Necrolytic migratory erythema

Published on 19/03/2015 by admin

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Necrolytic migratory erythema

Sandra A. Kopp and Analisa Vincent Halpern

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

(Courtesy of Dr Anna Krishtul.)

Necrolytic migratory erythema (NME) is classically considered a paraneoplastic cutaneous reaction pattern associated with a pancreatic islet-cell neoplasm. It is usually seen in the context of new-onset or worsening diabetes mellitus, weight loss, normocytic anemia, and hyperglucagonemia as part of the glucagonoma syndrome. Other symptoms can include venous thromboembolism, stomatitis, steatorrhea or diarrhea, and neuropsychiatric changes. NME can be widespread but has a predilection for the intertriginous areas, buttocks, inferior abdomen, and lower extremities. It presents as a pruritic or painful erythematous patch with central bullous formation, leading to the classic appearance of a centrally crusted annular erosive plaque with a psoriasiform border. The plaques tend to wax and wane, healing with dyspigmentation. Associated onychoschizia and dyspareunia have also been reported.

NME is often mistaken for intertrigo, psoriasis, or seborrheic dermatitis. Parakeratosis and upper-level keratinocyte vacuolization are characteristic on histopathologic examination of early lesions. Excessive stimulation of basal metabolic pathways in the glucagonoma syndrome leads to a hypermetabolic state in which the patient becomes nutritionally deficient. It is thought that zinc, amino acid, and essential fatty acid deficiencies contribute to the cutaneous disease. In the absence of a glucagonoma, NME has also been reported with glucagon infusion-dependent states, hepatic disease, gluten-sensitive enteropathy, pancreatic insufficiency, glucagon cell adenomatosis, and other malabsorption or malnutritional states, such as cystic fibrosis. Metastatic neuroendocrine tumor and cholangiocarcinoma have also been reported with NME. Necrolytic acral erythema, associated with hepatitis C, is thought by some to be an acral variant of NME and may be part of the spectrum of NME.

Management strategy

Treatment of the underlying disease is the preferred therapy for NME. In the setting of glucagonoma, surgical excision of the tumor is the treatment of choice, although curative resection is possible in only a minority due to frequent metastasis. Chemotherapy, primarily with dacarbazine and streptozocin, is a frequent, albeit only moderately successful, adjunctive therapy. Octreotide and lantreotide, long-acting somatostatin analogs, alone or in combination with interferon-α, are useful in the treatment of metastases or inoperable tumors, and have shown some success in clearing NME regardless of tumor response. Newer agents being studied include peptide receptor radionuclide therapy, mTor inhibitors, and sunitinib. Some patients with NME secondary to glucagonoma have had improvement of skin lesions after intravenous infusions of amino acids and fatty acids. Adjunctive DVT prophylaxis should also be advised due to the risk of thromboembolism with glucagonoma.

The occurrence of NME in the absence of glucagonoma should make one suspect the possibility of nutritional deficiencies encountered in hepatic disease, celiac disease, Crohn disease, other enteropathies, chronic pancreatitis, or other malignancies such as metastatic neuroendocrine tumor and cholangiocarcinoma. Hyperglucagonemia in the absence of a detectable mass on imaging can occur in glucagon cell adenomatosis. Any deficiency in amino acids, essential fatty acids, or zinc should be corrected if present. Glucagonomas can also arise in the setting of multiple endocrine neoplasia 1 syndrome (MEN1) or in the context of a polyfunctional endocrine tumor; therefore levels of fasting insulin, prolactin, parathyroid hormone, calcium, vasoactive intestinal peptide (VIP), gastrin, and ACTH should be considered. Rarely glucagonomas can be seen in von Hippel-Lindau disease, neurofibromatosis 1, and tuberous sclerosis.

Specific investigations

First-line therapies

image Tumor resection B
image Somatostatins B

Third-line therapies

image Streptozocin B
image Doxorubicin B
image Fluorouracil B
image Everolimus A
image Sunitinib A
image Dacarbazine D
image Liver transplantation E

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Necrolytic migratory erythema

Sandra A. Kopp and Analisa Vincent Halpern

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

(Courtesy of Dr Anna Krishtul.)

Necrolytic migratory erythema (NME) is classically considered a paraneoplastic cutaneous reaction pattern associated with a pancreatic islet-cell neoplasm. It is usually seen in the context of new-onset or worsening diabetes mellitus, weight loss, normocytic anemia, and hyperglucagonemia as part of the glucagonoma syndrome. Other symptoms can include venous thromboembolism, stomatitis, steatorrhea or diarrhea, and neuropsychiatric changes. NME can be widespread but has a predilection for the intertriginous areas, buttocks, inferior abdomen, and lower extremities. It presents as a pruritic or painful erythematous patch with central bullous formation, leading to the classic appearance of a centrally crusted annular erosive plaque with a psoriasiform border. The plaques tend to wax and wane, healing with dyspigmentation. Associated onychoschizia and dyspareunia have also been reported.

NME is often mistaken for intertrigo, psoriasis, or seborrheic dermatitis. Parakeratosis and upper-level keratinocyte vacuolization are characteristic on histopathologic examination of early lesions. Excessive stimulation of basal metabolic pathways in the glucagonoma syndrome leads to a hypermetabolic state in which the patient becomes nutritionally deficient. It is thought that zinc, amino acid, and essential fatty acid deficiencies contribute to the cutaneous disease. In the absence of a glucagonoma, NME has also been reported with glucagon infusion-dependent states, hepatic disease, gluten-sensitive enteropathy, pancreatic insufficiency, glucagon cell adenomatosis, and other malabsorption or malnutritional states, such as cystic fibrosis. Metastatic neuroendocrine tumor and cholangiocarcinoma have also been reported with NME. Necrolytic acral erythema, associated with hepatitis C, is thought by some to be an acral variant of NME and may be part of the spectrum of NME.

Management strategy

Treatment of the underlying disease is the preferred therapy for NME. In the setting of glucagonoma, surgical excision of the tumor is the treatment of choice, although curative resection is possible in only a minority due to frequent metastasis. Chemotherapy, primarily with dacarbazine and streptozocin, is a frequent, albeit only moderately successful, adjunctive therapy. Octreotide and lantreotide, long-acting somatostatin analogs, alone or in combination with interferon-α, are useful in the treatment of metastases or inoperable tumors, and have shown some success in clearing NME regardless of tumor response. Newer agents being studied include peptide receptor radionuclide therapy, mTor inhibitors, and sunitinib. Some patients with NME secondary to glucagonoma have had improvement of skin lesions after intravenous infusions of amino acids and fatty acids. Adjunctive DVT prophylaxis should also be advised due to the risk of thromboembolism with glucagonoma.

The occurrence of NME in the absence of glucagonoma should make one suspect the possibility of nutritional deficiencies encountered in hepatic disease, celiac disease, Crohn disease, other enteropathies, chronic pancreatitis, or other malignancies such as metastatic neuroendocrine tumor and cholangiocarcinoma. Hyperglucagonemia in the absence of a detectable mass on imaging can occur in glucagon cell adenomatosis. Any deficiency in amino acids, essential fatty acids, or zinc should be corrected if present. Glucagonomas can also arise in the setting of multiple endocrine neoplasia 1 syndrome (MEN1) or in the context of a polyfunctional endocrine tumor; therefore levels of fasting insulin, prolactin, parathyroid hormone, calcium, vasoactive intestinal peptide (VIP), gastrin, and ACTH should be considered. Rarely glucagonomas can be seen in von Hippel-Lindau disease, neurofibromatosis 1, and tuberous sclerosis.