Quiz

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

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).