologically they demonstrate dilated capillaries in lobular structures accompanied by larger thick-walled vessels.^3,10,11

Tufted angiomas may mimic a variety of other conditions. Epithelioid hemangioma, considered by some to be on the same morphologic spectrum as angiolymphoid hyperplasia with eosinophilia, classically occurs in young adults on the head and in the neck region. It histologically demonstrates a lobular appearance at low power; however, these lobules are made up of vessels with histiocytoid to epithelioid endothelial cells surrounded by a prominent inflammatory infiltrate consisting of lymphocytes and eosinophils.¹²

Kaposi sarcoma may appear on the neck but most often presents as macules and patches on the extremities that may form nodules with a rubbery consistency. In tufted angiomas, the cellular nodules with dilated channels at the margins bear a resemblance to Kaposi sarcoma or kaposiform hemangioendothelioma; however, in tufted angiomas the lobules are composed of bland spindle cells and slitlike vessels at the periphery.^3,13,14 Tufted angiomas are negative for human herpesvirus 8 and typically do not have an associated inflammatory infiltrate with plasma cells.^11,15

Moreover, it is important to differentiate tufted angioma from a cutaneous manifestation of an underlying malignancy, which has been described previously in cases of breast cancer.^16,17 Our case illustrates a rare vascular tumor arising in the novel context of a pregnant patient with breast cancer. Distinguishing tufted angioma from other benign or malignant vascular tumors is necessary to avoid inappropriate therapeutic interventions.

The Diagnosis: Granulomatous Cheilitis

A punch biopsy of the lip revealed a noncaseating microgranuloma in the submucosa with modest submucosal vascular ectasia and perivascular lymphoplasmacytic infiltrates (Figure). Comprehensive metabolic panel, complete blood cell count, angiotensinconverting enzyme (ACE) levels, and inflammatory markers (ie, erythrocyte sedimentation rate, C-reactive protein) all were within reference range. A serum environmental allergen test was negative except for ragweed. Levels of complements—C1 esterase inhibitor (C1-INH) antigen and function, C1q, C3, and C4—and antinuclear antibodies all were normal. Chest radiography was unremarkable. In lieu of a colonoscopy, a fecal calprotectin obtained by gastroenterology was normal. Given the clinical presentation and histopathologic findings, a diagnosis of granulomatous cheilitis (GC) was made.

Granulomatous cheilitis (also known as Miescher cheilitis) is an idiopathic condition characterized by recurrent or persistent swelling of one or both lips. Granulomatous cheilitis usually is an isolated finding but can occur in the setting of Melkersson-Rosenthal syndrome, which refers to a triad of orofacial swelling, facial paralysis, and fissured tongue. Orofacial granulomatosis is a unifying term for any orofacial swelling associated with histologic findings of noncaseating granulomas without evidence of a systemic disease.

Granulomatous cheilitis is a rare disease that most commonly occurs in young adults without any sex predilection.¹ The etiology still is unknown, but genetic predisposition, idiopathic influx of inflammatory cells, sensitivity to food or dental materials, and infections have been implicated.² Granulomatous cheilitis initially presents as soft, nonerythematous, nontender swelling affecting one or both lips. The first episode usually resolves in hours or days, but the frequency and duration of the attacks may increase until the swelling becomes persistent and indurated.³ Granulomatous cheilitis often is a diagnosis of exclusion. A tissue biopsy may show noncaseating epithelioid and multinucleated giant cells with associated lymphedema and fibrosis⁴; however, histologic findings may be nonspecific, especially early in the disease course, and may be indistinguishable from those of other granulomatous diseases such as sarcoidosis and Crohn disease (CD).⁵

Lip swelling may be an oral manifestation of CD. Compared with GC, however, CD more commonly is associated with ulcerations, buccal sulcus involvement, abnormalities in complete blood cell count such as anemia and thrombocytosis, and elevated C-reactive protein and erythrocyte sedimentation rate. Although infrequent, GC may coincide with or precede the onset of CD.⁶ Thus, a detailed gastrointestinal history and appropriate laboratory tests are needed to rule out undiagnosed CD. Nevertheless, performing a routine colonoscopy in the absence of gastrointestinal symptoms is debated.^7,8

Sarcoidosis is a systemic granulomatous disease that can have oral involvement in the form of edema, nodules, or ulcers. Oral sarcoidosis usually occurs in patients with chronic multisystemic sarcoidosis and likely is accompanied by pulmonary manifestations such as hilar adenopathy and infiltrates on chest radiography, which are found in more than 90% of patients with sarcoidosis.^9,10 A diagnosis of sarcoidosis is additionally supported by other organ involvement such as the joints, skin, or eyes, as well as elevated ACE and calcium levels.

Foreign bodies are another source of granulomatous inflammation and may present with nonspecific findings of swelling, masses, erythema, pain, or ulceration in oral tissues.¹¹ Foreign body reactions to dental materials, retained sutures, and cosmetic fillers have been reported.^12-14 In many cases, the foreign material is evident on biopsy.

Angioedema may mimic GC and should be excluded before more extensive testing is done, as it can result in life-threatening respiratory compromise. Numerous etiologies of angioedema have been identified including allergens, acquired or hereditary C1-INH deficiency, nonsteroidal anti-inflammatory drugs, ACE inhibitors, autoimmune disorders, and chronic infections.¹⁵ Patients with angioedema may have abnormalities in C4 and C1-INH levels or report certain medication use, allergen exposure, or family history of unexplained recurrent swellings or gastrointestinal symptoms.

There currently is no established treatment of GC due to the unclear etiology and unpredictable clinical course that can lead to spontaneous remissions or frequent recurrences. Corticosteroids administered systemically, intralesionally, or topically have been the mainstay treatment of GC.² In particular, intralesional injections have been reported as effective in reducing swelling and preventing recurrences in several studies.^16,17 Numerous other treatments have been reported in the literature with inconsistent outcomes, including antibiotics such as minocycline, metronidazole, and roxithromycin; clofazimine; thalidomide; immunomodulators such as tumor necrosis factor inhibitors and methotrexate; fumaric acid esters; and cheiloplasty in severe cases.16 Our patient showed near-complete resolution of the lip swelling after a single intralesional injection of 0.5 cc of triamcinolone acetonide 5 mg/mL. The patient has since received 5 additional maintenance injections of 0.1 to 0.2 cc of triamcinolone acetonide 2.5 to 5 mg/mL spaced 2 to 4 months apart with excellent control of the lip swelling, which the patient feels has resolved. We anticipate that repeated injections and monitoring of recurrences may be required for long-term remission.

The Diagnosis: Granulomatous Cheilitis

A punch biopsy of the lip revealed a noncaseating microgranuloma in the submucosa with modest submucosal vascular ectasia and perivascular lymphoplasmacytic infiltrates (Figure). Comprehensive metabolic panel, complete blood cell count, angiotensinconverting enzyme (ACE) levels, and inflammatory markers (ie, erythrocyte sedimentation rate, C-reactive protein) all were within reference range. A serum environmental allergen test was negative except for ragweed. Levels of complements—C1 esterase inhibitor (C1-INH) antigen and function, C1q, C3, and C4—and antinuclear antibodies all were normal. Chest radiography was unremarkable. In lieu of a colonoscopy, a fecal calprotectin obtained by gastroenterology was normal. Given the clinical presentation and histopathologic findings, a diagnosis of granulomatous cheilitis (GC) was made.

Granulomatous cheilitis (also known as Miescher cheilitis) is an idiopathic condition characterized by recurrent or persistent swelling of one or both lips. Granulomatous cheilitis usually is an isolated finding but can occur in the setting of Melkersson-Rosenthal syndrome, which refers to a triad of orofacial swelling, facial paralysis, and fissured tongue. Orofacial granulomatosis is a unifying term for any orofacial swelling associated with histologic findings of noncaseating granulomas without evidence of a systemic disease.

Granulomatous cheilitis is a rare disease that most commonly occurs in young adults without any sex predilection.¹ The etiology still is unknown, but genetic predisposition, idiopathic influx of inflammatory cells, sensitivity to food or dental materials, and infections have been implicated.² Granulomatous cheilitis initially presents as soft, nonerythematous, nontender swelling affecting one or both lips. The first episode usually resolves in hours or days, but the frequency and duration of the attacks may increase until the swelling becomes persistent and indurated.³ Granulomatous cheilitis often is a diagnosis of exclusion. A tissue biopsy may show noncaseating epithelioid and multinucleated giant cells with associated lymphedema and fibrosis⁴; however, histologic findings may be nonspecific, especially early in the disease course, and may be indistinguishable from those of other granulomatous diseases such as sarcoidosis and Crohn disease (CD).⁵

Lip swelling may be an oral manifestation of CD. Compared with GC, however, CD more commonly is associated with ulcerations, buccal sulcus involvement, abnormalities in complete blood cell count such as anemia and thrombocytosis, and elevated C-reactive protein and erythrocyte sedimentation rate. Although infrequent, GC may coincide with or precede the onset of CD.⁶ Thus, a detailed gastrointestinal history and appropriate laboratory tests are needed to rule out undiagnosed CD. Nevertheless, performing a routine colonoscopy in the absence of gastrointestinal symptoms is debated.^7,8

Sarcoidosis is a systemic granulomatous disease that can have oral involvement in the form of edema, nodules, or ulcers. Oral sarcoidosis usually occurs in patients with chronic multisystemic sarcoidosis and likely is accompanied by pulmonary manifestations such as hilar adenopathy and infiltrates on chest radiography, which are found in more than 90% of patients with sarcoidosis.^9,10 A diagnosis of sarcoidosis is additionally supported by other organ involvement such as the joints, skin, or eyes, as well as elevated ACE and calcium levels.

Foreign bodies are another source of granulomatous inflammation and may present with nonspecific findings of swelling, masses, erythema, pain, or ulceration in oral tissues.¹¹ Foreign body reactions to dental materials, retained sutures, and cosmetic fillers have been reported.^12-14 In many cases, the foreign material is evident on biopsy.

Angioedema may mimic GC and should be excluded before more extensive testing is done, as it can result in life-threatening respiratory compromise. Numerous etiologies of angioedema have been identified including allergens, acquired or hereditary C1-INH deficiency, nonsteroidal anti-inflammatory drugs, ACE inhibitors, autoimmune disorders, and chronic infections.¹⁵ Patients with angioedema may have abnormalities in C4 and C1-INH levels or report certain medication use, allergen exposure, or family history of unexplained recurrent swellings or gastrointestinal symptoms.

There currently is no established treatment of GC due to the unclear etiology and unpredictable clinical course that can lead to spontaneous remissions or frequent recurrences. Corticosteroids administered systemically, intralesionally, or topically have been the mainstay treatment of GC.² In particular, intralesional injections have been reported as effective in reducing swelling and preventing recurrences in several studies.^16,17 Numerous other treatments have been reported in the literature with inconsistent outcomes, including antibiotics such as minocycline, metronidazole, and roxithromycin; clofazimine; thalidomide; immunomodulators such as tumor necrosis factor inhibitors and methotrexate; fumaric acid esters; and cheiloplasty in severe cases.16 Our patient showed near-complete resolution of the lip swelling after a single intralesional injection of 0.5 cc of triamcinolone acetonide 5 mg/mL. The patient has since received 5 additional maintenance injections of 0.1 to 0.2 cc of triamcinolone acetonide 2.5 to 5 mg/mL spaced 2 to 4 months apart with excellent control of the lip swelling, which the patient feels has resolved. We anticipate that repeated injections and monitoring of recurrences may be required for long-term remission.

The Diagnosis: Granulomatous Cheilitis

A punch biopsy of the lip revealed a noncaseating microgranuloma in the submucosa with modest submucosal vascular ectasia and perivascular lymphoplasmacytic infiltrates (Figure). Comprehensive metabolic panel, complete blood cell count, angiotensinconverting enzyme (ACE) levels, and inflammatory markers (ie, erythrocyte sedimentation rate, C-reactive protein) all were within reference range. A serum environmental allergen test was negative except for ragweed. Levels of complements—C1 esterase inhibitor (C1-INH) antigen and function, C1q, C3, and C4—and antinuclear antibodies all were normal. Chest radiography was unremarkable. In lieu of a colonoscopy, a fecal calprotectin obtained by gastroenterology was normal. Given the clinical presentation and histopathologic findings, a diagnosis of granulomatous cheilitis (GC) was made.

Granulomatous cheilitis (also known as Miescher cheilitis) is an idiopathic condition characterized by recurrent or persistent swelling of one or both lips. Granulomatous cheilitis usually is an isolated finding but can occur in the setting of Melkersson-Rosenthal syndrome, which refers to a triad of orofacial swelling, facial paralysis, and fissured tongue. Orofacial granulomatosis is a unifying term for any orofacial swelling associated with histologic findings of noncaseating granulomas without evidence of a systemic disease.

Granulomatous cheilitis is a rare disease that most commonly occurs in young adults without any sex predilection.¹ The etiology still is unknown, but genetic predisposition, idiopathic influx of inflammatory cells, sensitivity to food or dental materials, and infections have been implicated.² Granulomatous cheilitis initially presents as soft, nonerythematous, nontender swelling affecting one or both lips. The first episode usually resolves in hours or days, but the frequency and duration of the attacks may increase until the swelling becomes persistent and indurated.³ Granulomatous cheilitis often is a diagnosis of exclusion. A tissue biopsy may show noncaseating epithelioid and multinucleated giant cells with associated lymphedema and fibrosis⁴; however, histologic findings may be nonspecific, especially early in the disease course, and may be indistinguishable from those of other granulomatous diseases such as sarcoidosis and Crohn disease (CD).⁵

Lip swelling may be an oral manifestation of CD. Compared with GC, however, CD more commonly is associated with ulcerations, buccal sulcus involvement, abnormalities in complete blood cell count such as anemia and thrombocytosis, and elevated C-reactive protein and erythrocyte sedimentation rate. Although infrequent, GC may coincide with or precede the onset of CD.⁶ Thus, a detailed gastrointestinal history and appropriate laboratory tests are needed to rule out undiagnosed CD. Nevertheless, performing a routine colonoscopy in the absence of gastrointestinal symptoms is debated.^7,8

Sarcoidosis is a systemic granulomatous disease that can have oral involvement in the form of edema, nodules, or ulcers. Oral sarcoidosis usually occurs in patients with chronic multisystemic sarcoidosis and likely is accompanied by pulmonary manifestations such as hilar adenopathy and infiltrates on chest radiography, which are found in more than 90% of patients with sarcoidosis.^9,10 A diagnosis of sarcoidosis is additionally supported by other organ involvement such as the joints, skin, or eyes, as well as elevated ACE and calcium levels.

Foreign bodies are another source of granulomatous inflammation and may present with nonspecific findings of swelling, masses, erythema, pain, or ulceration in oral tissues.¹¹ Foreign body reactions to dental materials, retained sutures, and cosmetic fillers have been reported.^12-14 In many cases, the foreign material is evident on biopsy.

Angioedema may mimic GC and should be excluded before more extensive testing is done, as it can result in life-threatening respiratory compromise. Numerous etiologies of angioedema have been identified including allergens, acquired or hereditary C1-INH deficiency, nonsteroidal anti-inflammatory drugs, ACE inhibitors, autoimmune disorders, and chronic infections.¹⁵ Patients with angioedema may have abnormalities in C4 and C1-INH levels or report certain medication use, allergen exposure, or family history of unexplained recurrent swellings or gastrointestinal symptoms.

There currently is no established treatment of GC due to the unclear etiology and unpredictable clinical course that can lead to spontaneous remissions or frequent recurrences. Corticosteroids administered systemically, intralesionally, or topically have been the mainstay treatment of GC.² In particular, intralesional injections have been reported as effective in reducing swelling and preventing recurrences in several studies.^16,17 Numerous other treatments have been reported in the literature with inconsistent outcomes, including antibiotics such as minocycline, metronidazole, and roxithromycin; clofazimine; thalidomide; immunomodulators such as tumor necrosis factor inhibitors and methotrexate; fumaric acid esters; and cheiloplasty in severe cases.16 Our patient showed near-complete resolution of the lip swelling after a single intralesional injection of 0.5 cc of triamcinolone acetonide 5 mg/mL. The patient has since received 5 additional maintenance injections of 0.1 to 0.2 cc of triamcinolone acetonide 2.5 to 5 mg/mL spaced 2 to 4 months apart with excellent control of the lip swelling, which the patient feels has resolved. We anticipate that repeated injections and monitoring of recurrences may be required for long-term remission.

Background and Clinical Presentation

Seabather’s Eruption—Seabather’s eruption is a type I and IV hypersensitivity reaction caused by nematocysts of larval-stage thimble jellyfish (Linuche unguiculata), sea anemones (eg, Edwardsiella lineata), and larval cnidarians.¹Linuche unguiculata commonly is found along the southeast coast of the United States and in the Caribbean, the Gulf of Mexico, and the coasts of Florida; less commonly, it has been reported along the coasts of Brazil and Papua New Guinea. Edwardsiella lineata more commonly is seen along the East Coast of the United States.² Seabather’s eruption presents as numerous scattered, pruritic, red macules and papules (measuring 1 mm to 1.5 cm in size) distributed in areas covered by skin folds, wet clothing, or hair following exposure to marine water (Figure 1). This maculopapular rash generally appears shortly after exiting the water and can last up to several weeks in some cases.³ The cause for this delayed presentation is that the marine organisms become entrapped between the skin of the human contact and another object (eg, swimwear) but do not release their preformed antivenom until they are exposed to air after removal from the water, at which point the organisms die and cell lysis results in injection of the venom.

Diver’s Dermatitis—Diver’s dermatitis (also referred to as “swimmer’s itch”) is a type I and IV hypersensitivity reaction caused by schistosome cercariae released by aquatic snails.⁴ There are several different cercarial species known to be capable of causing diver dermatitis, but the most commonly implicated genera are Trichobilharzia and Gigantobilharzia. These parasites most commonly are found in freshwater lakes but also occur in oceans, particularly in brackish areas adjacent to freshwater access. Factors associated with increased concentrations of these parasites include shallow, slow-moving water and prolonged onshore wind causing accumulation near the shoreline. It also is thought that the snail host will shed greater concentrations of the parasitic worm in the morning hours and after prolonged exposure to sunlight.⁴ These flatworm trematodes have a 2-host life cycle. The snails function as intermediate hosts for the parasites before they enter their final host, which are birds. Humans only function as incidental and nonviable hosts for these worms. The parasites gain access to the human body by burrowing into exposed skin. Because the parasite is unable to survive on human hosts, it dies shortly after penetrating the skin, which leads to an intense inflammatory response causing symptoms of pruritus within hours of exposure (Figure 2). The initial eruption progresses over a few days into a diffuse, maculopapular, pruritic rash, similar to that seen in seabather’s eruption. This rash then regresses completely in 1 to 3 weeks. Subsequent exposure to the same parasite is associated with increased severity of future rashes, likely due to antibody-mediated sensitization.⁴

Photograph courtesy of Tomas Machacek, PhD (Prague, Czechia).

Diagnosis—Marine-derived dermatoses from various sources can present very similarly; thus, it is difficult to discern the specific etiology behind the clinical presentation. No commonly utilized imaging modalities can differentiate between seabather’s eruption and diver’s dermatitis, but eliciting a thorough patient history often can aid in differentiation of the cause of the eruption. For example, lesions located only on nonexposed areas of the skin increases the likelihood of seabather’s eruption due to nematocysts being trapped between clothing and the skin. In contrast, diver’s dermatitis generally appears on areas of the skin that were directly exposed to water and uncovered by clothing.⁵ Patient reports of a lack of symptoms until shortly after exiting the water further support a diagnosis of seabather’s eruption, as this delayed presentation of symptoms is caused by lysis of the culprit organisms following removal from the marine environment. The cell lysis is responsible for the widespread injection of preformed venom via the numerous nematocysts trapped between clothing and the patient’s body.¹

Treatment

For both conditions, the symptoms are treated with hydrocortisone or other topical steroid solutions in conjunction with oral hydroxyzine. Alternative treatments include calamine lotion with 1% menthol and nonsteroidal anti-inflammatory drugs. Taking baths with oatmeal, Epsom salts, or baking soda also may alleviate some of the pruritic symptoms.²

Prevention

The ability to diagnose the precise cause of these similar marine rashes can bring peace of mind to both patients and physicians regardless of their similar management strategies. Severe contact dermatitis of unknown etiology can be disconcerting for patients. Additionally, documenting the causes of marine rashes in particular geographic locations can be beneficial for establishing which organisms are most likely to affect visitors to those areas. This type of data collection can be utilized to develop preventative recommendations, such as deciding when to avoid the water. Education of the public can be done with the use of informational posters located near popular swimming areas and online public service announcements. Informing the general public about the dangers of entering the ocean, especially during certain times of the year when nematocyst-equipped sea creatures are in abundance, could serve to prevent numerous cases of seabather’s eruption. Likewise, advising against immersion in shallow, slow-moving water during the morning hours or after prolonged sun exposure in trematode-endemic areas could prevent numerous cases of diver’s dermatitis. Basic information on what to expect if afflicted by a marine rash also may reduce the number of emergency department visits for these conditions, thus providing economic benefit for patients and for hospitals since patients would better know how to acutely treat these rashes and lessen the patient load at hospital emergency departments. If individuals can assure themselves of the self-limited nature of these types of dermatoses, they may be less inclined to seek medical consultation.

Final Thoughts

As the climate continues to change, the incidence of marine rashes such as seabather’s eruption and diver’s dermatitis is expected to increase due to warmer surface temperatures causing more frequent and earlier blooms of L unguiculata and E lineata. Cases of diver’s dermatitis also could increase due to a longer season of more frequent human exposure from an increase in warmer temperatures. The projected uptick in incidences of these marine rashes makes understanding these pathologies even more pertinent for physicians.⁶ Increasing our understanding of the different types of marine rashes and their causes will help guide future recommendations for the general public when visiting the ocean.

Future research may wish to investigate unique ways in which to prevent contact between these organisms and humans. Past research on mice indicated that topical application of DEET (N,N-diethyl-meta-toluamide) prior to trematode exposure prevented penetration of the skin by parasitic worms.⁷ Future studies are needed to examine the effectiveness of this preventative technique on humans. For now, dermatologists may counsel our ocean-going patients on preventative behaviors as well as provide reassurance and symptomatic relief when they present to our clinics with marine rashes.

Background and Clinical Presentation

Seabather’s Eruption—Seabather’s eruption is a type I and IV hypersensitivity reaction caused by nematocysts of larval-stage thimble jellyfish (Linuche unguiculata), sea anemones (eg, Edwardsiella lineata), and larval cnidarians.¹Linuche unguiculata commonly is found along the southeast coast of the United States and in the Caribbean, the Gulf of Mexico, and the coasts of Florida; less commonly, it has been reported along the coasts of Brazil and Papua New Guinea. Edwardsiella lineata more commonly is seen along the East Coast of the United States.² Seabather’s eruption presents as numerous scattered, pruritic, red macules and papules (measuring 1 mm to 1.5 cm in size) distributed in areas covered by skin folds, wet clothing, or hair following exposure to marine water (Figure 1). This maculopapular rash generally appears shortly after exiting the water and can last up to several weeks in some cases.³ The cause for this delayed presentation is that the marine organisms become entrapped between the skin of the human contact and another object (eg, swimwear) but do not release their preformed antivenom until they are exposed to air after removal from the water, at which point the organisms die and cell lysis results in injection of the venom.

Diver’s Dermatitis—Diver’s dermatitis (also referred to as “swimmer’s itch”) is a type I and IV hypersensitivity reaction caused by schistosome cercariae released by aquatic snails.⁴ There are several different cercarial species known to be capable of causing diver dermatitis, but the most commonly implicated genera are Trichobilharzia and Gigantobilharzia. These parasites most commonly are found in freshwater lakes but also occur in oceans, particularly in brackish areas adjacent to freshwater access. Factors associated with increased concentrations of these parasites include shallow, slow-moving water and prolonged onshore wind causing accumulation near the shoreline. It also is thought that the snail host will shed greater concentrations of the parasitic worm in the morning hours and after prolonged exposure to sunlight.⁴ These flatworm trematodes have a 2-host life cycle. The snails function as intermediate hosts for the parasites before they enter their final host, which are birds. Humans only function as incidental and nonviable hosts for these worms. The parasites gain access to the human body by burrowing into exposed skin. Because the parasite is unable to survive on human hosts, it dies shortly after penetrating the skin, which leads to an intense inflammatory response causing symptoms of pruritus within hours of exposure (Figure 2). The initial eruption progresses over a few days into a diffuse, maculopapular, pruritic rash, similar to that seen in seabather’s eruption. This rash then regresses completely in 1 to 3 weeks. Subsequent exposure to the same parasite is associated with increased severity of future rashes, likely due to antibody-mediated sensitization.⁴

Photograph courtesy of Tomas Machacek, PhD (Prague, Czechia).

Diagnosis—Marine-derived dermatoses from various sources can present very similarly; thus, it is difficult to discern the specific etiology behind the clinical presentation. No commonly utilized imaging modalities can differentiate between seabather’s eruption and diver’s dermatitis, but eliciting a thorough patient history often can aid in differentiation of the cause of the eruption. For example, lesions located only on nonexposed areas of the skin increases the likelihood of seabather’s eruption due to nematocysts being trapped between clothing and the skin. In contrast, diver’s dermatitis generally appears on areas of the skin that were directly exposed to water and uncovered by clothing.⁵ Patient reports of a lack of symptoms until shortly after exiting the water further support a diagnosis of seabather’s eruption, as this delayed presentation of symptoms is caused by lysis of the culprit organisms following removal from the marine environment. The cell lysis is responsible for the widespread injection of preformed venom via the numerous nematocysts trapped between clothing and the patient’s body.¹

Treatment

For both conditions, the symptoms are treated with hydrocortisone or other topical steroid solutions in conjunction with oral hydroxyzine. Alternative treatments include calamine lotion with 1% menthol and nonsteroidal anti-inflammatory drugs. Taking baths with oatmeal, Epsom salts, or baking soda also may alleviate some of the pruritic symptoms.²

Prevention

The ability to diagnose the precise cause of these similar marine rashes can bring peace of mind to both patients and physicians regardless of their similar management strategies. Severe contact dermatitis of unknown etiology can be disconcerting for patients. Additionally, documenting the causes of marine rashes in particular geographic locations can be beneficial for establishing which organisms are most likely to affect visitors to those areas. This type of data collection can be utilized to develop preventative recommendations, such as deciding when to avoid the water. Education of the public can be done with the use of informational posters located near popular swimming areas and online public service announcements. Informing the general public about the dangers of entering the ocean, especially during certain times of the year when nematocyst-equipped sea creatures are in abundance, could serve to prevent numerous cases of seabather’s eruption. Likewise, advising against immersion in shallow, slow-moving water during the morning hours or after prolonged sun exposure in trematode-endemic areas could prevent numerous cases of diver’s dermatitis. Basic information on what to expect if afflicted by a marine rash also may reduce the number of emergency department visits for these conditions, thus providing economic benefit for patients and for hospitals since patients would better know how to acutely treat these rashes and lessen the patient load at hospital emergency departments. If individuals can assure themselves of the self-limited nature of these types of dermatoses, they may be less inclined to seek medical consultation.

Final Thoughts

As the climate continues to change, the incidence of marine rashes such as seabather’s eruption and diver’s dermatitis is expected to increase due to warmer surface temperatures causing more frequent and earlier blooms of L unguiculata and E lineata. Cases of diver’s dermatitis also could increase due to a longer season of more frequent human exposure from an increase in warmer temperatures. The projected uptick in incidences of these marine rashes makes understanding these pathologies even more pertinent for physicians.⁶ Increasing our understanding of the different types of marine rashes and their causes will help guide future recommendations for the general public when visiting the ocean.

Future research may wish to investigate unique ways in which to prevent contact between these organisms and humans. Past research on mice indicated that topical application of DEET (N,N-diethyl-meta-toluamide) prior to trematode exposure prevented penetration of the skin by parasitic worms.⁷ Future studies are needed to examine the effectiveness of this preventative technique on humans. For now, dermatologists may counsel our ocean-going patients on preventative behaviors as well as provide reassurance and symptomatic relief when they present to our clinics with marine rashes.

Background and Clinical Presentation

Seabather’s Eruption—Seabather’s eruption is a type I and IV hypersensitivity reaction caused by nematocysts of larval-stage thimble jellyfish (Linuche unguiculata), sea anemones (eg, Edwardsiella lineata), and larval cnidarians.¹Linuche unguiculata commonly is found along the southeast coast of the United States and in the Caribbean, the Gulf of Mexico, and the coasts of Florida; less commonly, it has been reported along the coasts of Brazil and Papua New Guinea. Edwardsiella lineata more commonly is seen along the East Coast of the United States.² Seabather’s eruption presents as numerous scattered, pruritic, red macules and papules (measuring 1 mm to 1.5 cm in size) distributed in areas covered by skin folds, wet clothing, or hair following exposure to marine water (Figure 1). This maculopapular rash generally appears shortly after exiting the water and can last up to several weeks in some cases.³ The cause for this delayed presentation is that the marine organisms become entrapped between the skin of the human contact and another object (eg, swimwear) but do not release their preformed antivenom until they are exposed to air after removal from the water, at which point the organisms die and cell lysis results in injection of the venom.

Diver’s Dermatitis—Diver’s dermatitis (also referred to as “swimmer’s itch”) is a type I and IV hypersensitivity reaction caused by schistosome cercariae released by aquatic snails.⁴ There are several different cercarial species known to be capable of causing diver dermatitis, but the most commonly implicated genera are Trichobilharzia and Gigantobilharzia. These parasites most commonly are found in freshwater lakes but also occur in oceans, particularly in brackish areas adjacent to freshwater access. Factors associated with increased concentrations of these parasites include shallow, slow-moving water and prolonged onshore wind causing accumulation near the shoreline. It also is thought that the snail host will shed greater concentrations of the parasitic worm in the morning hours and after prolonged exposure to sunlight.⁴ These flatworm trematodes have a 2-host life cycle. The snails function as intermediate hosts for the parasites before they enter their final host, which are birds. Humans only function as incidental and nonviable hosts for these worms. The parasites gain access to the human body by burrowing into exposed skin. Because the parasite is unable to survive on human hosts, it dies shortly after penetrating the skin, which leads to an intense inflammatory response causing symptoms of pruritus within hours of exposure (Figure 2). The initial eruption progresses over a few days into a diffuse, maculopapular, pruritic rash, similar to that seen in seabather’s eruption. This rash then regresses completely in 1 to 3 weeks. Subsequent exposure to the same parasite is associated with increased severity of future rashes, likely due to antibody-mediated sensitization.⁴

Photograph courtesy of Tomas Machacek, PhD (Prague, Czechia).

Diagnosis—Marine-derived dermatoses from various sources can present very similarly; thus, it is difficult to discern the specific etiology behind the clinical presentation. No commonly utilized imaging modalities can differentiate between seabather’s eruption and diver’s dermatitis, but eliciting a thorough patient history often can aid in differentiation of the cause of the eruption. For example, lesions located only on nonexposed areas of the skin increases the likelihood of seabather’s eruption due to nematocysts being trapped between clothing and the skin. In contrast, diver’s dermatitis generally appears on areas of the skin that were directly exposed to water and uncovered by clothing.⁵ Patient reports of a lack of symptoms until shortly after exiting the water further support a diagnosis of seabather’s eruption, as this delayed presentation of symptoms is caused by lysis of the culprit organisms following removal from the marine environment. The cell lysis is responsible for the widespread injection of preformed venom via the numerous nematocysts trapped between clothing and the patient’s body.¹

Treatment

For both conditions, the symptoms are treated with hydrocortisone or other topical steroid solutions in conjunction with oral hydroxyzine. Alternative treatments include calamine lotion with 1% menthol and nonsteroidal anti-inflammatory drugs. Taking baths with oatmeal, Epsom salts, or baking soda also may alleviate some of the pruritic symptoms.²

Prevention

The ability to diagnose the precise cause of these similar marine rashes can bring peace of mind to both patients and physicians regardless of their similar management strategies. Severe contact dermatitis of unknown etiology can be disconcerting for patients. Additionally, documenting the causes of marine rashes in particular geographic locations can be beneficial for establishing which organisms are most likely to affect visitors to those areas. This type of data collection can be utilized to develop preventative recommendations, such as deciding when to avoid the water. Education of the public can be done with the use of informational posters located near popular swimming areas and online public service announcements. Informing the general public about the dangers of entering the ocean, especially during certain times of the year when nematocyst-equipped sea creatures are in abundance, could serve to prevent numerous cases of seabather’s eruption. Likewise, advising against immersion in shallow, slow-moving water during the morning hours or after prolonged sun exposure in trematode-endemic areas could prevent numerous cases of diver’s dermatitis. Basic information on what to expect if afflicted by a marine rash also may reduce the number of emergency department visits for these conditions, thus providing economic benefit for patients and for hospitals since patients would better know how to acutely treat these rashes and lessen the patient load at hospital emergency departments. If individuals can assure themselves of the self-limited nature of these types of dermatoses, they may be less inclined to seek medical consultation.

Final Thoughts

As the climate continues to change, the incidence of marine rashes such as seabather’s eruption and diver’s dermatitis is expected to increase due to warmer surface temperatures causing more frequent and earlier blooms of L unguiculata and E lineata. Cases of diver’s dermatitis also could increase due to a longer season of more frequent human exposure from an increase in warmer temperatures. The projected uptick in incidences of these marine rashes makes understanding these pathologies even more pertinent for physicians.⁶ Increasing our understanding of the different types of marine rashes and their causes will help guide future recommendations for the general public when visiting the ocean.

Future research may wish to investigate unique ways in which to prevent contact between these organisms and humans. Past research on mice indicated that topical application of DEET (N,N-diethyl-meta-toluamide) prior to trematode exposure prevented penetration of the skin by parasitic worms.⁷ Future studies are needed to examine the effectiveness of this preventative technique on humans. For now, dermatologists may counsel our ocean-going patients on preventative behaviors as well as provide reassurance and symptomatic relief when they present to our clinics with marine rashes.

The Diagnosis: Metastatic Clear Cell Renal Cell Carcinoma

Renal cell carcinoma (RCC) is a common genitourinary system malignancy with incidence peaking between 50 and 70 years of age and a male predominance.¹ The clear cell variant is the most common subtype of RCC, accounting for 70% to 75% of all cases. It is known to be a highly aggressive malignancy that frequently metastasizes to the lungs, lymphatics, bones, liver, and brain.^2,3 Approximately 20% to 50% of patients with RCC eventually will develop metastasis after nephrectomy.⁴ Survival with metastatic RCC to any site typically is in the range of 10 to 22 months.^5,6 Cutaneous metastases of RCC rarely have been reported in the literature (3%–6% of cases⁷) and most commonly are found on the scalp, followed by the chest or abdomen. ⁸ Cutaneous metastases generally are regarded as a late manifestation of the disease with a very poor prognosis. ⁹ It is unusual to identify cutaneous RCC metastasis without known RCC or other symptoms consistent with advanced RCC, such as hematuria or abdominal/flank pain. Renal cell carcinoma accounts for an estimated 6% to 7% of all cutaneous metastatic lesions.¹⁰ Cutaneous metastatic lesions of RCC often are solitary and grow rapidly, with the clinical appearance of an erythematous or violaceous, nodular, highly vascular, and often hemorrhagic growth.^9,11,12

Following the histologic diagnosis of metastatic clear cell RCC, our patient was referred to medical oncology for further workup. Magnetic resonance imaging and a positron emission tomography scan demonstrated widespread disease with a 7-cm left renal mass, liver and lung metastases, and bilateral mediastinal lymphadenopathy. The patient was started on combination immunotherapy as a palliative treatment given the widespread disease.

Histologically, clear cell RCC is characterized by lipid and glycogen-rich cells with ample cytoplasm and a well-developed vascular network, which often is thin walled with a chicken wire–like architecture. Metastatic clear cell RCC tumor cells may form glandular, acinar, or papillary structures with variable lymphocytic inflammatory infiltrates and abundant capillary formation. Immunohistochemically, the tumor cells should demonstrate positivity for paired box gene 8, PAX8, and RCC marker antigen.¹³ Vimentin and carcinoembryonic antigen may be utilized to distinguish from hidradenoma as carcinoembryonic antigen will be positive in hidradenoma and vimentin will be negative.¹⁴ Renal cell carcinoma also has a common molecular signature of von Hippel-Lindau tumor suppressor gene inactivation as well as upregulation of hypoxia inducible factor and vascular endothelial growth factor.¹⁵

Balloon cell nevi often clinically present in young patients as bicolored nevi that sometimes are polypoid or verrucous in appearance with central yellow globules surrounded by a peripheral reticular pattern on dermoscopy. Histologically, balloon cell nevi are characterized by large cells with small, round, centrally located basophilic nuclei and clear foamy cytoplasm (Figure 1), which are thought to be formed by progressive vacuolization of melanocytes due to the enlargement and disintegration of melanosomes. This ballooning change reflects an seen in malignant melanoma, in which case nuclear pleomorphism, atypia, and increased mitotic activity also are observed. The prominent vascular network characteristic of RCC typically is not present.¹⁶

Clear cell hidradenomas are benign skin appendage tumors that often present as small, firm, solitary dermal nodules that may extend into the subcutaneous fat. They have a predilection for the head, face, and arms and demonstrate 2 predominant cell types, including a polyhedral cell with a rounded nucleus and slightly basophilic cytoplasm as well as a round cell with clear cytoplasm and bland nuclei (Figure 2). The latter cell type is less common, representing the predominant cell type in less than one-third of hidradenomas, and can present a diagnostic quandary based on histologic similarity to other clear cell neoplasms. The clear cells contain glycogen but no lipid. Ductlike structures often are present, and the intervening stroma varies from delicate vascularized cords of fibrous tissue to dense hyalinized collagen. Immunohistochemistry may be required for definitive diagnosis, and clear cell hidradenomas should react with monoclonal antibodies that label both eccrine and apocrine secretory elements, such as cytokeratins 6/18, 7, and 8/18.¹⁷

Pyogenic granulomas (also referred to as lobular capillary hemangiomas) are common and present clinically as rapidly growing, polypoid, red masses surrounded by a thickened epidermis that often are found on the fingers or lips. This entity is benign and often regresses spontaneously. Histologically, pyogenic granulomas are characterized by a lobular pattern of vascular proliferation associated with edema and inflammation resembling granulation tissue, with acanthosis and hyperkeratosis at the edges of the lesion (Figure 3).¹⁸

Sebaceous carcinoma is a locally aggressive malignant neoplasm arising from the cells of the sebaceous glands and occurring most commonly in the periorbital area. This neoplasm most often affects older adults, with a mean age at diagnosis of 63 to 77 years. It commonly presents as a solitary nodule with yellowish discoloration and madarosis, which is a key distinguishing feature to differentiate this entity from a chalazion or hordeolum. Histologically, sebaceous carcinoma is a dermal-based infiltrative, nodular tumor with varying degrees of clear cell changes—well-differentiated tumors show more clear cell change as compared to more poorly differentiated variants—along with basaloid or squamous features and abundant mitotic activity (Figure 4), which may be useful in distinguishing it from the other entities in the clear cell neoplasm differential.^19-22

The Diagnosis: Metastatic Clear Cell Renal Cell Carcinoma

Renal cell carcinoma (RCC) is a common genitourinary system malignancy with incidence peaking between 50 and 70 years of age and a male predominance.¹ The clear cell variant is the most common subtype of RCC, accounting for 70% to 75% of all cases. It is known to be a highly aggressive malignancy that frequently metastasizes to the lungs, lymphatics, bones, liver, and brain.^2,3 Approximately 20% to 50% of patients with RCC eventually will develop metastasis after nephrectomy.⁴ Survival with metastatic RCC to any site typically is in the range of 10 to 22 months.^5,6 Cutaneous metastases of RCC rarely have been reported in the literature (3%–6% of cases⁷) and most commonly are found on the scalp, followed by the chest or abdomen. ⁸ Cutaneous metastases generally are regarded as a late manifestation of the disease with a very poor prognosis. ⁹ It is unusual to identify cutaneous RCC metastasis without known RCC or other symptoms consistent with advanced RCC, such as hematuria or abdominal/flank pain. Renal cell carcinoma accounts for an estimated 6% to 7% of all cutaneous metastatic lesions.¹⁰ Cutaneous metastatic lesions of RCC often are solitary and grow rapidly, with the clinical appearance of an erythematous or violaceous, nodular, highly vascular, and often hemorrhagic growth.^9,11,12

Following the histologic diagnosis of metastatic clear cell RCC, our patient was referred to medical oncology for further workup. Magnetic resonance imaging and a positron emission tomography scan demonstrated widespread disease with a 7-cm left renal mass, liver and lung metastases, and bilateral mediastinal lymphadenopathy. The patient was started on combination immunotherapy as a palliative treatment given the widespread disease.

Histologically, clear cell RCC is characterized by lipid and glycogen-rich cells with ample cytoplasm and a well-developed vascular network, which often is thin walled with a chicken wire–like architecture. Metastatic clear cell RCC tumor cells may form glandular, acinar, or papillary structures with variable lymphocytic inflammatory infiltrates and abundant capillary formation. Immunohistochemically, the tumor cells should demonstrate positivity for paired box gene 8, PAX8, and RCC marker antigen.¹³ Vimentin and carcinoembryonic antigen may be utilized to distinguish from hidradenoma as carcinoembryonic antigen will be positive in hidradenoma and vimentin will be negative.¹⁴ Renal cell carcinoma also has a common molecular signature of von Hippel-Lindau tumor suppressor gene inactivation as well as upregulation of hypoxia inducible factor and vascular endothelial growth factor.¹⁵

Balloon cell nevi often clinically present in young patients as bicolored nevi that sometimes are polypoid or verrucous in appearance with central yellow globules surrounded by a peripheral reticular pattern on dermoscopy. Histologically, balloon cell nevi are characterized by large cells with small, round, centrally located basophilic nuclei and clear foamy cytoplasm (Figure 1), which are thought to be formed by progressive vacuolization of melanocytes due to the enlargement and disintegration of melanosomes. This ballooning change reflects an seen in malignant melanoma, in which case nuclear pleomorphism, atypia, and increased mitotic activity also are observed. The prominent vascular network characteristic of RCC typically is not present.¹⁶

Clear cell hidradenomas are benign skin appendage tumors that often present as small, firm, solitary dermal nodules that may extend into the subcutaneous fat. They have a predilection for the head, face, and arms and demonstrate 2 predominant cell types, including a polyhedral cell with a rounded nucleus and slightly basophilic cytoplasm as well as a round cell with clear cytoplasm and bland nuclei (Figure 2). The latter cell type is less common, representing the predominant cell type in less than one-third of hidradenomas, and can present a diagnostic quandary based on histologic similarity to other clear cell neoplasms. The clear cells contain glycogen but no lipid. Ductlike structures often are present, and the intervening stroma varies from delicate vascularized cords of fibrous tissue to dense hyalinized collagen. Immunohistochemistry may be required for definitive diagnosis, and clear cell hidradenomas should react with monoclonal antibodies that label both eccrine and apocrine secretory elements, such as cytokeratins 6/18, 7, and 8/18.¹⁷

Pyogenic granulomas (also referred to as lobular capillary hemangiomas) are common and present clinically as rapidly growing, polypoid, red masses surrounded by a thickened epidermis that often are found on the fingers or lips. This entity is benign and often regresses spontaneously. Histologically, pyogenic granulomas are characterized by a lobular pattern of vascular proliferation associated with edema and inflammation resembling granulation tissue, with acanthosis and hyperkeratosis at the edges of the lesion (Figure 3).¹⁸

Sebaceous carcinoma is a locally aggressive malignant neoplasm arising from the cells of the sebaceous glands and occurring most commonly in the periorbital area. This neoplasm most often affects older adults, with a mean age at diagnosis of 63 to 77 years. It commonly presents as a solitary nodule with yellowish discoloration and madarosis, which is a key distinguishing feature to differentiate this entity from a chalazion or hordeolum. Histologically, sebaceous carcinoma is a dermal-based infiltrative, nodular tumor with varying degrees of clear cell changes—well-differentiated tumors show more clear cell change as compared to more poorly differentiated variants—along with basaloid or squamous features and abundant mitotic activity (Figure 4), which may be useful in distinguishing it from the other entities in the clear cell neoplasm differential.^19-22

The Diagnosis: Metastatic Clear Cell Renal Cell Carcinoma

Renal cell carcinoma (RCC) is a common genitourinary system malignancy with incidence peaking between 50 and 70 years of age and a male predominance.¹ The clear cell variant is the most common subtype of RCC, accounting for 70% to 75% of all cases. It is known to be a highly aggressive malignancy that frequently metastasizes to the lungs, lymphatics, bones, liver, and brain.^2,3 Approximately 20% to 50% of patients with RCC eventually will develop metastasis after nephrectomy.⁴ Survival with metastatic RCC to any site typically is in the range of 10 to 22 months.^5,6 Cutaneous metastases of RCC rarely have been reported in the literature (3%–6% of cases⁷) and most commonly are found on the scalp, followed by the chest or abdomen. ⁸ Cutaneous metastases generally are regarded as a late manifestation of the disease with a very poor prognosis. ⁹ It is unusual to identify cutaneous RCC metastasis without known RCC or other symptoms consistent with advanced RCC, such as hematuria or abdominal/flank pain. Renal cell carcinoma accounts for an estimated 6% to 7% of all cutaneous metastatic lesions.¹⁰ Cutaneous metastatic lesions of RCC often are solitary and grow rapidly, with the clinical appearance of an erythematous or violaceous, nodular, highly vascular, and often hemorrhagic growth.^9,11,12

Following the histologic diagnosis of metastatic clear cell RCC, our patient was referred to medical oncology for further workup. Magnetic resonance imaging and a positron emission tomography scan demonstrated widespread disease with a 7-cm left renal mass, liver and lung metastases, and bilateral mediastinal lymphadenopathy. The patient was started on combination immunotherapy as a palliative treatment given the widespread disease.

Histologically, clear cell RCC is characterized by lipid and glycogen-rich cells with ample cytoplasm and a well-developed vascular network, which often is thin walled with a chicken wire–like architecture. Metastatic clear cell RCC tumor cells may form glandular, acinar, or papillary structures with variable lymphocytic inflammatory infiltrates and abundant capillary formation. Immunohistochemically, the tumor cells should demonstrate positivity for paired box gene 8, PAX8, and RCC marker antigen.¹³ Vimentin and carcinoembryonic antigen may be utilized to distinguish from hidradenoma as carcinoembryonic antigen will be positive in hidradenoma and vimentin will be negative.¹⁴ Renal cell carcinoma also has a common molecular signature of von Hippel-Lindau tumor suppressor gene inactivation as well as upregulation of hypoxia inducible factor and vascular endothelial growth factor.¹⁵

Balloon cell nevi often clinically present in young patients as bicolored nevi that sometimes are polypoid or verrucous in appearance with central yellow globules surrounded by a peripheral reticular pattern on dermoscopy. Histologically, balloon cell nevi are characterized by large cells with small, round, centrally located basophilic nuclei and clear foamy cytoplasm (Figure 1), which are thought to be formed by progressive vacuolization of melanocytes due to the enlargement and disintegration of melanosomes. This ballooning change reflects an seen in malignant melanoma, in which case nuclear pleomorphism, atypia, and increased mitotic activity also are observed. The prominent vascular network characteristic of RCC typically is not present.¹⁶

Clear cell hidradenomas are benign skin appendage tumors that often present as small, firm, solitary dermal nodules that may extend into the subcutaneous fat. They have a predilection for the head, face, and arms and demonstrate 2 predominant cell types, including a polyhedral cell with a rounded nucleus and slightly basophilic cytoplasm as well as a round cell with clear cytoplasm and bland nuclei (Figure 2). The latter cell type is less common, representing the predominant cell type in less than one-third of hidradenomas, and can present a diagnostic quandary based on histologic similarity to other clear cell neoplasms. The clear cells contain glycogen but no lipid. Ductlike structures often are present, and the intervening stroma varies from delicate vascularized cords of fibrous tissue to dense hyalinized collagen. Immunohistochemistry may be required for definitive diagnosis, and clear cell hidradenomas should react with monoclonal antibodies that label both eccrine and apocrine secretory elements, such as cytokeratins 6/18, 7, and 8/18.¹⁷

Pyogenic granulomas (also referred to as lobular capillary hemangiomas) are common and present clinically as rapidly growing, polypoid, red masses surrounded by a thickened epidermis that often are found on the fingers or lips. This entity is benign and often regresses spontaneously. Histologically, pyogenic granulomas are characterized by a lobular pattern of vascular proliferation associated with edema and inflammation resembling granulation tissue, with acanthosis and hyperkeratosis at the edges of the lesion (Figure 3).¹⁸

Sebaceous carcinoma is a locally aggressive malignant neoplasm arising from the cells of the sebaceous glands and occurring most commonly in the periorbital area. This neoplasm most often affects older adults, with a mean age at diagnosis of 63 to 77 years. It commonly presents as a solitary nodule with yellowish discoloration and madarosis, which is a key distinguishing feature to differentiate this entity from a chalazion or hordeolum. Histologically, sebaceous carcinoma is a dermal-based infiltrative, nodular tumor with varying degrees of clear cell changes—well-differentiated tumors show more clear cell change as compared to more poorly differentiated variants—along with basaloid or squamous features and abundant mitotic activity (Figure 4), which may be useful in distinguishing it from the other entities in the clear cell neoplasm differential.^19-22

The Diagnosis: Lupus Erythematosus Tumidus

Histopathologic evaluation of a punch biopsy revealed focal dermal mucin deposition and CD123+ discrete clusters of plasmacytoid dendritic cells without interface changes (Figure 1), favoring a diagnosis of lupus erythematosus tumidus (LET) in our patient. There was no clinical improvement in symptoms when she previously was treated with topical antifungals or class III corticosteroid creams. Tacrolimus ointment 0.1% twice daily for 1 month did not result in substantial improvement in the appearance of the plaque, and it spontaneously resolved after 2 to 3 months. She declined treatment with hydroxychloroquine.

Lupus erythematosus tumidus is an uncommon subtype of chronic cutaneous lupus erythematosus with no distinct etiology. It is clinically characterized by edematous, urticarial, single or multiple plaques with a smooth surface affecting sun-exposed areas that can last for months to years.¹ In contrast to other variations of chronic cutaneous lupus such as discoid lupus erythematosus, LET lesions lack surface papulosquamous features such as scaling, atrophy, and follicular plugging.^1-4 Based solely on histologic findings, LET may be indistinguishable from reticular erythematous mucinosis and Jessner lymphocytic infiltration of the skin (JLIS) due to a similar lack of epidermal involvement and presence of a perivascular lymphocytic infiltrate (Figure 2).

The average age at disease onset is 36 years, nearly the same as that described in discoid lupus erythematosus.⁴ Lupus erythematosus tumidus has a favorable prognosis and commonly presents without other autoimmune signs, serologic abnormalities, or gender preference, with concomitant systemic lupus erythematosus sometimes reported.⁵

The absence of clinical and histological epidermal involvement are the most important clues to aid in the diagnosis. It has been postulated that JLIS could be an early cutaneous manifestation of LET.⁶ The differential diagnosis also may include erythema annulare centrifugum, granuloma annulare, and urticarial vasculitis. Lesions typically respond well to photoprotection, topical corticosteroids, and/or antimalarials. The addition of tacrolimus ointment 0.1% may result in complete regression without recurrence.⁷

Erythema annulare centrifugum is a reactive erythema that classically begins as a pink papule that gradually enlarges to form an annular erythematous plaque with a fine trailing scale that may recur.⁸ The histopathology of erythema annulare centrifugum shares features seen in LET, making the diagnosis difficult; however, secondary changes to the epidermis (eg, spongiosis, hyperkeratosis) may be seen. This condition has been associated with lymphoproliferative malignancies.⁸

Reticular erythematous mucinosis is clinically distinguished from LET, as it presents as reticular, rather than arciform, erythematous macules, papules, or plaques that may be asymptomatic or pruritic.⁹ Histopathology typically shows more superficial mucin deposition than in LET as well as superficial to mid-dermal perivascular and periadnexal lymphocytic infiltrates. Reticular erythematous mucinosis more frequently is reported in women in their 30s and 40s and has been associated with UV exposure and hormonal triggers, such as oral contraceptive medications and pregnancy.⁹

Granuloma annulare typically presents as asymptomatic, erythematous, annular plaques or papules in young women.¹⁰ There are several histologic subtypes that show focal collagen degeneration, inflammation with palisaded or interstitial histiocytes, and mucin deposition, regardless of clinical presentation. Granuloma annulare has been associated with systemic diseases including type 2 diabetes mellitus and thyroid disease. Localized granuloma annulare most commonly presents on the dorsal aspects of the hands or feet.¹⁰

We present a case of LET on the face. Although histologically similar to other dermatoses, LET often lacks epidermal involvement and presents on sun-exposed areas of the body. Jessner lymphocytic infiltration of the skin also should be considered in the differential, as there is an overlap of clinical and histopathological features; JLIS lacks mucin deposits.⁶ This case reinforces the importance of correlating clinical with histopathologic findings. Our patient was treated with tacrolimus ointment 0.1%, and the plaque eventually resolved in 2 to 3 months without recurrence. This condition should be included in the differential diagnosis of recurring annular plaques on sunexposed areas, particularly in middle-aged adults, even in the absence of systemic involvement.

The Diagnosis: Lupus Erythematosus Tumidus

Histopathologic evaluation of a punch biopsy revealed focal dermal mucin deposition and CD123+ discrete clusters of plasmacytoid dendritic cells without interface changes (Figure 1), favoring a diagnosis of lupus erythematosus tumidus (LET) in our patient. There was no clinical improvement in symptoms when she previously was treated with topical antifungals or class III corticosteroid creams. Tacrolimus ointment 0.1% twice daily for 1 month did not result in substantial improvement in the appearance of the plaque, and it spontaneously resolved after 2 to 3 months. She declined treatment with hydroxychloroquine.

Lupus erythematosus tumidus is an uncommon subtype of chronic cutaneous lupus erythematosus with no distinct etiology. It is clinically characterized by edematous, urticarial, single or multiple plaques with a smooth surface affecting sun-exposed areas that can last for months to years.¹ In contrast to other variations of chronic cutaneous lupus such as discoid lupus erythematosus, LET lesions lack surface papulosquamous features such as scaling, atrophy, and follicular plugging.^1-4 Based solely on histologic findings, LET may be indistinguishable from reticular erythematous mucinosis and Jessner lymphocytic infiltration of the skin (JLIS) due to a similar lack of epidermal involvement and presence of a perivascular lymphocytic infiltrate (Figure 2).

The average age at disease onset is 36 years, nearly the same as that described in discoid lupus erythematosus.⁴ Lupus erythematosus tumidus has a favorable prognosis and commonly presents without other autoimmune signs, serologic abnormalities, or gender preference, with concomitant systemic lupus erythematosus sometimes reported.⁵

The absence of clinical and histological epidermal involvement are the most important clues to aid in the diagnosis. It has been postulated that JLIS could be an early cutaneous manifestation of LET.⁶ The differential diagnosis also may include erythema annulare centrifugum, granuloma annulare, and urticarial vasculitis. Lesions typically respond well to photoprotection, topical corticosteroids, and/or antimalarials. The addition of tacrolimus ointment 0.1% may result in complete regression without recurrence.⁷

Erythema annulare centrifugum is a reactive erythema that classically begins as a pink papule that gradually enlarges to form an annular erythematous plaque with a fine trailing scale that may recur.⁸ The histopathology of erythema annulare centrifugum shares features seen in LET, making the diagnosis difficult; however, secondary changes to the epidermis (eg, spongiosis, hyperkeratosis) may be seen. This condition has been associated with lymphoproliferative malignancies.⁸

Reticular erythematous mucinosis is clinically distinguished from LET, as it presents as reticular, rather than arciform, erythematous macules, papules, or plaques that may be asymptomatic or pruritic.⁹ Histopathology typically shows more superficial mucin deposition than in LET as well as superficial to mid-dermal perivascular and periadnexal lymphocytic infiltrates. Reticular erythematous mucinosis more frequently is reported in women in their 30s and 40s and has been associated with UV exposure and hormonal triggers, such as oral contraceptive medications and pregnancy.⁹

Granuloma annulare typically presents as asymptomatic, erythematous, annular plaques or papules in young women.¹⁰ There are several histologic subtypes that show focal collagen degeneration, inflammation with palisaded or interstitial histiocytes, and mucin deposition, regardless of clinical presentation. Granuloma annulare has been associated with systemic diseases including type 2 diabetes mellitus and thyroid disease. Localized granuloma annulare most commonly presents on the dorsal aspects of the hands or feet.¹⁰

We present a case of LET on the face. Although histologically similar to other dermatoses, LET often lacks epidermal involvement and presents on sun-exposed areas of the body. Jessner lymphocytic infiltration of the skin also should be considered in the differential, as there is an overlap of clinical and histopathological features; JLIS lacks mucin deposits.⁶ This case reinforces the importance of correlating clinical with histopathologic findings. Our patient was treated with tacrolimus ointment 0.1%, and the plaque eventually resolved in 2 to 3 months without recurrence. This condition should be included in the differential diagnosis of recurring annular plaques on sunexposed areas, particularly in middle-aged adults, even in the absence of systemic involvement.

The Diagnosis: Lupus Erythematosus Tumidus

Histopathologic evaluation of a punch biopsy revealed focal dermal mucin deposition and CD123+ discrete clusters of plasmacytoid dendritic cells without interface changes (Figure 1), favoring a diagnosis of lupus erythematosus tumidus (LET) in our patient. There was no clinical improvement in symptoms when she previously was treated with topical antifungals or class III corticosteroid creams. Tacrolimus ointment 0.1% twice daily for 1 month did not result in substantial improvement in the appearance of the plaque, and it spontaneously resolved after 2 to 3 months. She declined treatment with hydroxychloroquine.

Lupus erythematosus tumidus is an uncommon subtype of chronic cutaneous lupus erythematosus with no distinct etiology. It is clinically characterized by edematous, urticarial, single or multiple plaques with a smooth surface affecting sun-exposed areas that can last for months to years.¹ In contrast to other variations of chronic cutaneous lupus such as discoid lupus erythematosus, LET lesions lack surface papulosquamous features such as scaling, atrophy, and follicular plugging.^1-4 Based solely on histologic findings, LET may be indistinguishable from reticular erythematous mucinosis and Jessner lymphocytic infiltration of the skin (JLIS) due to a similar lack of epidermal involvement and presence of a perivascular lymphocytic infiltrate (Figure 2).

The average age at disease onset is 36 years, nearly the same as that described in discoid lupus erythematosus.⁴ Lupus erythematosus tumidus has a favorable prognosis and commonly presents without other autoimmune signs, serologic abnormalities, or gender preference, with concomitant systemic lupus erythematosus sometimes reported.⁵

The absence of clinical and histological epidermal involvement are the most important clues to aid in the diagnosis. It has been postulated that JLIS could be an early cutaneous manifestation of LET.⁶ The differential diagnosis also may include erythema annulare centrifugum, granuloma annulare, and urticarial vasculitis. Lesions typically respond well to photoprotection, topical corticosteroids, and/or antimalarials. The addition of tacrolimus ointment 0.1% may result in complete regression without recurrence.⁷

Erythema annulare centrifugum is a reactive erythema that classically begins as a pink papule that gradually enlarges to form an annular erythematous plaque with a fine trailing scale that may recur.⁸ The histopathology of erythema annulare centrifugum shares features seen in LET, making the diagnosis difficult; however, secondary changes to the epidermis (eg, spongiosis, hyperkeratosis) may be seen. This condition has been associated with lymphoproliferative malignancies.⁸

Reticular erythematous mucinosis is clinically distinguished from LET, as it presents as reticular, rather than arciform, erythematous macules, papules, or plaques that may be asymptomatic or pruritic.⁹ Histopathology typically shows more superficial mucin deposition than in LET as well as superficial to mid-dermal perivascular and periadnexal lymphocytic infiltrates. Reticular erythematous mucinosis more frequently is reported in women in their 30s and 40s and has been associated with UV exposure and hormonal triggers, such as oral contraceptive medications and pregnancy.⁹

Granuloma annulare typically presents as asymptomatic, erythematous, annular plaques or papules in young women.¹⁰ There are several histologic subtypes that show focal collagen degeneration, inflammation with palisaded or interstitial histiocytes, and mucin deposition, regardless of clinical presentation. Granuloma annulare has been associated with systemic diseases including type 2 diabetes mellitus and thyroid disease. Localized granuloma annulare most commonly presents on the dorsal aspects of the hands or feet.¹⁰

We present a case of LET on the face. Although histologically similar to other dermatoses, LET often lacks epidermal involvement and presents on sun-exposed areas of the body. Jessner lymphocytic infiltration of the skin also should be considered in the differential, as there is an overlap of clinical and histopathological features; JLIS lacks mucin deposits.⁶ This case reinforces the importance of correlating clinical with histopathologic findings. Our patient was treated with tacrolimus ointment 0.1%, and the plaque eventually resolved in 2 to 3 months without recurrence. This condition should be included in the differential diagnosis of recurring annular plaques on sunexposed areas, particularly in middle-aged adults, even in the absence of systemic involvement.

Primary cutaneous marginal zone lymphoma (PCMZL) is a form of cutaneous lymphoma that typically remains indolent and is limited to the skin. Recurrences may occur. Rarely, lymph nodes, the gastrointestinal system, lung, bone and bone marrow may be involved as extracutaneous sites.

Primary cutaneous B-cell lymphomas account for approximately 25% of all cutaneous lymphomas. Clinically, patients present with either solitary or multiple papules or plaques, typically on the upper extremities or trunk.

Histopathology is vital for the correct diagnosis. In this patient, the histologic report was written as follows: “The findings are those of a well-differentiated but atypical diffuse mixed small lymphocytic infiltrate representing a mixture of T-cells and B-cells. The minor component of the infiltrate is of T-cell lineage, whereby the cells do not show any phenotypic abnormalities. The background cell population is interpreted as reactive. However, the dominant cell population is in fact of B-cell lineage. It is extensively highlighted by CD20. Only a minor component of the B cell infiltrate appeared to be in the context of representing germinal centers as characterized by small foci of centrocytic and centroblastic infiltration highlighted by BCL6 and CD10. The overwhelming B-cell component is a non–germinal center small B cell that does demonstrate BCL2 positivity and significant immunoreactivity for CD23. This small lymphocytic infiltrate obscures the germinal centers. There are only a few plasma cells; they do not show light chain restriction.”

The pathologist remarked that “this type of morphology of a diffuse small B-cell lymphocytic infiltrate that is without any evidence of light chain restriction amidst plasma cells, whereby the B cell component is dominant over the T-cell component would in fact be consistent with a unique variant of marginal zone lymphoma derived from a naive mantle zone.”

PCMZL has an excellent prognosis. When limited to the skin, local radiation or excision are effective treatments. Intravenous rituximab has been used to treat multifocal PCMZL. This patient was found to have no extracutaneous involvement and was treated with radiation.

This case and photo were submitted by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

Virmani P et al. JAAD Case Rep. 2017 Jun 14;3(4):269-72.

Magro CM and Olson LC. Ann Diagn Pathol. 2018 Jun;34:116-21.

Primary cutaneous marginal zone lymphoma (PCMZL) is a form of cutaneous lymphoma that typically remains indolent and is limited to the skin. Recurrences may occur. Rarely, lymph nodes, the gastrointestinal system, lung, bone and bone marrow may be involved as extracutaneous sites.

Primary cutaneous B-cell lymphomas account for approximately 25% of all cutaneous lymphomas. Clinically, patients present with either solitary or multiple papules or plaques, typically on the upper extremities or trunk.

Histopathology is vital for the correct diagnosis. In this patient, the histologic report was written as follows: “The findings are those of a well-differentiated but atypical diffuse mixed small lymphocytic infiltrate representing a mixture of T-cells and B-cells. The minor component of the infiltrate is of T-cell lineage, whereby the cells do not show any phenotypic abnormalities. The background cell population is interpreted as reactive. However, the dominant cell population is in fact of B-cell lineage. It is extensively highlighted by CD20. Only a minor component of the B cell infiltrate appeared to be in the context of representing germinal centers as characterized by small foci of centrocytic and centroblastic infiltration highlighted by BCL6 and CD10. The overwhelming B-cell component is a non–germinal center small B cell that does demonstrate BCL2 positivity and significant immunoreactivity for CD23. This small lymphocytic infiltrate obscures the germinal centers. There are only a few plasma cells; they do not show light chain restriction.”

The pathologist remarked that “this type of morphology of a diffuse small B-cell lymphocytic infiltrate that is without any evidence of light chain restriction amidst plasma cells, whereby the B cell component is dominant over the T-cell component would in fact be consistent with a unique variant of marginal zone lymphoma derived from a naive mantle zone.”

PCMZL has an excellent prognosis. When limited to the skin, local radiation or excision are effective treatments. Intravenous rituximab has been used to treat multifocal PCMZL. This patient was found to have no extracutaneous involvement and was treated with radiation.

This case and photo were submitted by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

Virmani P et al. JAAD Case Rep. 2017 Jun 14;3(4):269-72.

Magro CM and Olson LC. Ann Diagn Pathol. 2018 Jun;34:116-21.

Primary cutaneous marginal zone lymphoma (PCMZL) is a form of cutaneous lymphoma that typically remains indolent and is limited to the skin. Recurrences may occur. Rarely, lymph nodes, the gastrointestinal system, lung, bone and bone marrow may be involved as extracutaneous sites.

Primary cutaneous B-cell lymphomas account for approximately 25% of all cutaneous lymphomas. Clinically, patients present with either solitary or multiple papules or plaques, typically on the upper extremities or trunk.

Histopathology is vital for the correct diagnosis. In this patient, the histologic report was written as follows: “The findings are those of a well-differentiated but atypical diffuse mixed small lymphocytic infiltrate representing a mixture of T-cells and B-cells. The minor component of the infiltrate is of T-cell lineage, whereby the cells do not show any phenotypic abnormalities. The background cell population is interpreted as reactive. However, the dominant cell population is in fact of B-cell lineage. It is extensively highlighted by CD20. Only a minor component of the B cell infiltrate appeared to be in the context of representing germinal centers as characterized by small foci of centrocytic and centroblastic infiltration highlighted by BCL6 and CD10. The overwhelming B-cell component is a non–germinal center small B cell that does demonstrate BCL2 positivity and significant immunoreactivity for CD23. This small lymphocytic infiltrate obscures the germinal centers. There are only a few plasma cells; they do not show light chain restriction.”

The pathologist remarked that “this type of morphology of a diffuse small B-cell lymphocytic infiltrate that is without any evidence of light chain restriction amidst plasma cells, whereby the B cell component is dominant over the T-cell component would in fact be consistent with a unique variant of marginal zone lymphoma derived from a naive mantle zone.”

PCMZL has an excellent prognosis. When limited to the skin, local radiation or excision are effective treatments. Intravenous rituximab has been used to treat multifocal PCMZL. This patient was found to have no extracutaneous involvement and was treated with radiation.

This case and photo were submitted by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

Virmani P et al. JAAD Case Rep. 2017 Jun 14;3(4):269-72.

Magro CM and Olson LC. Ann Diagn Pathol. 2018 Jun;34:116-21.

The Diagnosis: Calciphylaxis

Histopathology revealed epidermal and dermal necrosis, a perivascular neutrophilic infiltrate, and scattered microcalcifications within small- and medium-sized subcutaneous vessels, consistent with a diagnosis of calciphylaxis (Figure). Calciphylaxis (also known as calcific uremic arteriolopathy) is a rare, severe, and often fatal vasculopathy that predominately occurs in patients with end-stage renal failure.¹ The pathogenesis of calciphylaxis remains poorly understood; however, it generally is thought that an imbalance in calcium homeostasis in susceptible hosts results in the precipitation of calcium phosphate within vessel walls leading to endothelial damage with subsequent thrombotic vasculopathy and ischemic tissue damage. Acquired and congenital hypercoagulable states have been implicated in the pathogenesis of calciphylaxis.²

Treatment of calciphylaxis is directed at normalizing abnormal calcium metabolism; removing possible exacerbating agents, such as warfarin, systemic corticosteroids, calcium, and iron; and transitioning patients with end-stage renal disease to hemodialysis, if not already initiated. The treatment approach is multifaceted, and numerous therapies usually are attempted simultaneously. Vitamin K supplementation, low-calcium dialysate, non–calcium carbonate phosphate binders, cinacalcet, becaplermin, bisphosphonates, hyperbaric oxygen, and intravenous sodium thiosulfate all have been utilized with some success. Currently, intravenous sodium thiosulfate is the mainstay therapy for the treatment of calciphylaxis.² Although the mechanism of sodium thiosulfate is not entirely understood, it is known to have anticalcification, vasodilatory, and antioxidant properties.

Retiform purpura clinically is characterized by reticulated, branching, purpuric skin lesions. It occurs following vascular insult by way of vessel lumen occlusion (thrombotic vasculopathy) and less frequently by vessel wall inflammation (vasculitis). The differential diagnosis for retiform purpura includes various causes of microvascular occlusion, including hypercoagulable states and type I cryoglobulinemia, calciphylaxis, infections, autoimmune vasculitic conditions, and embolic causes.³

Cutaneous disease in individuals with antiphospholipid antibodies may present similarly with retiform purpura in the form of necrotizing livedo reticularis, leg ulcers, or widespread cutaneous necrosis. Histopathologic findings include vascular thrombi with partial or complete obstruction of the small- to medium-sized arteries at the dermoepidermal junction, often in the absence of an inflammatory infiltrate.⁴ True vasculitis is not typical of antiphospholipid syndrome.

Medium vessel vasculitides, such as polyarteritis nodosa, clinically present with livedo reticularis, subcutaneous nodules, and tissue necrosis. Dermatopathologic evaluation of a medium-sized vessel vasculitis would demonstrate a neutrophilic vasculitis involving vessels within the deep dermis and septa of subcutaneous fat.⁵ Tissue sampling should be deep and wide enough to visualize the pathology, as shallow biopsies may show intraluminal thrombi of the superficial dermal plexus only, while a narrow specimen may result in falsenegative findings due to the focal nature of vessel involvement in conditions such as polyarteritis nodosa.

Type I cryoglobulinemia often is a manifestation of plasma cell dyscrasia and commonly presents with Raynaud phenomenon, livedo reticularis, and acrocyanosis of helices⁶ ; pathology demonstrates vessel occlusion and erythrocyte extravasation. In contrast, types II and III, also known as mixed cryoglobulinemia, are associated with hepatitis C and autoimmune connective tissue disease. They clinically present as purpuric plaques and nodules that have a propensity to vesiculate and ulcerate.⁷ Histopathologically, features of leukocytoclastic vasculitis are seen, and direct immunofluorescence demonstrates perivascular granular deposits consisting predominantly of IgM and C3 in the papillary dermis.⁸

Warfarin therapy, particularly in high initial doses, can induce lesions of cutaneous necrosis, which clinically may resemble the appearance of calciphylaxis. Warfarininduced skin necrosis typically occurs 3 to 5 days after the initiation of therapy and is the result of a temporary prothrombotic state.9 The half-life of antithrombotic protein C is shorter than vitamin K–dependent prothrombotic factors II, X, and IX. Early in warfarin treatment, an acquired state of reduced protein C level exists, which can lead to vessel thrombosis and subsequent cutaneous necrosis. Treatment of warfarin-induced skin necrosis involves cessation of warfarin, supplementation with vitamin K to reverse the effects of warfarin, and the initiation of heparin or low-molecular-weight heparin.⁹

The Diagnosis: Calciphylaxis

Histopathology revealed epidermal and dermal necrosis, a perivascular neutrophilic infiltrate, and scattered microcalcifications within small- and medium-sized subcutaneous vessels, consistent with a diagnosis of calciphylaxis (Figure). Calciphylaxis (also known as calcific uremic arteriolopathy) is a rare, severe, and often fatal vasculopathy that predominately occurs in patients with end-stage renal failure.¹ The pathogenesis of calciphylaxis remains poorly understood; however, it generally is thought that an imbalance in calcium homeostasis in susceptible hosts results in the precipitation of calcium phosphate within vessel walls leading to endothelial damage with subsequent thrombotic vasculopathy and ischemic tissue damage. Acquired and congenital hypercoagulable states have been implicated in the pathogenesis of calciphylaxis.²

Treatment of calciphylaxis is directed at normalizing abnormal calcium metabolism; removing possible exacerbating agents, such as warfarin, systemic corticosteroids, calcium, and iron; and transitioning patients with end-stage renal disease to hemodialysis, if not already initiated. The treatment approach is multifaceted, and numerous therapies usually are attempted simultaneously. Vitamin K supplementation, low-calcium dialysate, non–calcium carbonate phosphate binders, cinacalcet, becaplermin, bisphosphonates, hyperbaric oxygen, and intravenous sodium thiosulfate all have been utilized with some success. Currently, intravenous sodium thiosulfate is the mainstay therapy for the treatment of calciphylaxis.² Although the mechanism of sodium thiosulfate is not entirely understood, it is known to have anticalcification, vasodilatory, and antioxidant properties.

Retiform purpura clinically is characterized by reticulated, branching, purpuric skin lesions. It occurs following vascular insult by way of vessel lumen occlusion (thrombotic vasculopathy) and less frequently by vessel wall inflammation (vasculitis). The differential diagnosis for retiform purpura includes various causes of microvascular occlusion, including hypercoagulable states and type I cryoglobulinemia, calciphylaxis, infections, autoimmune vasculitic conditions, and embolic causes.³

Cutaneous disease in individuals with antiphospholipid antibodies may present similarly with retiform purpura in the form of necrotizing livedo reticularis, leg ulcers, or widespread cutaneous necrosis. Histopathologic findings include vascular thrombi with partial or complete obstruction of the small- to medium-sized arteries at the dermoepidermal junction, often in the absence of an inflammatory infiltrate.⁴ True vasculitis is not typical of antiphospholipid syndrome.

Medium vessel vasculitides, such as polyarteritis nodosa, clinically present with livedo reticularis, subcutaneous nodules, and tissue necrosis. Dermatopathologic evaluation of a medium-sized vessel vasculitis would demonstrate a neutrophilic vasculitis involving vessels within the deep dermis and septa of subcutaneous fat.⁵ Tissue sampling should be deep and wide enough to visualize the pathology, as shallow biopsies may show intraluminal thrombi of the superficial dermal plexus only, while a narrow specimen may result in falsenegative findings due to the focal nature of vessel involvement in conditions such as polyarteritis nodosa.

Type I cryoglobulinemia often is a manifestation of plasma cell dyscrasia and commonly presents with Raynaud phenomenon, livedo reticularis, and acrocyanosis of helices⁶ ; pathology demonstrates vessel occlusion and erythrocyte extravasation. In contrast, types II and III, also known as mixed cryoglobulinemia, are associated with hepatitis C and autoimmune connective tissue disease. They clinically present as purpuric plaques and nodules that have a propensity to vesiculate and ulcerate.⁷ Histopathologically, features of leukocytoclastic vasculitis are seen, and direct immunofluorescence demonstrates perivascular granular deposits consisting predominantly of IgM and C3 in the papillary dermis.⁸

Warfarin therapy, particularly in high initial doses, can induce lesions of cutaneous necrosis, which clinically may resemble the appearance of calciphylaxis. Warfarininduced skin necrosis typically occurs 3 to 5 days after the initiation of therapy and is the result of a temporary prothrombotic state.9 The half-life of antithrombotic protein C is shorter than vitamin K–dependent prothrombotic factors II, X, and IX. Early in warfarin treatment, an acquired state of reduced protein C level exists, which can lead to vessel thrombosis and subsequent cutaneous necrosis. Treatment of warfarin-induced skin necrosis involves cessation of warfarin, supplementation with vitamin K to reverse the effects of warfarin, and the initiation of heparin or low-molecular-weight heparin.⁹

The Diagnosis: Calciphylaxis

Histopathology revealed epidermal and dermal necrosis, a perivascular neutrophilic infiltrate, and scattered microcalcifications within small- and medium-sized subcutaneous vessels, consistent with a diagnosis of calciphylaxis (Figure). Calciphylaxis (also known as calcific uremic arteriolopathy) is a rare, severe, and often fatal vasculopathy that predominately occurs in patients with end-stage renal failure.¹ The pathogenesis of calciphylaxis remains poorly understood; however, it generally is thought that an imbalance in calcium homeostasis in susceptible hosts results in the precipitation of calcium phosphate within vessel walls leading to endothelial damage with subsequent thrombotic vasculopathy and ischemic tissue damage. Acquired and congenital hypercoagulable states have been implicated in the pathogenesis of calciphylaxis.²

Treatment of calciphylaxis is directed at normalizing abnormal calcium metabolism; removing possible exacerbating agents, such as warfarin, systemic corticosteroids, calcium, and iron; and transitioning patients with end-stage renal disease to hemodialysis, if not already initiated. The treatment approach is multifaceted, and numerous therapies usually are attempted simultaneously. Vitamin K supplementation, low-calcium dialysate, non–calcium carbonate phosphate binders, cinacalcet, becaplermin, bisphosphonates, hyperbaric oxygen, and intravenous sodium thiosulfate all have been utilized with some success. Currently, intravenous sodium thiosulfate is the mainstay therapy for the treatment of calciphylaxis.² Although the mechanism of sodium thiosulfate is not entirely understood, it is known to have anticalcification, vasodilatory, and antioxidant properties.

Retiform purpura clinically is characterized by reticulated, branching, purpuric skin lesions. It occurs following vascular insult by way of vessel lumen occlusion (thrombotic vasculopathy) and less frequently by vessel wall inflammation (vasculitis). The differential diagnosis for retiform purpura includes various causes of microvascular occlusion, including hypercoagulable states and type I cryoglobulinemia, calciphylaxis, infections, autoimmune vasculitic conditions, and embolic causes.³

Cutaneous disease in individuals with antiphospholipid antibodies may present similarly with retiform purpura in the form of necrotizing livedo reticularis, leg ulcers, or widespread cutaneous necrosis. Histopathologic findings include vascular thrombi with partial or complete obstruction of the small- to medium-sized arteries at the dermoepidermal junction, often in the absence of an inflammatory infiltrate.⁴ True vasculitis is not typical of antiphospholipid syndrome.

Medium vessel vasculitides, such as polyarteritis nodosa, clinically present with livedo reticularis, subcutaneous nodules, and tissue necrosis. Dermatopathologic evaluation of a medium-sized vessel vasculitis would demonstrate a neutrophilic vasculitis involving vessels within the deep dermis and septa of subcutaneous fat.⁵ Tissue sampling should be deep and wide enough to visualize the pathology, as shallow biopsies may show intraluminal thrombi of the superficial dermal plexus only, while a narrow specimen may result in falsenegative findings due to the focal nature of vessel involvement in conditions such as polyarteritis nodosa.

Type I cryoglobulinemia often is a manifestation of plasma cell dyscrasia and commonly presents with Raynaud phenomenon, livedo reticularis, and acrocyanosis of helices⁶ ; pathology demonstrates vessel occlusion and erythrocyte extravasation. In contrast, types II and III, also known as mixed cryoglobulinemia, are associated with hepatitis C and autoimmune connective tissue disease. They clinically present as purpuric plaques and nodules that have a propensity to vesiculate and ulcerate.⁷ Histopathologically, features of leukocytoclastic vasculitis are seen, and direct immunofluorescence demonstrates perivascular granular deposits consisting predominantly of IgM and C3 in the papillary dermis.⁸

Warfarin therapy, particularly in high initial doses, can induce lesions of cutaneous necrosis, which clinically may resemble the appearance of calciphylaxis. Warfarininduced skin necrosis typically occurs 3 to 5 days after the initiation of therapy and is the result of a temporary prothrombotic state.9 The half-life of antithrombotic protein C is shorter than vitamin K–dependent prothrombotic factors II, X, and IX. Early in warfarin treatment, an acquired state of reduced protein C level exists, which can lead to vessel thrombosis and subsequent cutaneous necrosis. Treatment of warfarin-induced skin necrosis involves cessation of warfarin, supplementation with vitamin K to reverse the effects of warfarin, and the initiation of heparin or low-molecular-weight heparin.⁹