Fnu Nutan, MD

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: 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.