Photo Challenge

The Diagnosis: Dermal Cylindroma

Microsopic evaluation of a tangential biopsy revealed findings of a dermal process consisting of well-circumscribed islands of pale and darker blue cells with little cytoplasm outlined by a hyaline basement membrane (Figure). These cellular islands were arranged in a jigsawlike configuration. These findings were thought to be consistent with a diagnosis of cylindroma.

Well-circumscribed dermal islands of both pale and darker blue cells outlined by a hyaline basement membrane. These cellular islands were arranged in a jigsawlike configuration (A and B)(both H&E, original magnifications ×20 and ×200).

Cylindromas are benign appendageal neoplasms with a somewhat controversial histogenesis. Munger and colleagues¹ investigated the pattern of acid mucopolysaccharide secretion by these tumors in association with prosecretory vacuoles in proximity to the Golgi apparatus, which led to their impression that cylindromas most resemble eccrine rather than apocrine sweat glands. Other researchers, however, have concluded that cylindromas are of apocrine derivation.²

Clinically, cylindromas appear most often in 2 settings: isolated or as a manifestation of one of several inherited familial syndromes. One such syndrome is familial cylindromatosis, a rare autosomal-dominant disorder in which affected individuals develop multiple cylindromas, usually on the head and neck. The merging of multiple lesions gives rise to the often-employed term turban tumor.³ This syndrome has been linked to mutations in the cylindromatosis gene, CYLD.⁴ Brooke-Spiegler syndrome also has been associated with the development of multiple cylindromas. Similar to familial cylindromatosis, it is inherited in an autosomal-dominant fashion. Brooke-Spiegler syndrome is typified by the appearance of multiple cylindromas, trichoepitheliomas, and less commonly spiradenomas. Mutations in the CYLD gene also have been linked to Brooke-Spiegler syndrome in some cases.⁵

Although considered a benign entity, in rare cases cylindromas have shown evidence of malignant transformation to cylindrocarcinoma. This more aggressive tumor may occur in the setting of isolated cylindromas or more commonly in individuals with numerous lesions, as with both familial cylindromatosis and Brooke-Spiegler syndrome. These lesions may appear to grow rapidly, ulcerate, or bleed, traits that are not associated with their benign counterparts.

Diagnosis of cylindromas rests on histopathologic confirmation, which demonstrates well-defined dermal islands of epithelial cells comprised of dark- and pale-staining nuclei. These tumor islands are surrounded by a hyaline basement membrane and often take on the appearance of a jigsaw puzzle. Cylindrocarcinomas exhibit greater cellular pleomorphism and higher mitotic rates.

Dermal cylindromas require no further treatment but can be electively excised, while treatment of cylindrocarcinoma with excision is curative.⁶ Definitive excision was offered to our patient, but she declined treatment.

The Diagnosis: Dermal Cylindroma

Microsopic evaluation of a tangential biopsy revealed findings of a dermal process consisting of well-circumscribed islands of pale and darker blue cells with little cytoplasm outlined by a hyaline basement membrane (Figure). These cellular islands were arranged in a jigsawlike configuration. These findings were thought to be consistent with a diagnosis of cylindroma.

Well-circumscribed dermal islands of both pale and darker blue cells outlined by a hyaline basement membrane. These cellular islands were arranged in a jigsawlike configuration (A and B)(both H&E, original magnifications ×20 and ×200).

Cylindromas are benign appendageal neoplasms with a somewhat controversial histogenesis. Munger and colleagues¹ investigated the pattern of acid mucopolysaccharide secretion by these tumors in association with prosecretory vacuoles in proximity to the Golgi apparatus, which led to their impression that cylindromas most resemble eccrine rather than apocrine sweat glands. Other researchers, however, have concluded that cylindromas are of apocrine derivation.²

Clinically, cylindromas appear most often in 2 settings: isolated or as a manifestation of one of several inherited familial syndromes. One such syndrome is familial cylindromatosis, a rare autosomal-dominant disorder in which affected individuals develop multiple cylindromas, usually on the head and neck. The merging of multiple lesions gives rise to the often-employed term turban tumor.³ This syndrome has been linked to mutations in the cylindromatosis gene, CYLD.⁴ Brooke-Spiegler syndrome also has been associated with the development of multiple cylindromas. Similar to familial cylindromatosis, it is inherited in an autosomal-dominant fashion. Brooke-Spiegler syndrome is typified by the appearance of multiple cylindromas, trichoepitheliomas, and less commonly spiradenomas. Mutations in the CYLD gene also have been linked to Brooke-Spiegler syndrome in some cases.⁵

Although considered a benign entity, in rare cases cylindromas have shown evidence of malignant transformation to cylindrocarcinoma. This more aggressive tumor may occur in the setting of isolated cylindromas or more commonly in individuals with numerous lesions, as with both familial cylindromatosis and Brooke-Spiegler syndrome. These lesions may appear to grow rapidly, ulcerate, or bleed, traits that are not associated with their benign counterparts.

Diagnosis of cylindromas rests on histopathologic confirmation, which demonstrates well-defined dermal islands of epithelial cells comprised of dark- and pale-staining nuclei. These tumor islands are surrounded by a hyaline basement membrane and often take on the appearance of a jigsaw puzzle. Cylindrocarcinomas exhibit greater cellular pleomorphism and higher mitotic rates.

Dermal cylindromas require no further treatment but can be electively excised, while treatment of cylindrocarcinoma with excision is curative.⁶ Definitive excision was offered to our patient, but she declined treatment.

The Diagnosis: Dermal Cylindroma

Microsopic evaluation of a tangential biopsy revealed findings of a dermal process consisting of well-circumscribed islands of pale and darker blue cells with little cytoplasm outlined by a hyaline basement membrane (Figure). These cellular islands were arranged in a jigsawlike configuration. These findings were thought to be consistent with a diagnosis of cylindroma.

Well-circumscribed dermal islands of both pale and darker blue cells outlined by a hyaline basement membrane. These cellular islands were arranged in a jigsawlike configuration (A and B)(both H&E, original magnifications ×20 and ×200).

Cylindromas are benign appendageal neoplasms with a somewhat controversial histogenesis. Munger and colleagues¹ investigated the pattern of acid mucopolysaccharide secretion by these tumors in association with prosecretory vacuoles in proximity to the Golgi apparatus, which led to their impression that cylindromas most resemble eccrine rather than apocrine sweat glands. Other researchers, however, have concluded that cylindromas are of apocrine derivation.²

Clinically, cylindromas appear most often in 2 settings: isolated or as a manifestation of one of several inherited familial syndromes. One such syndrome is familial cylindromatosis, a rare autosomal-dominant disorder in which affected individuals develop multiple cylindromas, usually on the head and neck. The merging of multiple lesions gives rise to the often-employed term turban tumor.³ This syndrome has been linked to mutations in the cylindromatosis gene, CYLD.⁴ Brooke-Spiegler syndrome also has been associated with the development of multiple cylindromas. Similar to familial cylindromatosis, it is inherited in an autosomal-dominant fashion. Brooke-Spiegler syndrome is typified by the appearance of multiple cylindromas, trichoepitheliomas, and less commonly spiradenomas. Mutations in the CYLD gene also have been linked to Brooke-Spiegler syndrome in some cases.⁵

Although considered a benign entity, in rare cases cylindromas have shown evidence of malignant transformation to cylindrocarcinoma. This more aggressive tumor may occur in the setting of isolated cylindromas or more commonly in individuals with numerous lesions, as with both familial cylindromatosis and Brooke-Spiegler syndrome. These lesions may appear to grow rapidly, ulcerate, or bleed, traits that are not associated with their benign counterparts.

Diagnosis of cylindromas rests on histopathologic confirmation, which demonstrates well-defined dermal islands of epithelial cells comprised of dark- and pale-staining nuclei. These tumor islands are surrounded by a hyaline basement membrane and often take on the appearance of a jigsaw puzzle. Cylindrocarcinomas exhibit greater cellular pleomorphism and higher mitotic rates.

Dermal cylindromas require no further treatment but can be electively excised, while treatment of cylindrocarcinoma with excision is curative.⁶ Definitive excision was offered to our patient, but she declined treatment.

The Diagnosis: Phytophotodermatitis

Phytophotodermatitis (PPD) is a nonimmunologic cutaneous phototoxic inflammatory reaction resulting from the activation of photosensitizing botanical agents such as furanocoumarins in contact with the skin by exposure to UVA light.^1,2 Furanocoumarins, including psoralens and angelicins, become photoexcited and covalently bind to pyrimidine bases on DNA strands, resulting in acute damage to epidermal, dermal, and endothelial cells.^1,3

Vegetation most commonly implicated in this plant solar dermatitis are celery, fennel, parsnip, parsley, and hogweed (Apiaceae [formerly known as the Umbelliferae family]), as well as oranges, lemons, limes, and grapefruits (Rutaceae or citrus family).^1,3 Psoralens found in the Persian lime have been noted to cause phototoxic eruptions in the United States, with the rind containing higher concentrations than the pulp.⁴

Clinical features of PPD include erythema, edema, and vesicle or bullae formation 12 to 36 hours after psoralen and UV light exposure. Burning and pain may be present, but pruritus is not a common characteristic of the eruptions, distinguishing PPD from allergic phytodermatitis.

Hyperpigmentation appears on resolution of the lesions and slowly fades over months to years.^1,3,5 Mild exposure may lead to hyperpigmentation without a vesicular or erythematous eruption.¹ Phytophotodermatitis follows a benign course and often spontaneously resolves; however, prolonged hyperpigmentation may cause concern for these patients.

Phytophotodermatitis is common among patients preparing drinks and foods with citrus juices or after gardening. Our patient had prepared limeade 3 weeks prior to presentation. The distribution of cutaneous exposure to furanocoumarins influences clinical presentation and may range from blotches and streaks to distinct fingerprint smudges and handprints, as seen in our patient. The distinct full handprint on the right arm was striking. The bullous lesions and resulting hyperpigmentation may mimic burns and healing bruises. In children, PPD often is mistaken for child abuse.^1,6,7 In adults, it often is misdiagnosed as poison oak dermatitis, erythema multiforme, and thrombocytopenic purpura.^1,3 It is important to recognize PPD to avoid delay in or misdiagnosis and to better counsel patients on how to avoid recurrent episodes of PPD.

The Diagnosis: Phytophotodermatitis

Phytophotodermatitis (PPD) is a nonimmunologic cutaneous phototoxic inflammatory reaction resulting from the activation of photosensitizing botanical agents such as furanocoumarins in contact with the skin by exposure to UVA light.^1,2 Furanocoumarins, including psoralens and angelicins, become photoexcited and covalently bind to pyrimidine bases on DNA strands, resulting in acute damage to epidermal, dermal, and endothelial cells.^1,3

Vegetation most commonly implicated in this plant solar dermatitis are celery, fennel, parsnip, parsley, and hogweed (Apiaceae [formerly known as the Umbelliferae family]), as well as oranges, lemons, limes, and grapefruits (Rutaceae or citrus family).^1,3 Psoralens found in the Persian lime have been noted to cause phototoxic eruptions in the United States, with the rind containing higher concentrations than the pulp.⁴

Clinical features of PPD include erythema, edema, and vesicle or bullae formation 12 to 36 hours after psoralen and UV light exposure. Burning and pain may be present, but pruritus is not a common characteristic of the eruptions, distinguishing PPD from allergic phytodermatitis.

Hyperpigmentation appears on resolution of the lesions and slowly fades over months to years.^1,3,5 Mild exposure may lead to hyperpigmentation without a vesicular or erythematous eruption.¹ Phytophotodermatitis follows a benign course and often spontaneously resolves; however, prolonged hyperpigmentation may cause concern for these patients.

Phytophotodermatitis is common among patients preparing drinks and foods with citrus juices or after gardening. Our patient had prepared limeade 3 weeks prior to presentation. The distribution of cutaneous exposure to furanocoumarins influences clinical presentation and may range from blotches and streaks to distinct fingerprint smudges and handprints, as seen in our patient. The distinct full handprint on the right arm was striking. The bullous lesions and resulting hyperpigmentation may mimic burns and healing bruises. In children, PPD often is mistaken for child abuse.^1,6,7 In adults, it often is misdiagnosed as poison oak dermatitis, erythema multiforme, and thrombocytopenic purpura.^1,3 It is important to recognize PPD to avoid delay in or misdiagnosis and to better counsel patients on how to avoid recurrent episodes of PPD.

The Diagnosis: Phytophotodermatitis

Phytophotodermatitis (PPD) is a nonimmunologic cutaneous phototoxic inflammatory reaction resulting from the activation of photosensitizing botanical agents such as furanocoumarins in contact with the skin by exposure to UVA light.^1,2 Furanocoumarins, including psoralens and angelicins, become photoexcited and covalently bind to pyrimidine bases on DNA strands, resulting in acute damage to epidermal, dermal, and endothelial cells.^1,3

Vegetation most commonly implicated in this plant solar dermatitis are celery, fennel, parsnip, parsley, and hogweed (Apiaceae [formerly known as the Umbelliferae family]), as well as oranges, lemons, limes, and grapefruits (Rutaceae or citrus family).^1,3 Psoralens found in the Persian lime have been noted to cause phototoxic eruptions in the United States, with the rind containing higher concentrations than the pulp.⁴

Clinical features of PPD include erythema, edema, and vesicle or bullae formation 12 to 36 hours after psoralen and UV light exposure. Burning and pain may be present, but pruritus is not a common characteristic of the eruptions, distinguishing PPD from allergic phytodermatitis.

Hyperpigmentation appears on resolution of the lesions and slowly fades over months to years.^1,3,5 Mild exposure may lead to hyperpigmentation without a vesicular or erythematous eruption.¹ Phytophotodermatitis follows a benign course and often spontaneously resolves; however, prolonged hyperpigmentation may cause concern for these patients.

Phytophotodermatitis is common among patients preparing drinks and foods with citrus juices or after gardening. Our patient had prepared limeade 3 weeks prior to presentation. The distribution of cutaneous exposure to furanocoumarins influences clinical presentation and may range from blotches and streaks to distinct fingerprint smudges and handprints, as seen in our patient. The distinct full handprint on the right arm was striking. The bullous lesions and resulting hyperpigmentation may mimic burns and healing bruises. In children, PPD often is mistaken for child abuse.^1,6,7 In adults, it often is misdiagnosed as poison oak dermatitis, erythema multiforme, and thrombocytopenic purpura.^1,3 It is important to recognize PPD to avoid delay in or misdiagnosis and to better counsel patients on how to avoid recurrent episodes of PPD.

The Diagnosis: Lepromatous Leprosy

Histopathologic examination of a punch biopsy specimen (Figures 1 and 2) disclosed a grenz zone and a diffuse infiltrative process beneath a normal-appearing epidermis. Higher-power examination revealed areas containing macrophages (Virchow cells) with cloudy regions devoid of nuclei (globi). Fite stain demonstrated numerous intracytoplasmic acid-fast bacilli (Figure 3). Laboratory test results for rapid plasma reagin and human immunodeficiency virus were negative, and a complete blood cell count was normal.

On further questioning the patient revealed he was an immigrant from Micronesia, and he described decreased sensation and numbness in the lesions that had been present from onset. Physical examination was consistent with this history and revealed hypoesthesia of the lesions, particularly over the central aspect of the depigmented macules. Based on the clinical examination and histopathologic findings, a diagnosis of lepromatous leprosy was made.

Therapy with rifampin, clofazimine, and dapsone was initiated. Unfortunately, compliance was poor, and at clinic follow-up 10 months later the patient demonstrated formation of new indurated lesions as well as mild eyelid swelling and edema of the hands thought to be consistent with erythema nodosum leprosum. Prednisone was then initiated and the dose of clofazimine was increased from 50 mg daily to 100 mg daily with excellent clinical response.

Mycobacterium leprae is a small, slightly curved rod that is an acid-fast, obligate, intracellular organism. It remains endemic in Brazil and Southeast Asia but may present outside of these areas secondary to immigration.¹

Hallmarks of the disease are anesthetic skin or mucous membrane lesions with thickened peripheral nerves.² It grows best at 27°C to 33°C, thereby affecting cooler areas of the human body such as earlobes, knees, and distal extremities.³ It is most likely spread by aerosolized respiratory droplets and less commonly by direct contact. There have been reports suggesting transmission via armadillos.⁴

Genetic susceptibility influences the development of leprosy, while HLA type influences the immune response and hence the type of leprosy.⁵ Ridley and Jopling⁶ devised a classification system based on the immunologic response to M leprae. Highly reactive hosts with a vigorous cell-mediated response to M leprae develop tuberculoid leprosy and exhibit few skin lesions containing rare organisms. In contrast, anergic hosts develop lepromatous leprosy, characterized by multiple skin lesions, abundant organisms, and diffuse disease. Borderline tuberculoid, borderline, and borderline lepromatous make up the middle of the spectrum.^6-9 Skin lesions can present with poorly defined, hypopigmented macules of indeterminate leprosy on one end and diffuse skin involvement of lepromatous leprosy on the opposite end. Diffuse involvement includes facial skin thickening, classic leonine facies, loss of eyebrows and eyelashes, anesthetic lesions, and anhidrosis.

Erythema nodosum leprosum occurs with chronic infection from M leprae, most commonly lepromatous leprosy. Immune complex deposition results in vasculitis and inflammatory foci. This phenomenon is thought to be secondary to high antigen load released by dying mycobacteria, causing secretion of tumor necrosis factor a from macrophages.¹ Erythema nodosum leprosum demonstrates rapid onset of tender erythematous plaques or nodules, most commonly on the face and extensor surfaces of the extremities, with fever, malaise, iritis, arthralgia, and orchitis. Clofazimine therapy probably decreases the occurence.¹ Treatment includes systemic corticosteroids and/or thalidomide.

The Diagnosis: Lepromatous Leprosy

Histopathologic examination of a punch biopsy specimen (Figures 1 and 2) disclosed a grenz zone and a diffuse infiltrative process beneath a normal-appearing epidermis. Higher-power examination revealed areas containing macrophages (Virchow cells) with cloudy regions devoid of nuclei (globi). Fite stain demonstrated numerous intracytoplasmic acid-fast bacilli (Figure 3). Laboratory test results for rapid plasma reagin and human immunodeficiency virus were negative, and a complete blood cell count was normal.

On further questioning the patient revealed he was an immigrant from Micronesia, and he described decreased sensation and numbness in the lesions that had been present from onset. Physical examination was consistent with this history and revealed hypoesthesia of the lesions, particularly over the central aspect of the depigmented macules. Based on the clinical examination and histopathologic findings, a diagnosis of lepromatous leprosy was made.

Therapy with rifampin, clofazimine, and dapsone was initiated. Unfortunately, compliance was poor, and at clinic follow-up 10 months later the patient demonstrated formation of new indurated lesions as well as mild eyelid swelling and edema of the hands thought to be consistent with erythema nodosum leprosum. Prednisone was then initiated and the dose of clofazimine was increased from 50 mg daily to 100 mg daily with excellent clinical response.

Mycobacterium leprae is a small, slightly curved rod that is an acid-fast, obligate, intracellular organism. It remains endemic in Brazil and Southeast Asia but may present outside of these areas secondary to immigration.¹

Hallmarks of the disease are anesthetic skin or mucous membrane lesions with thickened peripheral nerves.² It grows best at 27°C to 33°C, thereby affecting cooler areas of the human body such as earlobes, knees, and distal extremities.³ It is most likely spread by aerosolized respiratory droplets and less commonly by direct contact. There have been reports suggesting transmission via armadillos.⁴

Genetic susceptibility influences the development of leprosy, while HLA type influences the immune response and hence the type of leprosy.⁵ Ridley and Jopling⁶ devised a classification system based on the immunologic response to M leprae. Highly reactive hosts with a vigorous cell-mediated response to M leprae develop tuberculoid leprosy and exhibit few skin lesions containing rare organisms. In contrast, anergic hosts develop lepromatous leprosy, characterized by multiple skin lesions, abundant organisms, and diffuse disease. Borderline tuberculoid, borderline, and borderline lepromatous make up the middle of the spectrum.^6-9 Skin lesions can present with poorly defined, hypopigmented macules of indeterminate leprosy on one end and diffuse skin involvement of lepromatous leprosy on the opposite end. Diffuse involvement includes facial skin thickening, classic leonine facies, loss of eyebrows and eyelashes, anesthetic lesions, and anhidrosis.

Erythema nodosum leprosum occurs with chronic infection from M leprae, most commonly lepromatous leprosy. Immune complex deposition results in vasculitis and inflammatory foci. This phenomenon is thought to be secondary to high antigen load released by dying mycobacteria, causing secretion of tumor necrosis factor a from macrophages.¹ Erythema nodosum leprosum demonstrates rapid onset of tender erythematous plaques or nodules, most commonly on the face and extensor surfaces of the extremities, with fever, malaise, iritis, arthralgia, and orchitis. Clofazimine therapy probably decreases the occurence.¹ Treatment includes systemic corticosteroids and/or thalidomide.

The Diagnosis: Lepromatous Leprosy

Histopathologic examination of a punch biopsy specimen (Figures 1 and 2) disclosed a grenz zone and a diffuse infiltrative process beneath a normal-appearing epidermis. Higher-power examination revealed areas containing macrophages (Virchow cells) with cloudy regions devoid of nuclei (globi). Fite stain demonstrated numerous intracytoplasmic acid-fast bacilli (Figure 3). Laboratory test results for rapid plasma reagin and human immunodeficiency virus were negative, and a complete blood cell count was normal.

On further questioning the patient revealed he was an immigrant from Micronesia, and he described decreased sensation and numbness in the lesions that had been present from onset. Physical examination was consistent with this history and revealed hypoesthesia of the lesions, particularly over the central aspect of the depigmented macules. Based on the clinical examination and histopathologic findings, a diagnosis of lepromatous leprosy was made.

Therapy with rifampin, clofazimine, and dapsone was initiated. Unfortunately, compliance was poor, and at clinic follow-up 10 months later the patient demonstrated formation of new indurated lesions as well as mild eyelid swelling and edema of the hands thought to be consistent with erythema nodosum leprosum. Prednisone was then initiated and the dose of clofazimine was increased from 50 mg daily to 100 mg daily with excellent clinical response.

Mycobacterium leprae is a small, slightly curved rod that is an acid-fast, obligate, intracellular organism. It remains endemic in Brazil and Southeast Asia but may present outside of these areas secondary to immigration.¹

Hallmarks of the disease are anesthetic skin or mucous membrane lesions with thickened peripheral nerves.² It grows best at 27°C to 33°C, thereby affecting cooler areas of the human body such as earlobes, knees, and distal extremities.³ It is most likely spread by aerosolized respiratory droplets and less commonly by direct contact. There have been reports suggesting transmission via armadillos.⁴

Genetic susceptibility influences the development of leprosy, while HLA type influences the immune response and hence the type of leprosy.⁵ Ridley and Jopling⁶ devised a classification system based on the immunologic response to M leprae. Highly reactive hosts with a vigorous cell-mediated response to M leprae develop tuberculoid leprosy and exhibit few skin lesions containing rare organisms. In contrast, anergic hosts develop lepromatous leprosy, characterized by multiple skin lesions, abundant organisms, and diffuse disease. Borderline tuberculoid, borderline, and borderline lepromatous make up the middle of the spectrum.^6-9 Skin lesions can present with poorly defined, hypopigmented macules of indeterminate leprosy on one end and diffuse skin involvement of lepromatous leprosy on the opposite end. Diffuse involvement includes facial skin thickening, classic leonine facies, loss of eyebrows and eyelashes, anesthetic lesions, and anhidrosis.

Erythema nodosum leprosum occurs with chronic infection from M leprae, most commonly lepromatous leprosy. Immune complex deposition results in vasculitis and inflammatory foci. This phenomenon is thought to be secondary to high antigen load released by dying mycobacteria, causing secretion of tumor necrosis factor a from macrophages.¹ Erythema nodosum leprosum demonstrates rapid onset of tender erythematous plaques or nodules, most commonly on the face and extensor surfaces of the extremities, with fever, malaise, iritis, arthralgia, and orchitis. Clofazimine therapy probably decreases the occurence.¹ Treatment includes systemic corticosteroids and/or thalidomide.

The Diagnosis: Myeloid Leukemia Cutis

Leukemia cutis represents the infiltration of leukemic cells into the skin. It has been described in the setting of both myeloid and lymphoid leukemia. In the setting of acute myeloid leukemia, it has been reported to occur in 2% to 13% of patients overall,^1,2 but it may occur in 31% of patients with the acute myelomonocytic or acute monocytic leukemia subtypes.³ Leukemia cutis is less common, with chronic myeloid leukemia occurring in 2.7% of patients in one study.⁴ In another study, 65% of patients with myeloid leukemia cutis had an acute myeloid leukemia.⁵

Myeloid leukemia cutis has been reported in patients aged 22 days to 90 years, with a median age of 62 years. There is a male predominance (1.4:1 ratio).^5,6 The diagnosis of leukemia cutis is made concurrently with the diagnosis of leukemia in approximately 30% of cases, subsequent to the diagnosis of leukemia in approximately 60% of cases, and prior to the diagnosis of leukemia in approximately 10% of cases.⁵

Clinically, myeloid leukemia cutis presents as an asymptomatic solitary lesion in 23% of cases or as multiple lesions in 77% of cases. Lesions consist of pink to red to violaceous papules, nodules, and macules that are occasionally purpuric and involve any cutaneous surface.⁵

Histologically, the epidermis is unremarkable. Beneath a grenz zone within the dermis and usually extending into the subcutis there is a diffuse or nodular proliferation of neoplastic cells, often with perivascular and periadnexal accentuation and sometimes single filing of cells between collagen bundles (Figure 1). The cells are immature myeloid cells with irregular nuclear contours that may be indented or reniform (Figure 2). Nuclei contain finely dispersed chromatin with variably prominent nucleoli.^5,6 Immunohistochemically, CD68 is positive in approximately 97% of cases, myeloperoxidase in 62%, and lysozyme in 85%. CD168, CD14, CD4, CD33, CD117, CD34, CD56, CD123, and CD303 are variably positive. CD3 and CD20, markers of lymphoid leukemia, are negative.^5-8

Leukemia cutis in the setting of a myeloid leukemia portends a grave prognosis. In a series of 18 patients, 16 had additional extramedullary leukemia, including meningeal leukemia in 6 patients.² Most patients with myeloid leukemia cutis die within an average of 1 to 8 months of diagnosis.⁹

The Diagnosis: Myeloid Leukemia Cutis

Leukemia cutis represents the infiltration of leukemic cells into the skin. It has been described in the setting of both myeloid and lymphoid leukemia. In the setting of acute myeloid leukemia, it has been reported to occur in 2% to 13% of patients overall,^1,2 but it may occur in 31% of patients with the acute myelomonocytic or acute monocytic leukemia subtypes.³ Leukemia cutis is less common, with chronic myeloid leukemia occurring in 2.7% of patients in one study.⁴ In another study, 65% of patients with myeloid leukemia cutis had an acute myeloid leukemia.⁵

Myeloid leukemia cutis has been reported in patients aged 22 days to 90 years, with a median age of 62 years. There is a male predominance (1.4:1 ratio).^5,6 The diagnosis of leukemia cutis is made concurrently with the diagnosis of leukemia in approximately 30% of cases, subsequent to the diagnosis of leukemia in approximately 60% of cases, and prior to the diagnosis of leukemia in approximately 10% of cases.⁵

Clinically, myeloid leukemia cutis presents as an asymptomatic solitary lesion in 23% of cases or as multiple lesions in 77% of cases. Lesions consist of pink to red to violaceous papules, nodules, and macules that are occasionally purpuric and involve any cutaneous surface.⁵

Histologically, the epidermis is unremarkable. Beneath a grenz zone within the dermis and usually extending into the subcutis there is a diffuse or nodular proliferation of neoplastic cells, often with perivascular and periadnexal accentuation and sometimes single filing of cells between collagen bundles (Figure 1). The cells are immature myeloid cells with irregular nuclear contours that may be indented or reniform (Figure 2). Nuclei contain finely dispersed chromatin with variably prominent nucleoli.^5,6 Immunohistochemically, CD68 is positive in approximately 97% of cases, myeloperoxidase in 62%, and lysozyme in 85%. CD168, CD14, CD4, CD33, CD117, CD34, CD56, CD123, and CD303 are variably positive. CD3 and CD20, markers of lymphoid leukemia, are negative.^5-8

Leukemia cutis in the setting of a myeloid leukemia portends a grave prognosis. In a series of 18 patients, 16 had additional extramedullary leukemia, including meningeal leukemia in 6 patients.² Most patients with myeloid leukemia cutis die within an average of 1 to 8 months of diagnosis.⁹

The Diagnosis: Myeloid Leukemia Cutis

Leukemia cutis represents the infiltration of leukemic cells into the skin. It has been described in the setting of both myeloid and lymphoid leukemia. In the setting of acute myeloid leukemia, it has been reported to occur in 2% to 13% of patients overall,^1,2 but it may occur in 31% of patients with the acute myelomonocytic or acute monocytic leukemia subtypes.³ Leukemia cutis is less common, with chronic myeloid leukemia occurring in 2.7% of patients in one study.⁴ In another study, 65% of patients with myeloid leukemia cutis had an acute myeloid leukemia.⁵

Myeloid leukemia cutis has been reported in patients aged 22 days to 90 years, with a median age of 62 years. There is a male predominance (1.4:1 ratio).^5,6 The diagnosis of leukemia cutis is made concurrently with the diagnosis of leukemia in approximately 30% of cases, subsequent to the diagnosis of leukemia in approximately 60% of cases, and prior to the diagnosis of leukemia in approximately 10% of cases.⁵

Clinically, myeloid leukemia cutis presents as an asymptomatic solitary lesion in 23% of cases or as multiple lesions in 77% of cases. Lesions consist of pink to red to violaceous papules, nodules, and macules that are occasionally purpuric and involve any cutaneous surface.⁵

Histologically, the epidermis is unremarkable. Beneath a grenz zone within the dermis and usually extending into the subcutis there is a diffuse or nodular proliferation of neoplastic cells, often with perivascular and periadnexal accentuation and sometimes single filing of cells between collagen bundles (Figure 1). The cells are immature myeloid cells with irregular nuclear contours that may be indented or reniform (Figure 2). Nuclei contain finely dispersed chromatin with variably prominent nucleoli.^5,6 Immunohistochemically, CD68 is positive in approximately 97% of cases, myeloperoxidase in 62%, and lysozyme in 85%. CD168, CD14, CD4, CD33, CD117, CD34, CD56, CD123, and CD303 are variably positive. CD3 and CD20, markers of lymphoid leukemia, are negative.^5-8

Leukemia cutis in the setting of a myeloid leukemia portends a grave prognosis. In a series of 18 patients, 16 had additional extramedullary leukemia, including meningeal leukemia in 6 patients.² Most patients with myeloid leukemia cutis die within an average of 1 to 8 months of diagnosis.⁹

The Diagnosis: Merkel Cell Carcinoma

Histopathology showed small round cells (Figure 1) that stained positive for cytokeratin 20 in a paranuclear dotlike pattern (Figure 2). The tumor stained negative for lymphoma (CD45) marker. Fluorodeoxyglucose positron emission tomography showed focally increased activity at cutaneous sites corresponding to the nodules, but lymph nodes and visceral sites did not show areas of increased metabolic activity. She underwent an above-knee amputation. She was started on a chemotherapy regimen of etoposide and carboplatin given that the pathology of the excised limb demonstrated vascular and lymphatic invasion by the tumor cells in the proximal skin margin. After 4 months she presented with gangrenous changes of the amputated limb and evidence of metastasis to the region of the skin flap. Similar tumors presented on the ipsilateral hip. Given her general poor condition and aggressive nature of the tumor, the patient decided to pursue hospice care 6 months after her diagnosis of Merkel cell carcinoma (MCC).

Figure 1. The tumor was composed of sheets of cells with a high nuclear-cytoplasmic ratio and fine chromatin without nucleoli (H&E, original magnification ×40).

Figure 2. Immunohistochemical staining for cytokera-tin 20 showed positivity in a paranuclear dotlike pattern (original magnification ×40).

Merkel cell carcinoma usually presents as firm, red to purple papules on sun-exposed skin in older patients with light skin. Factors strongly associated with the development of MCC are age (>65 years), lighter skin types, history of extensive sun exposure, and chronic immune suppression (eg, kidney or heart transplantation, human immunodeficiency virus).¹ The rate of MCC has increased 3-fold between 1986 and 2001; the rate of MCC was 0.15 cases per 100,000 individuals in 1986, climbing up to 0.44 cases per 100,000 individuals in 2001.² Our patient had been on immunosuppressants—prednisone, cyclosporine, and sirolimus—for nearly a decade following kidney transplants, which had been discontinued 2 years prior to presentation.

Heath et al³ defined an acronym AEIOU (asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years, UV-exposed site on a person with fair skin) for MCC features derived from 195 patients. They advised that a biopsy is warranted if the patient presents with more than 3 of these features.³

The 1991 MCC staging system was revised in 1999 and 2005 based on experience at Memorial Sloan Kettering Cancer Center (New York, New York).⁴ In 2010 the American Joint Committee on Cancer staging was introduced for MCC, which follows other skin malignancies.⁵ Using this TNM staging system for primary tumors, regional lymph nodes, and distant metastasis, our patient at the time of presentation was stage IIB (T3N0M0), with tumor size greater than 5 cm, nodes negative by clinical examination, and no distant metastasis. In a span of 3 months, she had metastasis to the skin, subcutaneous tissue, and distant lymph nodes, which resulted in classification as stage IV, proving the aggressive nature of the tumor.

The newly discovered Merkel cell polyomavirus (MCPyV) is found integrating into the Merkel cell genome. Merkel cell polyomavirus is present in 80% of cancers and is expressed in a clonal pattern, while 90% of MCC patients are seropositive for the same. Unlike antibodies to MCPyV VP1 protein, antibodies to the T antigen for MCPyV track disease burden and may be a useful biomarker for MCC in the future.⁶

A study of 251 patients in 1970-2002 showed that pathologic nodal staging identifies a group of patients with excellent long-term survival.¹ Our patient preferred to undergo positron emission tomography rather than a sentinel lymph node biopsy prior to surgery. Also, after margin-negative excision and pathologic nodal staging, local and nodal recurrence rates were low. Adjuvant chemotherapy for stage III patients showed a trend (P=.08) to decreased survival compared with stage II patients who did not receive chemotherapy.⁷ A multidisciplinary approach to treatment including surgery, radiation,⁸ and chemotherapy needs to be created for each individual patient. Merkel cell carcinoma is the cause of death in 35% of patients within 3 years of diagnosis.⁹

Merkel cell carcinoma is a rare orphan tumor with rapidly increasing incidence in an era of immunosuppression. It has a grave prognosis, as demonstrated in our case, if not detected early. People at increased risk for MCC must have regular skin checks. Unfortunately, our patient was a nursing home resident and had not had a skin check for 2 years prior to presentation.

The Diagnosis: Merkel Cell Carcinoma

Histopathology showed small round cells (Figure 1) that stained positive for cytokeratin 20 in a paranuclear dotlike pattern (Figure 2). The tumor stained negative for lymphoma (CD45) marker. Fluorodeoxyglucose positron emission tomography showed focally increased activity at cutaneous sites corresponding to the nodules, but lymph nodes and visceral sites did not show areas of increased metabolic activity. She underwent an above-knee amputation. She was started on a chemotherapy regimen of etoposide and carboplatin given that the pathology of the excised limb demonstrated vascular and lymphatic invasion by the tumor cells in the proximal skin margin. After 4 months she presented with gangrenous changes of the amputated limb and evidence of metastasis to the region of the skin flap. Similar tumors presented on the ipsilateral hip. Given her general poor condition and aggressive nature of the tumor, the patient decided to pursue hospice care 6 months after her diagnosis of Merkel cell carcinoma (MCC).

Figure 1. The tumor was composed of sheets of cells with a high nuclear-cytoplasmic ratio and fine chromatin without nucleoli (H&E, original magnification ×40).

Figure 2. Immunohistochemical staining for cytokera-tin 20 showed positivity in a paranuclear dotlike pattern (original magnification ×40).

Merkel cell carcinoma usually presents as firm, red to purple papules on sun-exposed skin in older patients with light skin. Factors strongly associated with the development of MCC are age (>65 years), lighter skin types, history of extensive sun exposure, and chronic immune suppression (eg, kidney or heart transplantation, human immunodeficiency virus).¹ The rate of MCC has increased 3-fold between 1986 and 2001; the rate of MCC was 0.15 cases per 100,000 individuals in 1986, climbing up to 0.44 cases per 100,000 individuals in 2001.² Our patient had been on immunosuppressants—prednisone, cyclosporine, and sirolimus—for nearly a decade following kidney transplants, which had been discontinued 2 years prior to presentation.

Heath et al³ defined an acronym AEIOU (asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years, UV-exposed site on a person with fair skin) for MCC features derived from 195 patients. They advised that a biopsy is warranted if the patient presents with more than 3 of these features.³

The 1991 MCC staging system was revised in 1999 and 2005 based on experience at Memorial Sloan Kettering Cancer Center (New York, New York).⁴ In 2010 the American Joint Committee on Cancer staging was introduced for MCC, which follows other skin malignancies.⁵ Using this TNM staging system for primary tumors, regional lymph nodes, and distant metastasis, our patient at the time of presentation was stage IIB (T3N0M0), with tumor size greater than 5 cm, nodes negative by clinical examination, and no distant metastasis. In a span of 3 months, she had metastasis to the skin, subcutaneous tissue, and distant lymph nodes, which resulted in classification as stage IV, proving the aggressive nature of the tumor.

The newly discovered Merkel cell polyomavirus (MCPyV) is found integrating into the Merkel cell genome. Merkel cell polyomavirus is present in 80% of cancers and is expressed in a clonal pattern, while 90% of MCC patients are seropositive for the same. Unlike antibodies to MCPyV VP1 protein, antibodies to the T antigen for MCPyV track disease burden and may be a useful biomarker for MCC in the future.⁶

A study of 251 patients in 1970-2002 showed that pathologic nodal staging identifies a group of patients with excellent long-term survival.¹ Our patient preferred to undergo positron emission tomography rather than a sentinel lymph node biopsy prior to surgery. Also, after margin-negative excision and pathologic nodal staging, local and nodal recurrence rates were low. Adjuvant chemotherapy for stage III patients showed a trend (P=.08) to decreased survival compared with stage II patients who did not receive chemotherapy.⁷ A multidisciplinary approach to treatment including surgery, radiation,⁸ and chemotherapy needs to be created for each individual patient. Merkel cell carcinoma is the cause of death in 35% of patients within 3 years of diagnosis.⁹

Merkel cell carcinoma is a rare orphan tumor with rapidly increasing incidence in an era of immunosuppression. It has a grave prognosis, as demonstrated in our case, if not detected early. People at increased risk for MCC must have regular skin checks. Unfortunately, our patient was a nursing home resident and had not had a skin check for 2 years prior to presentation.

The Diagnosis: Merkel Cell Carcinoma

Histopathology showed small round cells (Figure 1) that stained positive for cytokeratin 20 in a paranuclear dotlike pattern (Figure 2). The tumor stained negative for lymphoma (CD45) marker. Fluorodeoxyglucose positron emission tomography showed focally increased activity at cutaneous sites corresponding to the nodules, but lymph nodes and visceral sites did not show areas of increased metabolic activity. She underwent an above-knee amputation. She was started on a chemotherapy regimen of etoposide and carboplatin given that the pathology of the excised limb demonstrated vascular and lymphatic invasion by the tumor cells in the proximal skin margin. After 4 months she presented with gangrenous changes of the amputated limb and evidence of metastasis to the region of the skin flap. Similar tumors presented on the ipsilateral hip. Given her general poor condition and aggressive nature of the tumor, the patient decided to pursue hospice care 6 months after her diagnosis of Merkel cell carcinoma (MCC).

Figure 1. The tumor was composed of sheets of cells with a high nuclear-cytoplasmic ratio and fine chromatin without nucleoli (H&E, original magnification ×40).

Figure 2. Immunohistochemical staining for cytokera-tin 20 showed positivity in a paranuclear dotlike pattern (original magnification ×40).

Merkel cell carcinoma usually presents as firm, red to purple papules on sun-exposed skin in older patients with light skin. Factors strongly associated with the development of MCC are age (>65 years), lighter skin types, history of extensive sun exposure, and chronic immune suppression (eg, kidney or heart transplantation, human immunodeficiency virus).¹ The rate of MCC has increased 3-fold between 1986 and 2001; the rate of MCC was 0.15 cases per 100,000 individuals in 1986, climbing up to 0.44 cases per 100,000 individuals in 2001.² Our patient had been on immunosuppressants—prednisone, cyclosporine, and sirolimus—for nearly a decade following kidney transplants, which had been discontinued 2 years prior to presentation.

Heath et al³ defined an acronym AEIOU (asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years, UV-exposed site on a person with fair skin) for MCC features derived from 195 patients. They advised that a biopsy is warranted if the patient presents with more than 3 of these features.³

The 1991 MCC staging system was revised in 1999 and 2005 based on experience at Memorial Sloan Kettering Cancer Center (New York, New York).⁴ In 2010 the American Joint Committee on Cancer staging was introduced for MCC, which follows other skin malignancies.⁵ Using this TNM staging system for primary tumors, regional lymph nodes, and distant metastasis, our patient at the time of presentation was stage IIB (T3N0M0), with tumor size greater than 5 cm, nodes negative by clinical examination, and no distant metastasis. In a span of 3 months, she had metastasis to the skin, subcutaneous tissue, and distant lymph nodes, which resulted in classification as stage IV, proving the aggressive nature of the tumor.

The newly discovered Merkel cell polyomavirus (MCPyV) is found integrating into the Merkel cell genome. Merkel cell polyomavirus is present in 80% of cancers and is expressed in a clonal pattern, while 90% of MCC patients are seropositive for the same. Unlike antibodies to MCPyV VP1 protein, antibodies to the T antigen for MCPyV track disease burden and may be a useful biomarker for MCC in the future.⁶

A study of 251 patients in 1970-2002 showed that pathologic nodal staging identifies a group of patients with excellent long-term survival.¹ Our patient preferred to undergo positron emission tomography rather than a sentinel lymph node biopsy prior to surgery. Also, after margin-negative excision and pathologic nodal staging, local and nodal recurrence rates were low. Adjuvant chemotherapy for stage III patients showed a trend (P=.08) to decreased survival compared with stage II patients who did not receive chemotherapy.⁷ A multidisciplinary approach to treatment including surgery, radiation,⁸ and chemotherapy needs to be created for each individual patient. Merkel cell carcinoma is the cause of death in 35% of patients within 3 years of diagnosis.⁹

Merkel cell carcinoma is a rare orphan tumor with rapidly increasing incidence in an era of immunosuppression. It has a grave prognosis, as demonstrated in our case, if not detected early. People at increased risk for MCC must have regular skin checks. Unfortunately, our patient was a nursing home resident and had not had a skin check for 2 years prior to presentation.

The Diagnosis: Lichen Aureus

Lichen aureus (LA) is classified as a pigmented purpuric dermatosis (PPD), a collection of conditions that are characterized by petechiae, pigmentation, and occasionally telangiectasia without a causative underlying disorder. As in our case, the lesions of LA are usually asymptomatic. They appear as circumscribed areas of discrete or confluent macules and papules that can range in color from gold or copper to purple (Figure 1). The lesions typically occur unilaterally on the lower extremities but can occur on all body regions. The etiology is unknown, but explanations such as venous insufficiency,¹ contact allergens,² and drugs^3,4 have been proposed. Unlike other PPDs, LA tends to occur abruptly and then either stabilizes or progresses slowly over years. Studies have reported resolution in 2 to 7 years.⁵ The average age of onset is in the 20s and 30s, with pediatric cases accounting for only 17%.⁶ Pediatric cases are more likely to be self-limited and occur in uncommon sites such as the trunk and arms.⁷

Lichen aureus is characterized histopathologically by a dense, bandlike, dermal inflammatory infiltrate (Figure 2). Additionally, there is variable exocytosis of lymphocytes and marked accumulation of siderotic macrophages (Figure 3). These qualities in the proper clinical setting help differentiate LA from other PPDs that share findings of capillaritis, hemosiderin deposition, and erythrocyte extravasation near dermal vessels. An iron stain assists in the diagnosis of LA (Figure 3), as it differentiates the disease from other lichenoid conditions such as lichen planus. Zaballos et al⁸ also demonstrated a role for dermoscopy to clinically differentiate LA from other similar-appearing lesions such as lichen planus.  

The lesions of LA are benign. Because the predominantly T-cell infiltrate is monoclonal in approximately 50% of cases,^2,9-11 authors have suggested the possibility of progression to cutaneous T-cell lymphoma.^9,12 Guitart and Magro¹³ classified LA as a T-cell lymphoid dyscrasia with potential for progression. Despite these reports, the general consensus is that LA is a benign, self-limiting condition. The benign nature of LA is supported by Fink-Puches et al² who followed 23 patients for a mean 102.1 months and did not observe a single case of progression to malignancy.

There have been many treatment regimens attempted for patients with LA. Topical corticosteroids have not been found to be beneficial¹⁴; however, there have been isolated cases reporting its efficacy in children.^7,15 Other medications that have been effective in small trials include psoralen plus UVA,¹⁶ topical pimecrolimus,⁵ calcium dobesilate,¹⁷ and combination therapy with pentoxifylline and prostacyclin.¹⁸ Despite some reported benefit, the use of potent immunomodulating medications is not indicated due to the benign nature of the disease. Alternative supplements including oral bioflavonoids and ascorbic acid have also been explored with modest benefit.¹⁹

The Diagnosis: Lichen Aureus

Lichen aureus (LA) is classified as a pigmented purpuric dermatosis (PPD), a collection of conditions that are characterized by petechiae, pigmentation, and occasionally telangiectasia without a causative underlying disorder. As in our case, the lesions of LA are usually asymptomatic. They appear as circumscribed areas of discrete or confluent macules and papules that can range in color from gold or copper to purple (Figure 1). The lesions typically occur unilaterally on the lower extremities but can occur on all body regions. The etiology is unknown, but explanations such as venous insufficiency,¹ contact allergens,² and drugs^3,4 have been proposed. Unlike other PPDs, LA tends to occur abruptly and then either stabilizes or progresses slowly over years. Studies have reported resolution in 2 to 7 years.⁵ The average age of onset is in the 20s and 30s, with pediatric cases accounting for only 17%.⁶ Pediatric cases are more likely to be self-limited and occur in uncommon sites such as the trunk and arms.⁷

Lichen aureus is characterized histopathologically by a dense, bandlike, dermal inflammatory infiltrate (Figure 2). Additionally, there is variable exocytosis of lymphocytes and marked accumulation of siderotic macrophages (Figure 3). These qualities in the proper clinical setting help differentiate LA from other PPDs that share findings of capillaritis, hemosiderin deposition, and erythrocyte extravasation near dermal vessels. An iron stain assists in the diagnosis of LA (Figure 3), as it differentiates the disease from other lichenoid conditions such as lichen planus. Zaballos et al⁸ also demonstrated a role for dermoscopy to clinically differentiate LA from other similar-appearing lesions such as lichen planus.  

The lesions of LA are benign. Because the predominantly T-cell infiltrate is monoclonal in approximately 50% of cases,^2,9-11 authors have suggested the possibility of progression to cutaneous T-cell lymphoma.^9,12 Guitart and Magro¹³ classified LA as a T-cell lymphoid dyscrasia with potential for progression. Despite these reports, the general consensus is that LA is a benign, self-limiting condition. The benign nature of LA is supported by Fink-Puches et al² who followed 23 patients for a mean 102.1 months and did not observe a single case of progression to malignancy.

There have been many treatment regimens attempted for patients with LA. Topical corticosteroids have not been found to be beneficial¹⁴; however, there have been isolated cases reporting its efficacy in children.^7,15 Other medications that have been effective in small trials include psoralen plus UVA,¹⁶ topical pimecrolimus,⁵ calcium dobesilate,¹⁷ and combination therapy with pentoxifylline and prostacyclin.¹⁸ Despite some reported benefit, the use of potent immunomodulating medications is not indicated due to the benign nature of the disease. Alternative supplements including oral bioflavonoids and ascorbic acid have also been explored with modest benefit.¹⁹

The Diagnosis: Lichen Aureus

Lichen aureus (LA) is classified as a pigmented purpuric dermatosis (PPD), a collection of conditions that are characterized by petechiae, pigmentation, and occasionally telangiectasia without a causative underlying disorder. As in our case, the lesions of LA are usually asymptomatic. They appear as circumscribed areas of discrete or confluent macules and papules that can range in color from gold or copper to purple (Figure 1). The lesions typically occur unilaterally on the lower extremities but can occur on all body regions. The etiology is unknown, but explanations such as venous insufficiency,¹ contact allergens,² and drugs^3,4 have been proposed. Unlike other PPDs, LA tends to occur abruptly and then either stabilizes or progresses slowly over years. Studies have reported resolution in 2 to 7 years.⁵ The average age of onset is in the 20s and 30s, with pediatric cases accounting for only 17%.⁶ Pediatric cases are more likely to be self-limited and occur in uncommon sites such as the trunk and arms.⁷

Lichen aureus is characterized histopathologically by a dense, bandlike, dermal inflammatory infiltrate (Figure 2). Additionally, there is variable exocytosis of lymphocytes and marked accumulation of siderotic macrophages (Figure 3). These qualities in the proper clinical setting help differentiate LA from other PPDs that share findings of capillaritis, hemosiderin deposition, and erythrocyte extravasation near dermal vessels. An iron stain assists in the diagnosis of LA (Figure 3), as it differentiates the disease from other lichenoid conditions such as lichen planus. Zaballos et al⁸ also demonstrated a role for dermoscopy to clinically differentiate LA from other similar-appearing lesions such as lichen planus.  

The lesions of LA are benign. Because the predominantly T-cell infiltrate is monoclonal in approximately 50% of cases,^2,9-11 authors have suggested the possibility of progression to cutaneous T-cell lymphoma.^9,12 Guitart and Magro¹³ classified LA as a T-cell lymphoid dyscrasia with potential for progression. Despite these reports, the general consensus is that LA is a benign, self-limiting condition. The benign nature of LA is supported by Fink-Puches et al² who followed 23 patients for a mean 102.1 months and did not observe a single case of progression to malignancy.

There have been many treatment regimens attempted for patients with LA. Topical corticosteroids have not been found to be beneficial¹⁴; however, there have been isolated cases reporting its efficacy in children.^7,15 Other medications that have been effective in small trials include psoralen plus UVA,¹⁶ topical pimecrolimus,⁵ calcium dobesilate,¹⁷ and combination therapy with pentoxifylline and prostacyclin.¹⁸ Despite some reported benefit, the use of potent immunomodulating medications is not indicated due to the benign nature of the disease. Alternative supplements including oral bioflavonoids and ascorbic acid have also been explored with modest benefit.¹⁹

A 70-year-old woman presented to our dermatology clinic with an enlarging lesion on the left anterior aspect of the scalp of 4 years’ duration. She had a history of breast carcinoma in the left breast with positive lymph nodes 2 years prior. Physical examination revealed a 2.5-cm pink, pearly, exophytic plaque on the left anterior aspect of the scalp. The lesion was removed with clear margins by excisional surgery.

The Diagnosis: Clear Cell Hidradenoma

Clear cell hidradenoma (CCH) is a variant of nodular hidradenoma that may contain varying quantities of solid and cystic components and comprises approximately one-third of hidradenomas.¹ Clear cell hidradenomas are slow-growing and fairly uncommon adnexal neoplasms derived from either eccrine sweat glands or apocrine glands. Some researchers have regarded hidradenomas as apocrine tumors due to evidence of apocrine decapitation secretion, whereas others note the lack of apocrine and ultrastructural features of immature eccrine glands.² Clear cell hidradenomas typically develop between the fourth and eighth decades of life, usually peaking during the sixth decade.³ Clear cell hidradenomas usually range in size from 5 to 30 mm and frequently present on the scalp, head, chest, and abdomen; rarely, CCHs present on the joint spaces of the shoulders and knees.^3-5 This neoplasm is more common in women than men³ and generally has a flesh-colored, erythematous, red-brown or blue appearance with a tendency to ulcerate and exude a serous discharge (Figure 1).⁵ The clinical differential diagnosis includes metastatic cancer (eg, renal cell carcinoma, keratoacanthoma, trichoblastoma, trichilemmoma) or other benign adnexal neoplasms.

Figure 1. A 2.5-cm pink plaque on the scalp.

Histopathologic examination of a CCH generally reveals an unencapsulated and circumscribed neoplasm in the mid or upper dermis with occasional extensions into the subcutaneous fat (Figure 2). The tumor typically presents with 2 types of cells: (1) round, fusiform, or polygonal cells with vesicular nuclei and eosinophilic cytoplasm, and (2) cells with clear cytoplasm and basophilic, often eccentrically located nuclei.⁶ Ducts are scattered within the neoplasm and are lined by a layer of cuboidal cells that can be highlighted on carcinoembryonic antigen and epithelial membrane antigen immunostaining.⁶ The tumor cells themselves are highlighted on cytokeratin AE1/AE3 staining.

Figure 2. Histopathologic examination revealed an endophytic/exophytic circumscribed neoplasm extending from the epidermis to the mid reticular dermis with several lobules composed of round cells with clear cytoplasm with several scattered ducts (H&E, original magnification ×4).

Malignant transformation rarely is associated with CCH, with de novo clear cell hidradenocarcinoma being more common. Only approximately 6.7% of CCHs have been shown to be malignant, and the malignant tumors feature nuclear atypia, abnormal mitotic figures, necrosis, and infiltration.^1,7 Although CCH is a benign adnexal neoplasm, it has a high recurrence rate (approximately 10%) following excision.⁷ The treatment of choice is complete surgical excision, though Mohs micrographic surgery is advocated, as it promotes thorough examination of the tumor margin to ensure complete tumor removal.8 Our case illustrates the importance of a broad differential diagnosis when treating patients with CCH as well as keeping in mind nonmalignant lesions are far more common than malignant lesions.  

A 70-year-old woman presented to our dermatology clinic with an enlarging lesion on the left anterior aspect of the scalp of 4 years’ duration. She had a history of breast carcinoma in the left breast with positive lymph nodes 2 years prior. Physical examination revealed a 2.5-cm pink, pearly, exophytic plaque on the left anterior aspect of the scalp. The lesion was removed with clear margins by excisional surgery.

The Diagnosis: Clear Cell Hidradenoma

Clear cell hidradenoma (CCH) is a variant of nodular hidradenoma that may contain varying quantities of solid and cystic components and comprises approximately one-third of hidradenomas.¹ Clear cell hidradenomas are slow-growing and fairly uncommon adnexal neoplasms derived from either eccrine sweat glands or apocrine glands. Some researchers have regarded hidradenomas as apocrine tumors due to evidence of apocrine decapitation secretion, whereas others note the lack of apocrine and ultrastructural features of immature eccrine glands.² Clear cell hidradenomas typically develop between the fourth and eighth decades of life, usually peaking during the sixth decade.³ Clear cell hidradenomas usually range in size from 5 to 30 mm and frequently present on the scalp, head, chest, and abdomen; rarely, CCHs present on the joint spaces of the shoulders and knees.^3-5 This neoplasm is more common in women than men³ and generally has a flesh-colored, erythematous, red-brown or blue appearance with a tendency to ulcerate and exude a serous discharge (Figure 1).⁵ The clinical differential diagnosis includes metastatic cancer (eg, renal cell carcinoma, keratoacanthoma, trichoblastoma, trichilemmoma) or other benign adnexal neoplasms.

Figure 1. A 2.5-cm pink plaque on the scalp.

Histopathologic examination of a CCH generally reveals an unencapsulated and circumscribed neoplasm in the mid or upper dermis with occasional extensions into the subcutaneous fat (Figure 2). The tumor typically presents with 2 types of cells: (1) round, fusiform, or polygonal cells with vesicular nuclei and eosinophilic cytoplasm, and (2) cells with clear cytoplasm and basophilic, often eccentrically located nuclei.⁶ Ducts are scattered within the neoplasm and are lined by a layer of cuboidal cells that can be highlighted on carcinoembryonic antigen and epithelial membrane antigen immunostaining.⁶ The tumor cells themselves are highlighted on cytokeratin AE1/AE3 staining.

Figure 2. Histopathologic examination revealed an endophytic/exophytic circumscribed neoplasm extending from the epidermis to the mid reticular dermis with several lobules composed of round cells with clear cytoplasm with several scattered ducts (H&E, original magnification ×4).

Malignant transformation rarely is associated with CCH, with de novo clear cell hidradenocarcinoma being more common. Only approximately 6.7% of CCHs have been shown to be malignant, and the malignant tumors feature nuclear atypia, abnormal mitotic figures, necrosis, and infiltration.^1,7 Although CCH is a benign adnexal neoplasm, it has a high recurrence rate (approximately 10%) following excision.⁷ The treatment of choice is complete surgical excision, though Mohs micrographic surgery is advocated, as it promotes thorough examination of the tumor margin to ensure complete tumor removal.8 Our case illustrates the importance of a broad differential diagnosis when treating patients with CCH as well as keeping in mind nonmalignant lesions are far more common than malignant lesions.  

A 70-year-old woman presented to our dermatology clinic with an enlarging lesion on the left anterior aspect of the scalp of 4 years’ duration. She had a history of breast carcinoma in the left breast with positive lymph nodes 2 years prior. Physical examination revealed a 2.5-cm pink, pearly, exophytic plaque on the left anterior aspect of the scalp. The lesion was removed with clear margins by excisional surgery.

The Diagnosis: Clear Cell Hidradenoma

Clear cell hidradenoma (CCH) is a variant of nodular hidradenoma that may contain varying quantities of solid and cystic components and comprises approximately one-third of hidradenomas.¹ Clear cell hidradenomas are slow-growing and fairly uncommon adnexal neoplasms derived from either eccrine sweat glands or apocrine glands. Some researchers have regarded hidradenomas as apocrine tumors due to evidence of apocrine decapitation secretion, whereas others note the lack of apocrine and ultrastructural features of immature eccrine glands.² Clear cell hidradenomas typically develop between the fourth and eighth decades of life, usually peaking during the sixth decade.³ Clear cell hidradenomas usually range in size from 5 to 30 mm and frequently present on the scalp, head, chest, and abdomen; rarely, CCHs present on the joint spaces of the shoulders and knees.^3-5 This neoplasm is more common in women than men³ and generally has a flesh-colored, erythematous, red-brown or blue appearance with a tendency to ulcerate and exude a serous discharge (Figure 1).⁵ The clinical differential diagnosis includes metastatic cancer (eg, renal cell carcinoma, keratoacanthoma, trichoblastoma, trichilemmoma) or other benign adnexal neoplasms.

Figure 1. A 2.5-cm pink plaque on the scalp.

Histopathologic examination of a CCH generally reveals an unencapsulated and circumscribed neoplasm in the mid or upper dermis with occasional extensions into the subcutaneous fat (Figure 2). The tumor typically presents with 2 types of cells: (1) round, fusiform, or polygonal cells with vesicular nuclei and eosinophilic cytoplasm, and (2) cells with clear cytoplasm and basophilic, often eccentrically located nuclei.⁶ Ducts are scattered within the neoplasm and are lined by a layer of cuboidal cells that can be highlighted on carcinoembryonic antigen and epithelial membrane antigen immunostaining.⁶ The tumor cells themselves are highlighted on cytokeratin AE1/AE3 staining.

Figure 2. Histopathologic examination revealed an endophytic/exophytic circumscribed neoplasm extending from the epidermis to the mid reticular dermis with several lobules composed of round cells with clear cytoplasm with several scattered ducts (H&E, original magnification ×4).

Malignant transformation rarely is associated with CCH, with de novo clear cell hidradenocarcinoma being more common. Only approximately 6.7% of CCHs have been shown to be malignant, and the malignant tumors feature nuclear atypia, abnormal mitotic figures, necrosis, and infiltration.^1,7 Although CCH is a benign adnexal neoplasm, it has a high recurrence rate (approximately 10%) following excision.⁷ The treatment of choice is complete surgical excision, though Mohs micrographic surgery is advocated, as it promotes thorough examination of the tumor margin to ensure complete tumor removal.8 Our case illustrates the importance of a broad differential diagnosis when treating patients with CCH as well as keeping in mind nonmalignant lesions are far more common than malignant lesions.  

The Diagnosis: Madelung Disease (Benign Symmetric Lipomatosis)

A 56-year-old man presented for evaluation of massive subcutaneous nodules the bilateral upper arms, shoulders, chest, abdomen, and lateral aspect of the proximal thighs (Figures 1 and 2) that developed over the last 12 to 18 months and continued to enlarge. In addition, he was beginning to develop symptoms of neuropathy of the bilateral hands. The patient had a long-standing history of alcohol abuse. Biopsies performed by the patient’s primary care physician revealed benign adipose tissue. He was referred to the dermatology clinic and subsequently diagnosed with Madelung disease.

Figure 1. Extensive symmetric fat deposits on the bilateral upper arms, shoulders, chest, and abdomen.

Figure 2. Masses of adipose tissue on the lateral aspect of the proximal thighs and abdomen.

Madelung disease, also known as benign symmetric lipomatosis and Launois-Bensaude syndrome, is characterized by multiple large masses of nonencapsulated adipose tissue. These masses are symmetric and most prominent on the head, neck, trunk, and proximal extremities. Classically, a pseudoathletic appearance is described. Madelung disease most frequently affects men aged 30 to 60 years. In more than 90% of cases, it is associated with alcoholism.

In general, the masses of adipose tissue are asymptomatic. However, airway compression and dysphagia requiring surgical intervention has been reported in the otolaryngology literature.¹ In addition, neuropathy develops in 84% of cases.² Nerve biopsies from patients with Madelung disease have revealed a pattern of axonopathy that is distinct from alcohol-induced neuropathy.³ This neuropathy can involve sensory and motor nerves, with the most prominent findings being muscle weakness, tendon areflexia, interosseous muscle atrophy, vibratory sensation loss, and hypoesthesia. Furthermore, dysfunction of the autonomic nervous system can lead to segmental hyperhidrosis, gustatory sweating, and abnormal autonomic cardiovascular reflexes.² Many patients who develop neuropathy will eventually become incapacitated.

The etiology of Madelung disease is not fully understood. There are several theories on the pathogenesis of this disease, most describing metabolic disturbances induced by alcohol. Specifically, studies have revealed chronic alcohol use causes numerous deletions in mitochondrial DNA.^4,5 The mitochondrial DNA damage may explain both the resistance of the lipomatous masses to lipolysis and the nerve-related changes. Comparisons between human immunodeficiency virus/highly active antiretroviral therapy–associated lipodystrophy and Madelung disease lend credence to the metabolic disturbance theory and may help clarify the specific mechanisms involved.⁶

There have been no cases of spontaneous resolution, even in patients who stop consuming alcohol. For this reason, most patients are referred to a surgeon. Many surgeons prefer open excision for debulking large lipomatous masses, but this technique typically requires general anesthesia. For those in whom this treatment is not an appropriate option, liposuction can be considered with tumescent anesthesia.⁷ A combination of these surgical modalities also is an option.

Madelung disease is a distinctive disorder typically affecting chronic alcoholics. Recognition of this clinical entity is important, as severe neuropathy and airway compromise may ensue. Although surgical excision is an attractive option for cosmesis and airway compromise, the associated neuropathy can be extremely difficult to treat and can be quite debilitating.

The Diagnosis: Madelung Disease (Benign Symmetric Lipomatosis)

A 56-year-old man presented for evaluation of massive subcutaneous nodules the bilateral upper arms, shoulders, chest, abdomen, and lateral aspect of the proximal thighs (Figures 1 and 2) that developed over the last 12 to 18 months and continued to enlarge. In addition, he was beginning to develop symptoms of neuropathy of the bilateral hands. The patient had a long-standing history of alcohol abuse. Biopsies performed by the patient’s primary care physician revealed benign adipose tissue. He was referred to the dermatology clinic and subsequently diagnosed with Madelung disease.

Figure 1. Extensive symmetric fat deposits on the bilateral upper arms, shoulders, chest, and abdomen.

Figure 2. Masses of adipose tissue on the lateral aspect of the proximal thighs and abdomen.

Madelung disease, also known as benign symmetric lipomatosis and Launois-Bensaude syndrome, is characterized by multiple large masses of nonencapsulated adipose tissue. These masses are symmetric and most prominent on the head, neck, trunk, and proximal extremities. Classically, a pseudoathletic appearance is described. Madelung disease most frequently affects men aged 30 to 60 years. In more than 90% of cases, it is associated with alcoholism.

In general, the masses of adipose tissue are asymptomatic. However, airway compression and dysphagia requiring surgical intervention has been reported in the otolaryngology literature.¹ In addition, neuropathy develops in 84% of cases.² Nerve biopsies from patients with Madelung disease have revealed a pattern of axonopathy that is distinct from alcohol-induced neuropathy.³ This neuropathy can involve sensory and motor nerves, with the most prominent findings being muscle weakness, tendon areflexia, interosseous muscle atrophy, vibratory sensation loss, and hypoesthesia. Furthermore, dysfunction of the autonomic nervous system can lead to segmental hyperhidrosis, gustatory sweating, and abnormal autonomic cardiovascular reflexes.² Many patients who develop neuropathy will eventually become incapacitated.

The etiology of Madelung disease is not fully understood. There are several theories on the pathogenesis of this disease, most describing metabolic disturbances induced by alcohol. Specifically, studies have revealed chronic alcohol use causes numerous deletions in mitochondrial DNA.^4,5 The mitochondrial DNA damage may explain both the resistance of the lipomatous masses to lipolysis and the nerve-related changes. Comparisons between human immunodeficiency virus/highly active antiretroviral therapy–associated lipodystrophy and Madelung disease lend credence to the metabolic disturbance theory and may help clarify the specific mechanisms involved.⁶

There have been no cases of spontaneous resolution, even in patients who stop consuming alcohol. For this reason, most patients are referred to a surgeon. Many surgeons prefer open excision for debulking large lipomatous masses, but this technique typically requires general anesthesia. For those in whom this treatment is not an appropriate option, liposuction can be considered with tumescent anesthesia.⁷ A combination of these surgical modalities also is an option.

Madelung disease is a distinctive disorder typically affecting chronic alcoholics. Recognition of this clinical entity is important, as severe neuropathy and airway compromise may ensue. Although surgical excision is an attractive option for cosmesis and airway compromise, the associated neuropathy can be extremely difficult to treat and can be quite debilitating.

The Diagnosis: Madelung Disease (Benign Symmetric Lipomatosis)

A 56-year-old man presented for evaluation of massive subcutaneous nodules the bilateral upper arms, shoulders, chest, abdomen, and lateral aspect of the proximal thighs (Figures 1 and 2) that developed over the last 12 to 18 months and continued to enlarge. In addition, he was beginning to develop symptoms of neuropathy of the bilateral hands. The patient had a long-standing history of alcohol abuse. Biopsies performed by the patient’s primary care physician revealed benign adipose tissue. He was referred to the dermatology clinic and subsequently diagnosed with Madelung disease.

Figure 1. Extensive symmetric fat deposits on the bilateral upper arms, shoulders, chest, and abdomen.

Figure 2. Masses of adipose tissue on the lateral aspect of the proximal thighs and abdomen.

Madelung disease, also known as benign symmetric lipomatosis and Launois-Bensaude syndrome, is characterized by multiple large masses of nonencapsulated adipose tissue. These masses are symmetric and most prominent on the head, neck, trunk, and proximal extremities. Classically, a pseudoathletic appearance is described. Madelung disease most frequently affects men aged 30 to 60 years. In more than 90% of cases, it is associated with alcoholism.

In general, the masses of adipose tissue are asymptomatic. However, airway compression and dysphagia requiring surgical intervention has been reported in the otolaryngology literature.¹ In addition, neuropathy develops in 84% of cases.² Nerve biopsies from patients with Madelung disease have revealed a pattern of axonopathy that is distinct from alcohol-induced neuropathy.³ This neuropathy can involve sensory and motor nerves, with the most prominent findings being muscle weakness, tendon areflexia, interosseous muscle atrophy, vibratory sensation loss, and hypoesthesia. Furthermore, dysfunction of the autonomic nervous system can lead to segmental hyperhidrosis, gustatory sweating, and abnormal autonomic cardiovascular reflexes.² Many patients who develop neuropathy will eventually become incapacitated.

The etiology of Madelung disease is not fully understood. There are several theories on the pathogenesis of this disease, most describing metabolic disturbances induced by alcohol. Specifically, studies have revealed chronic alcohol use causes numerous deletions in mitochondrial DNA.^4,5 The mitochondrial DNA damage may explain both the resistance of the lipomatous masses to lipolysis and the nerve-related changes. Comparisons between human immunodeficiency virus/highly active antiretroviral therapy–associated lipodystrophy and Madelung disease lend credence to the metabolic disturbance theory and may help clarify the specific mechanisms involved.⁶

There have been no cases of spontaneous resolution, even in patients who stop consuming alcohol. For this reason, most patients are referred to a surgeon. Many surgeons prefer open excision for debulking large lipomatous masses, but this technique typically requires general anesthesia. For those in whom this treatment is not an appropriate option, liposuction can be considered with tumescent anesthesia.⁷ A combination of these surgical modalities also is an option.

Madelung disease is a distinctive disorder typically affecting chronic alcoholics. Recognition of this clinical entity is important, as severe neuropathy and airway compromise may ensue. Although surgical excision is an attractive option for cosmesis and airway compromise, the associated neuropathy can be extremely difficult to treat and can be quite debilitating.

The Diagnosis: Levamisole-Induced Cutaneous Vasculopathy

In our patient, tender stellate purpura and occasional bullae were present on the ears, arms and legs, groin, and buttocks (Figure 1). Histopathologic examination revealed subepidermal detachment, perivascular neutrophilic infiltrate, and red blood cell extravasation, consistent with early leukocyctoclastic vasculitis (Figure 2).

Figure 1. Left arm with tender stellate purpura (A). Left side of the lower back with large area of purpura and few scattered tense bullae (B).

Levamisole-induced vasculopathy is a condition related primarily to cocaine use. Levamisole is an immunomodulatory agent, historically used as a disease-modifying antirheumatic drug for rheumatoid arthritis and as adjuvant chemotherapy for various types of cancer. However, levamisole for human use was banned from US and Canadian markets in 1999 and 2003, respectively, due to increased risk for agranulocytosis, retiform purpura, and epilepsy.¹ Currently, veterinarians use levamisole as an anthelminthic agent to deworm house and farm animals. In Europe, pediatric nephrologists use it as a steroid-sparing agent in children with steroid-dependent nephritic syndrome.

Over the last decade, levamisole has increasingly been used as a cocaine adulterant or bulking agent. This contaminant closely resembles cocaine physically and is theorized to prolong or attenuate cocaine’s “high.” Approximately 69% of cocaine sampled by the US Drug Enforcement Administration is adulterated with levamisole.² Similarly, levamisole-contaminated cocaine also has been found in Europe, Australia, and other parts of the world. Potential complications include vasculitis, thromboembolism, neutropenia, and agranulocytosis.³

Levamisole-induced vasculopathy appears to affect cocaine users of all ages, ethnicities, and genders. Cocaine can be smoked, snorted, or injected. In nearly all reported cases, patients characteristically present with hemorrhagic bullae of the bilateral ear helix, cheeks, or nasal tip. Any body site can be affected with retiform purpura or necrotic bullae. Along with skin lesions, arthralgia is commonly reported, as are constitutional symptoms (eg, fever, night sweats, weight loss, malaise)⁴; oral mucosal involvement also has been reported.⁵ Laboratory investigation can reveal neutropenia, positive antineutrophil cytoplasmic antibodies (ANCAs) in the perinuclear or cytoplasmic pattern, positive proteinase 3, and negative or mildly elevated antimyeloperoxidase.^3-5 Acute renal injury and pulmonary hemorrhage are other potentially serious copmlications.⁴ Antihuman neutrophil elastase antibody testing can help distinguish levamisole-induced vasculopathy from other forms of immune-mediated vasculitis and will be negative in immune-mediated vasculitides such as Churg-Strauss syndrome (allergic granulomatosis), Wegener granulomatosis (granulomatosis with polyangiitis), and polyarteritis nodosa.⁶ On histology, microvascular thrombosis or leukocytoclastic vasculitis can both, or individually, be seen. Epidermal necrosis, dermal hemorrhage, and endothelial hyperplasia have all been noted in skin biopsied from necrotic bullae.

Figure 2. Biopsy of the left arm revealed subepidermal detachment with a neutrophilic infiltrate (A)(H&E, original magnification ×40) and perivascular neutrophilic infiltration with nuclear debris and red blood cell extravasation, consistent with early leukocyctoclastic vasculitis (B)(H&E, original magnification ×100).

Levamisole’s short half-life (approximately 5–6 hours) makes it difficult to detect on routine blood draws. An astute physician suspecting this diagnosis on initial presentation can ask for levamisole detection on urine toxicology screening.⁷ Urine samples also can be sent for testing with gas chromatography–mass spectrometry, though this test may only be available at major research centers.⁸

Differential diagnosis of levamisole toxicity includes different types of vasculitides such as cryoglobulinemia (positive serum IgM and IgG cryoglobulins; possible hepatitis C infection), Wegener granulomatosis (cytoplasmic ANCA positive; associated with upper and lower respiratory tract inflammation, glomerulonephritis), Churg-Strauss syndrome (perinuclear ANCA positive; associated with asthma and eosinophilia), and polyarteritis nodosa (medium vessel involvement only; associated with livedo reticularis, subcutaneous nodules, ulcers).⁹ Necrotic lesions also may raise the possibility of warfarin necrosis, heparin necrosis, or cholesterol emboli. Cholesterol embolism most frequently presents with small vessel vasculitis and necrosis of distal extremities such as the toes. With large areas of skin involvement and bullae, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis also should be considered.⁹

Definitive treatment of this condition requires complete and immediate cessation of cocaine use. Levamisole also has been found as a contaminant in heroin.¹ Thus, it may be prudent to recommend heroin avoidance to the patient to prevent recurrences. Management of acute levamisole-induced vasculopathy is primarily symptomatic. Some patients with severe neutropenia at risk for infection have been treated with granulocyte colony-stimulating factor, while others have only required pain control, usually with nonsteroidal anti-inflammatory drugs.¹⁰ Oral prednisone and colchicine also have been used with reported success.⁵

Given the increasing incidence of levamisole toxicity and public health implications, clinicians should be aware of this association and the classic clinical and laboratory findings.

The Diagnosis: Levamisole-Induced Cutaneous Vasculopathy

In our patient, tender stellate purpura and occasional bullae were present on the ears, arms and legs, groin, and buttocks (Figure 1). Histopathologic examination revealed subepidermal detachment, perivascular neutrophilic infiltrate, and red blood cell extravasation, consistent with early leukocyctoclastic vasculitis (Figure 2).

Figure 1. Left arm with tender stellate purpura (A). Left side of the lower back with large area of purpura and few scattered tense bullae (B).

Levamisole-induced vasculopathy is a condition related primarily to cocaine use. Levamisole is an immunomodulatory agent, historically used as a disease-modifying antirheumatic drug for rheumatoid arthritis and as adjuvant chemotherapy for various types of cancer. However, levamisole for human use was banned from US and Canadian markets in 1999 and 2003, respectively, due to increased risk for agranulocytosis, retiform purpura, and epilepsy.¹ Currently, veterinarians use levamisole as an anthelminthic agent to deworm house and farm animals. In Europe, pediatric nephrologists use it as a steroid-sparing agent in children with steroid-dependent nephritic syndrome.

Over the last decade, levamisole has increasingly been used as a cocaine adulterant or bulking agent. This contaminant closely resembles cocaine physically and is theorized to prolong or attenuate cocaine’s “high.” Approximately 69% of cocaine sampled by the US Drug Enforcement Administration is adulterated with levamisole.² Similarly, levamisole-contaminated cocaine also has been found in Europe, Australia, and other parts of the world. Potential complications include vasculitis, thromboembolism, neutropenia, and agranulocytosis.³

Levamisole-induced vasculopathy appears to affect cocaine users of all ages, ethnicities, and genders. Cocaine can be smoked, snorted, or injected. In nearly all reported cases, patients characteristically present with hemorrhagic bullae of the bilateral ear helix, cheeks, or nasal tip. Any body site can be affected with retiform purpura or necrotic bullae. Along with skin lesions, arthralgia is commonly reported, as are constitutional symptoms (eg, fever, night sweats, weight loss, malaise)⁴; oral mucosal involvement also has been reported.⁵ Laboratory investigation can reveal neutropenia, positive antineutrophil cytoplasmic antibodies (ANCAs) in the perinuclear or cytoplasmic pattern, positive proteinase 3, and negative or mildly elevated antimyeloperoxidase.^3-5 Acute renal injury and pulmonary hemorrhage are other potentially serious copmlications.⁴ Antihuman neutrophil elastase antibody testing can help distinguish levamisole-induced vasculopathy from other forms of immune-mediated vasculitis and will be negative in immune-mediated vasculitides such as Churg-Strauss syndrome (allergic granulomatosis), Wegener granulomatosis (granulomatosis with polyangiitis), and polyarteritis nodosa.⁶ On histology, microvascular thrombosis or leukocytoclastic vasculitis can both, or individually, be seen. Epidermal necrosis, dermal hemorrhage, and endothelial hyperplasia have all been noted in skin biopsied from necrotic bullae.

Figure 2. Biopsy of the left arm revealed subepidermal detachment with a neutrophilic infiltrate (A)(H&E, original magnification ×40) and perivascular neutrophilic infiltration with nuclear debris and red blood cell extravasation, consistent with early leukocyctoclastic vasculitis (B)(H&E, original magnification ×100).

Levamisole’s short half-life (approximately 5–6 hours) makes it difficult to detect on routine blood draws. An astute physician suspecting this diagnosis on initial presentation can ask for levamisole detection on urine toxicology screening.⁷ Urine samples also can be sent for testing with gas chromatography–mass spectrometry, though this test may only be available at major research centers.⁸

Differential diagnosis of levamisole toxicity includes different types of vasculitides such as cryoglobulinemia (positive serum IgM and IgG cryoglobulins; possible hepatitis C infection), Wegener granulomatosis (cytoplasmic ANCA positive; associated with upper and lower respiratory tract inflammation, glomerulonephritis), Churg-Strauss syndrome (perinuclear ANCA positive; associated with asthma and eosinophilia), and polyarteritis nodosa (medium vessel involvement only; associated with livedo reticularis, subcutaneous nodules, ulcers).⁹ Necrotic lesions also may raise the possibility of warfarin necrosis, heparin necrosis, or cholesterol emboli. Cholesterol embolism most frequently presents with small vessel vasculitis and necrosis of distal extremities such as the toes. With large areas of skin involvement and bullae, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis also should be considered.⁹

Definitive treatment of this condition requires complete and immediate cessation of cocaine use. Levamisole also has been found as a contaminant in heroin.¹ Thus, it may be prudent to recommend heroin avoidance to the patient to prevent recurrences. Management of acute levamisole-induced vasculopathy is primarily symptomatic. Some patients with severe neutropenia at risk for infection have been treated with granulocyte colony-stimulating factor, while others have only required pain control, usually with nonsteroidal anti-inflammatory drugs.¹⁰ Oral prednisone and colchicine also have been used with reported success.⁵

Given the increasing incidence of levamisole toxicity and public health implications, clinicians should be aware of this association and the classic clinical and laboratory findings.

The Diagnosis: Levamisole-Induced Cutaneous Vasculopathy

In our patient, tender stellate purpura and occasional bullae were present on the ears, arms and legs, groin, and buttocks (Figure 1). Histopathologic examination revealed subepidermal detachment, perivascular neutrophilic infiltrate, and red blood cell extravasation, consistent with early leukocyctoclastic vasculitis (Figure 2).

Figure 1. Left arm with tender stellate purpura (A). Left side of the lower back with large area of purpura and few scattered tense bullae (B).

Levamisole-induced vasculopathy is a condition related primarily to cocaine use. Levamisole is an immunomodulatory agent, historically used as a disease-modifying antirheumatic drug for rheumatoid arthritis and as adjuvant chemotherapy for various types of cancer. However, levamisole for human use was banned from US and Canadian markets in 1999 and 2003, respectively, due to increased risk for agranulocytosis, retiform purpura, and epilepsy.¹ Currently, veterinarians use levamisole as an anthelminthic agent to deworm house and farm animals. In Europe, pediatric nephrologists use it as a steroid-sparing agent in children with steroid-dependent nephritic syndrome.

Over the last decade, levamisole has increasingly been used as a cocaine adulterant or bulking agent. This contaminant closely resembles cocaine physically and is theorized to prolong or attenuate cocaine’s “high.” Approximately 69% of cocaine sampled by the US Drug Enforcement Administration is adulterated with levamisole.² Similarly, levamisole-contaminated cocaine also has been found in Europe, Australia, and other parts of the world. Potential complications include vasculitis, thromboembolism, neutropenia, and agranulocytosis.³

Levamisole-induced vasculopathy appears to affect cocaine users of all ages, ethnicities, and genders. Cocaine can be smoked, snorted, or injected. In nearly all reported cases, patients characteristically present with hemorrhagic bullae of the bilateral ear helix, cheeks, or nasal tip. Any body site can be affected with retiform purpura or necrotic bullae. Along with skin lesions, arthralgia is commonly reported, as are constitutional symptoms (eg, fever, night sweats, weight loss, malaise)⁴; oral mucosal involvement also has been reported.⁵ Laboratory investigation can reveal neutropenia, positive antineutrophil cytoplasmic antibodies (ANCAs) in the perinuclear or cytoplasmic pattern, positive proteinase 3, and negative or mildly elevated antimyeloperoxidase.^3-5 Acute renal injury and pulmonary hemorrhage are other potentially serious copmlications.⁴ Antihuman neutrophil elastase antibody testing can help distinguish levamisole-induced vasculopathy from other forms of immune-mediated vasculitis and will be negative in immune-mediated vasculitides such as Churg-Strauss syndrome (allergic granulomatosis), Wegener granulomatosis (granulomatosis with polyangiitis), and polyarteritis nodosa.⁶ On histology, microvascular thrombosis or leukocytoclastic vasculitis can both, or individually, be seen. Epidermal necrosis, dermal hemorrhage, and endothelial hyperplasia have all been noted in skin biopsied from necrotic bullae.

Figure 2. Biopsy of the left arm revealed subepidermal detachment with a neutrophilic infiltrate (A)(H&E, original magnification ×40) and perivascular neutrophilic infiltration with nuclear debris and red blood cell extravasation, consistent with early leukocyctoclastic vasculitis (B)(H&E, original magnification ×100).

Levamisole’s short half-life (approximately 5–6 hours) makes it difficult to detect on routine blood draws. An astute physician suspecting this diagnosis on initial presentation can ask for levamisole detection on urine toxicology screening.⁷ Urine samples also can be sent for testing with gas chromatography–mass spectrometry, though this test may only be available at major research centers.⁸

Differential diagnosis of levamisole toxicity includes different types of vasculitides such as cryoglobulinemia (positive serum IgM and IgG cryoglobulins; possible hepatitis C infection), Wegener granulomatosis (cytoplasmic ANCA positive; associated with upper and lower respiratory tract inflammation, glomerulonephritis), Churg-Strauss syndrome (perinuclear ANCA positive; associated with asthma and eosinophilia), and polyarteritis nodosa (medium vessel involvement only; associated with livedo reticularis, subcutaneous nodules, ulcers).⁹ Necrotic lesions also may raise the possibility of warfarin necrosis, heparin necrosis, or cholesterol emboli. Cholesterol embolism most frequently presents with small vessel vasculitis and necrosis of distal extremities such as the toes. With large areas of skin involvement and bullae, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis also should be considered.⁹

Definitive treatment of this condition requires complete and immediate cessation of cocaine use. Levamisole also has been found as a contaminant in heroin.¹ Thus, it may be prudent to recommend heroin avoidance to the patient to prevent recurrences. Management of acute levamisole-induced vasculopathy is primarily symptomatic. Some patients with severe neutropenia at risk for infection have been treated with granulocyte colony-stimulating factor, while others have only required pain control, usually with nonsteroidal anti-inflammatory drugs.¹⁰ Oral prednisone and colchicine also have been used with reported success.⁵

Given the increasing incidence of levamisole toxicity and public health implications, clinicians should be aware of this association and the classic clinical and laboratory findings.

The Diagnosis: Circle Hairs

The patient’s hairs were visualized under dermoscopy (Figure 1). A skin biopsy showed a terminal hair in a horizontal distribution that was located beneath the stratum corneum (Figure 2). The patient was diagnosed with circle hairs.

Circle hairs were first described in 1963.¹ These peculiar hairs grow in a circular horizontal distribution beneath the stratum corneum and are considered benign incidental findings. Their exact cause is unknown. If taken out and unrolled, their length and diameter tends to be smaller than surrounding hairs. It has been hypothesized that they are the result of hairs that lack the size necessary to perforate the stratum corneum.² Others propose that they are vestigial remains that once had a part in preserving body heat.³ Circle hairs tend to grow in elderly, hairy, and obese males, predominantly on the torso and thighs.^2,4

It is important to distinguish between circle hairs and rolled hairs. Rolled hairs may be found on the surface or beneath the stratum corneum and are associated with inflammation and keratinization abnormalities.² If taken together, these latter findings can help differentiate between the two. The importance stands in recognizing that both circle hairs and rolled hairs are benign; however, rolled hairs can be related to other skin disorders that need additional treatment.

Figure 1. Dermatoscopic view of hair.

Figure 2. A skin biopsy showed a terminal hair in a horizontal distribution that was located beneath the stratum corneum (A and B)(both Verhoeff-van Gieson, original magnifications ×40).

The Diagnosis: Circle Hairs

The patient’s hairs were visualized under dermoscopy (Figure 1). A skin biopsy showed a terminal hair in a horizontal distribution that was located beneath the stratum corneum (Figure 2). The patient was diagnosed with circle hairs.

Circle hairs were first described in 1963.¹ These peculiar hairs grow in a circular horizontal distribution beneath the stratum corneum and are considered benign incidental findings. Their exact cause is unknown. If taken out and unrolled, their length and diameter tends to be smaller than surrounding hairs. It has been hypothesized that they are the result of hairs that lack the size necessary to perforate the stratum corneum.² Others propose that they are vestigial remains that once had a part in preserving body heat.³ Circle hairs tend to grow in elderly, hairy, and obese males, predominantly on the torso and thighs.^2,4

It is important to distinguish between circle hairs and rolled hairs. Rolled hairs may be found on the surface or beneath the stratum corneum and are associated with inflammation and keratinization abnormalities.² If taken together, these latter findings can help differentiate between the two. The importance stands in recognizing that both circle hairs and rolled hairs are benign; however, rolled hairs can be related to other skin disorders that need additional treatment.

Figure 1. Dermatoscopic view of hair.

Figure 2. A skin biopsy showed a terminal hair in a horizontal distribution that was located beneath the stratum corneum (A and B)(both Verhoeff-van Gieson, original magnifications ×40).

The Diagnosis: Circle Hairs

The patient’s hairs were visualized under dermoscopy (Figure 1). A skin biopsy showed a terminal hair in a horizontal distribution that was located beneath the stratum corneum (Figure 2). The patient was diagnosed with circle hairs.

Circle hairs were first described in 1963.¹ These peculiar hairs grow in a circular horizontal distribution beneath the stratum corneum and are considered benign incidental findings. Their exact cause is unknown. If taken out and unrolled, their length and diameter tends to be smaller than surrounding hairs. It has been hypothesized that they are the result of hairs that lack the size necessary to perforate the stratum corneum.² Others propose that they are vestigial remains that once had a part in preserving body heat.³ Circle hairs tend to grow in elderly, hairy, and obese males, predominantly on the torso and thighs.^2,4

It is important to distinguish between circle hairs and rolled hairs. Rolled hairs may be found on the surface or beneath the stratum corneum and are associated with inflammation and keratinization abnormalities.² If taken together, these latter findings can help differentiate between the two. The importance stands in recognizing that both circle hairs and rolled hairs are benign; however, rolled hairs can be related to other skin disorders that need additional treatment.

Figure 1. Dermatoscopic view of hair.

Figure 2. A skin biopsy showed a terminal hair in a horizontal distribution that was located beneath the stratum corneum (A and B)(both Verhoeff-van Gieson, original magnifications ×40).