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Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Necrolytic migratory erythema (NME) is a characteristic paraneoplastic cutaneous reaction classically associated with an underlying gastroenteropancreatic neuroendocrine tumor (NET), most commonly a pancreatic islet α-cell neoplasm. NME has also been associated with the pseudoglucagonoma syndrome (hyperglucagonemia in the absence of a glucagon-secreting tumor), metastatic NET, glucagon infusion–dependent states, hepatic disease, gluten-sensitive enteropathy, pancreatic insufficiency, glucagon cell adenomatosis, other malabsorption or malnutritional states, and cholangiocarcinoma. It may be associated with a polyfunctional endocrine tumor (MEN1).
NME is a rare disease that has an estimated yearly prevalence of one in 20,000,000. Most cases are associated with a glucagonoma, which make up a small proportion of the 1% of pancreatic tumors that are classified as NETs. NME presenting without glucagonoma has been reported largely through case reports and is likely to be even more uncommon. NME is the presenting symptom in over 70% of cases of glucagonoma, and, on presentation, 40–50% of glucagonomas are already metastatic, making the recognition of this rare clinical entity paramount for patient outcomes.
NME typically presents in the fifth decade of life and is classically accompanied by weight loss, new-onset or worsening diabetes mellitus, normocytic anemia, and hyperglucagonemia.
The lesions begin as pruritic or painful erythematous patches with central bullae formation leading to the classic appearance of a centrally crusted, annular erosive plaque with a psoriasiform border.
NME can be widespread but has a predilection for areas subject to pressure and friction such as the buttocks, inferior abdomen, lower extremities, and intertriginous areas.
Parakeratosis and upper-level keratinocyte vacuolization are characteristic on histopathologic examination of early lesions. The pathogenesis of NME has not been fully elucidated, although several theories have emerged from observations of patient responses to various treatment strategies. One theory suggests that the catabolic effects of glucagon lead to a hypermetabolic state, resulting in the deficiency of zinc and essential fatty acids. Given the multitude of various diseases that have been associated with NME, a multifactorial model for the pathogenesis of the disease has been hypothesized: (1) hyperglucagonemia-induced hypoalbuminemia leads to deficiencies in zinc (Zn), essential fatty acids (EFA), and amino acids (AA) such as tryptophan (albumin binds and circulates Zn, AA, and EFA throughout the body); (2) Zn deficiency induces primary cutaneous inflammation, as Zn plays a major role in restoring prostaglandin-mediated inflammatory response in the epidermis; and (3) subsequent tryptophan deficiency causes keratinocyte degradation without concomitant new cell formation. Tryptophan is essential for niacin biosynthesis; without adequate niacin, keratinocytes cannot regulate proper cellular turnover, capillary tone, and appropriate maturation of epidermis and mucosal epithelia. Theoretically, this constellation of elevated serum glucagon, hypoalbuminemia, zinc, EFA and AA deficiency, and potentially hepatic dysfunction ultimately leads to the increase in epidermal inflammation, breakdown, and necrolysis observed in NME.
Necrolytic acral erythema (NAE), often associated with hepatitis C virus infection, is considered by some to be an acral variant of NME. One should consider the diagnosis of atypical NAE in the differential diagnosis of NME.
Addressing the underlying cause of NME is paramount for treatment. In the setting of glucagonoma, surgical resection of the tumor is ideal; however, metastasis is commonly present at the time of diagnosis, obfuscating complete cure. Glucagonomas grow slowly and tend to be encapsulated, so if identified early and fully excised adjunctive therapy is usually unnecessary. The somatostatin agonists, octreotide and lanreotide, are considered the first-line treatment of choice in NME with or without associated glucagonoma. Streptozotocin (STZ)-based combination chemotherapy , such as STZ and doxorubicin (DOX) or 5-FU, may be considered for moderately and well-differentiated NETs. More recently, the combination of temozolomide and capecitabine has been studied for the treatment of advanced pancreatic NETs. For poorly differentiated NETs, a platinum-based chemotherapeutic regimen, such as STZ, 5-FU, and cisplatin (FCiSt), should be considered. Peptide receptor radioligand therapy with radiolabeled somatostatin agonists has been tried with moderate success, and the agent 177-LUDOTATE was recently approved by the US Food and Drug Administration for the treatment of gastroenteropancreatic NETs. Sunitinib, an inhibitor of the multiple receptor tyrosine kinases, and everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), have also demonstrated increased progression-free survival in patients with progressive, advanced pancreatic NETs. Adjunctive deep vein thrombosis prophylaxis should also be advised due to the risk of thromboembolism with glucagonoma. Additionally, correcting any nutritional deficiencies in general (with correction of AA, EFA, or zinc specifically) should be undertaken immediately, as supplementation has been associated with a marked improvement of the cutaneous lesions of NME.
A diagnosis of NME in the absence of glucagonoma should make one suspect possible underlying nutritional deficiencies or pseudoglucagonoma syndrome. These conditions can be encountered in hepatic disease and other causes of chronic malabsorption such as celiac disease, inflammatory bowel disease, chronic pancreatitis, or metastatic NET and cholangiocarcinoma. Glucagon cell adenomatosis, the diffuse enlargement of islets of Langerhans cells with resulting glucagon hypersecretion, should be expected when there is no evidence of a detectable pancreatic mass on imaging. If MEN1 or a polyfunctional endocrine tumor is suspected, one should consider investigating levels of fasting insulin , prolactin , parathyroid hormone , calcium , vasoactive intestinal peptide (VIP) , gastrin , and adrenocorticotropic hormone (ACTH) in the workup.
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Tolliver S, Graham J, Kaffenberger B. Int J Dermatol 2018; 57: 642–5.
This case report, which describes a patient presenting with NME who is diagnosed with glucagonoma, highlights the importance of recognizing NME as a presenting sign of glucagonoma.
Cunha-Silva M, da Costa JG, Faria GAS, et al. Autops Case Rep 2019; 9: e2019129.
This case report highlights diarrhea as an uncommon component of glucagonoma syndrome that can cause significant nutritional impairment, leading to poor patient outcomes.
Shah MH, Goldner WS, Halfdanarson TR, et al. J Natl Compr Canc Netw 2018; 16: 693–702.
These guidelines, developed by the National Comprehensive Cancer Center, were updated in 2018. Important additions include the upgraded recommendation of everolimus or peptide receptor radionuclide therapy (PRRT) with Lu-DOTATATE for progressive disease in pancreatic NETs.
Virani S, Prajapati V, Devani A, et al. J Am Acad Dermatol 2013; 68: e44–6.
A 56-year-old female with a history of ectopic Cushing syndrome with liver metastases was diagnosed with NME secondary to pseudoglucagonoma syndrome. Near resolution of lesions was observed after 4 weeks of subcutaneous administration of octreotide.
Koch LH, Lewis D, Williams JV. J Am Acad Dermatol 2008; 58: S29–30.
This case report supports the chronic malabsorption syndrome (CMS) theory as a cause of NME. Patients with CMS secondary to cystic fibrosis can present with psoriasiform lesions similar to NME. In this case report, the patient’s NME-like lesions resolved after nutritional therapy with zinc and hydrolyzed protein formula.
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