Background

This rare skin rash is classically associated with a malignant neuroendocrine tumor of the pancreas which produces glucagon. This glucagonoma produces a syndrome which has this characteristic skin rash. In addition, there is usually diabetes mellitus, diarrhea, and weight loss. Metastatic disease is common. Resection of the malignant tumor may produce a dramatic remission of the skin rash.

OUTLINE

Epidemiology
Disease Associations	Glucagonoma syndrome Liver disease Zinc deficiency
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms

EPIDEMIOLOGY	CHARACTERIZATION
INCIDENCE	Rare but in almost all cases of malignant glucagonoma

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
CANDIDIASIS
Necrolytic migratory erythema, presenting as candidiasis, due to a pancreatic glucagonoma. Katz R, Fischmann AB, Galotto J, Guccio JG, Higgins GA, Ortega LG, West WH, Recant L.	Cancer 1979 Aug;44(2):558-63 Abstract quote A 54-year-old male with diabetes, weight loss, glossitis and Candidiasis presented with the typical cutaneous eruption of necrolytic migratory erythema. The suspicion of pancreatic glucagonoma was confirmed by an elevated plasma glucagon level. Surgical removal of the pancreatic alpha cell tumor resulted in a complete disappearance of all symptoms. The importance of the recognition of the skin eruption of necrolytic migratory erythema as a clue to the presence of pancreatic glucagonoma is emphasized.
CELIAC DISEASE
Necrolytic migratory erythema with elevated plasma enteroglucagon in celiac disease. Kelly CP, Johnston CF, Nolan N, Keeling PW, Weir DG. Department of Clinical Medicine, Trinity College, Dublin, Ireland.	Gastroenterology 1989 May;96(5 Pt 1):1350-3 Abstract quote Necrolytic migratory erythema is the distinctive skin rash of the glucagonoma syndrome. Its presence is virtually pathognomonic of a glucagon-producing pancreatic islet cell neoplasm. Results of a study of a patient with hyperglucagonemia and necrolytic migratory erythema complicating untreated celiac disease are reported. Whereas pancreatic glucagon was only mildly elevated, there was marked elevation of enteroglucagon. Immunofluorescence staining demonstrated numerous (19.6 cells per square millimeter of mucosa) enteroglucagon-positive small intestinal crypt cells. Treatment with gluten-free diet not only resulted in resolution of malabsorption and improvement in small intestinal histology but was paralleled by disappearance of necrolytic migratory erythema, normalization of plasma glucagon levels, and marked reduction in the number of enteroglucagon-producing crypt cells (0.2/mm2 mucosa). The findings demonstrate that necrolytic migratory erythema is not an exclusively paraneoplastic phenomenon and that it can occur in association with excess production of enteroglucagon by the intestinal mucosa.
GLUCAGONOMA SYNDROME
Glucagonoma without cutaneous manifestations. Parr JH, Ramsay ID, Keeling PW, Thompson RP, Mallinson CN.	Postgrad Med J 1985 Aug;61(718):737-8 Abstract quote A 63 year old man presented with features of the glucagonoma syndrome, that is thromboembolic disease, weight loss, raised sedimentation rate, diabetes mellitus, hypoproteinaemia and reduced plasma amino acid levels, but without necrolytic migratory erythema. The plasma glucagon level was raised and the tumour was demonstrated by abdominal CT scan. Immunofluorescent studies of the resected tumour confirmed the diagnosis. The normal tissue zinc status supports the view that necrolytic migratory erythema is related to zinc deficiency.
Glucagonoma syndrome is an underdiagnosed clinical entity. Edney JA, Hofmann S, Thompson JS, Kessinger A. Department of Surgery, University of Nebraska Medical Center, Omaha.	Am J Surg 1990 Dec;160(6):625-8; discussion 628-9 Abstract quote Glucagonomas, considered among the rarest of the islet cell neoplasms, produce a well-defined clinical syndrome characterized by necrolytic migratory erythema, diabetes mellitus, glossitis, anemia, and weight loss. This report describes seven patients with glucagonoma treated at our institution. All seven had the characteristic dermatologic manifestations, present from 1 to 6 years prior to diagnosis. Five patients had extensive disease at the time of initial operation, three of whom underwent aggressive cytoreductive surgery, whereas the other two had biopsy only. The remaining two patients presented with a single nodule each, underwent distal pancreatectomy and splenectomy, and remain free of disease 2 and 6 years postoperatively. Earlier recognition of the distinctive physical findings peculiar to this syndrome should increase survival. Aggressive cytoreductive surgery results in prolonged remission.
Necrolytic migratory erythema: a report of three cases. Thorisdottir K, Camisa C, Tomecki KJ, Bergfeld WF. Department of Dermatology, Cleveland Clinic Foundation.	J Am Acad Dermatol 1994 Feb;30(2 Pt 2):324-9 Abstract quote Necrolytic migratory erythema (NME) is a cutaneous reaction pattern with specific histopathologic features that is typically associated with a functioning pancreatic islet cell neoplasm such as a glucagonoma. Three examples of NME, each associated with a different cause, are presented: glucagonoma, pancreatic insufficiency, and gluten-sensitive enteropathy. All three patients were successfully treated by surgical resection of the pancreatic tumor, total parenteral nutrition and pancreatic enzyme replacement, or a strict gluten-free diet, respectively. All remain free of skin disease more than 2 years later. Any patient with NME should be evaluated for glucagonoma and small bowel disease that may be associated with malabsorption and malnutrition.
The glucagonoma syndrome. Clinical and pathologic features in 21 patients. Wermers RA, Fatourechi V, Wynne AG, Kvols LK, Lloyd RV. Division of Endocrinology/Metabolism and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA.	Medicine (Baltimore) 1996 Mar;75(2):53-63 Abstract quote The glucagonoma syndrome is a rare disorder characterized by weight loss, necrolytic migratory erythema (NME), diabetes, stomatitis, and diarrhea. We identified 21 patients with the glucagonoma syndrome evaluated at the Mayo Clinic from 1975 to 1991. Although NME and diabetes help identify patients with glucagonomas, other manifestations of malignant disease often lead to the diagnosis. If the diagnosis is made after the tumor is metastatic, the potential for cure is limited. The most common presenting symptoms of the glucagonoma syndrome were weight loss (71%), NME (67%), diabetes mellitus (38%), cheilosis or stomatitis (29%), and diarrhea (29%). Although only 8 of the 21 patients had diabetes at presentation, diabetes eventually developed in 16 patients, 75% of whom required insulin therapy. Symptoms other than NME or diabetes mellitus led to the diagnosis of an islet cell tumor in 7 patients. The combination of NME and diabetes mellitus led to a more rapid diagnosis (7 months) than either symptom alone (4 years). Ten patients had diabetes mellitus before the onset of NME. No patients had NME clearly preceding diabetes mellitus. Increased levels of secondary hormones, such as gastrin (4 patients), vasoactive intestinal peptide (1 patient), serotonin (5 patients), insulin (6 patients, clinically significant in 1 only), human pancreatic polypeptide (2 patients), calcitonin (2 patients) and adrenocorticotropic hormone (2 patients), contributed to clinical symptoms leading to the diagnosis of an islet cell tumor before the onset of the full glucagonoma syndrome in 2 patients. All patients had metastatic disease at presentation. Surgical debulking, chemotherapy, somatostatin, and hepatic artery embolization offered palliation of NME, diabetes, weight loss, and diarrhea. Despite the malignant potential of the glucagonomas, only 9 of 21 patients had tumor-related deaths, occurring an average of 4.91 years after diagnosis. Twelve patients were still alive, with an average age follow-up of 3.67 years.
Clinical spectrum of hyperglucagonemia associated with malignant neuroendocrine tumors. Wermers RA, Fatourechi V, Kvols LK. Division of Endocrinology/Metabolism and Internal Medicine, Mayo Clinic Rochester, Minnesota 55905, USA.	Mayo Clin Proc 1996 Nov;71(11):1030-8 Abstract quote OBJECTIVE: To review the clinical features associated with hyperglucagonemia in malignant neuroendocrine tumors. MATERIAL AND METHODS: We retrospectively reviewed the medical records of patients with hyperglucagonemia encountered at our institution from Oct. 17, 1988, through February 1993 who had a fasting serum glucagon level of at least 120 pg/mL (twice the normal value). The 71 study patients also had no evidence of a secondary cause of hyperglucagonemia and had pathologic confirmation of a neuroendocrine tumor. RESULTS: The study group consisted of 46 men and 25 women with a median age of 57 years. Two patients had multiple endocrine neoplasia. Forty-nine patients had biochemically polyfunctional tumors, and 22 had hyperglucagonemia only. The most common initial symptoms were weight loss, abdominal pain, diarrhea, nausea, peptic ulcer disease, diabetes, and necrolytic migratory erythema (NME). Diabetes eventually developed in 25 patients and was associated with NME in 11. The highest median serum glucagon values occurred in patients with the glucagonoma syndrome or insulinomas, and the lowest median values were in those with carcinoid syndrome, Zollinger-Ellison syndrome, or diabetes without NME. Fasting glucagon and glucose measurements were not correlated. The most common hormonal syndromes were the Zollinger-Ellison syndrome and the glucagonoma syndrome. All the neuroendocrine tumors were malignant. Several methods of treatment, including surgical debulking, chemotherapy, somatostatin, and hepatic artery embolization, were used. Death occurred in 29 patients at a median of 2.79 years after diagnosis; 42 patients were alive at a median of 2.86 years after diagnosis. CONCLUSION: A mild degree of hyperglucagonemia can commonly be associated with multifunctional neuroendocrine tumors. The glucagonoma syndrome occurs in a few patients with malignant neuroendocrine tumors and hyperglucagonemia and is associated with very high serum glucagon levels. The correlation between serum glucagon levels and the development of diabetes is limited, and other factors such as insulin may be more important than hyperglucagonemia in the development of diabetes.
Cystic glucagonoma: A rare variant of an uncommon neuroendocrine pancreas tumor. Brown K, Kristopaitis T, Yong S, Chejfec G, Pickleman J. Department of Surgery, Loyola University Medical Center, Maywood, Illinois 60153, USA.	J Gastrointest Surg 1998 Nov-Dec;2(6):533-6 Abstract quote Glucagon-producing neuroendocrine tumors typically present with a characteristic constellation of symptoms including necrolytic migratory erythema, non-insulin-dependent diabetes, weight loss, anemia, glossitis, and an increased thrombotic tendency. Most glucagonomas are solid and arise in the body or tail of the pancreas. We report two cases of cystic glucagonoma, one found incidentally in an asymptomatic patient and one in a patient with weight loss and diabetes but no rash. In the first patient, distal pancreatectomy and splenectomy were curative, whereas the second patient continued to exhibit elevated serum glucagon levels and symptoms of glucose intolerance in the absence of demonstrable metastases. Cystic glucagonoma is a unique variant of classic glucagonoma and should be considered in the differential diagnosis of cystic pancreatic neoplasms.
Epidemiology, clinical features and diagnosis of gastroenteropancreatic endocrine tumours. Tomassetti P, Migliori M, Lalli S, Campana D, Tomassetti V, Corinaldesi R. Department of Internal Medicine and Gastroenterology, University ol Bologna, Italy.	Ann Oncol 2001;12 Suppl 2:S95-9 Abstract quote Gastroenteropancreatic (GEP) neoplasms originate from any of the various cell types belonging to the neuroendocrine system. A general characteristic of GEP endocrine tumours is that the vast majority produce and secrete a multitude of peptide hormones and amines. Many patients with malignant metastasising tumours present clinical symptoms related to hormone hyperproduction. These include the so-called carcinoid syndrome, characterised by flushing, diarrhoea, wheezing and right heart disease, which is predominantly associated with the serotonin- and tachykinins-producing carcinoids of the midgut. Several types of syndrome associated with GEP endocrine tumors are caused by overproduction of a specific hormone. For instance, the well-known Zollinger-Ellison syndrome is gastrin-mediated. The so-called 'insulinoma syndrome' depends on excessive production of insulin and proinsulin, resulting in hypoglycemia. The 'glucagonoma syndrome' is characterised by necrolytic migratory erythema, diabetes and diarrhoea. The Verner-Morrison syndrome, which is brought about by high circulating levels of vasointestinal peptide (VIP). produces severe secretory diarrhoea. Finally the 'somatostatinoma syndrome' involves gallbladder dysfunction and gallstones, diarrhoea with or without steatorrhea, and impaired glucose tolerance. The biochemical diagnosis of endocrine digestive tumors is based on general and specific markers. The best general markers are chromogranin A (CgA) and pancreatic polypeptide (PP). Specific markers for endocrine tumors include insulin, gastrin, glucagon, vaso intestinal polypeptide (VIP), somatostatin and the primary cathabolic product of serotonin, 5-hydroxyndoleacetic acid (5-HIAA). Localisation procedures commonly applied, in the diagnosis of endocrine tumours include ultrasound (US), computed tomography (CT) and somatostatin receptor scintigraphy (SRS).
LIVER DISEASE
Hyperglucagonaemia and necrolytic migratory erythema in cirrhosis--possible pseudoglucagonoma syndrome. Doyle JA, Schroeter AL, Rogers RS 3rd.	Br J Dermatol 1979 Nov;101(5):581-7 Abstract quote Necrolytic migratory erythema is the distinctive cutaneous eruption seen with glucagon-producing tumours of the pancreas. Recognition of this eruption is important because it may lead to the early diagnosis of a glucagonoma. Recently, we saw a patient who had necrolytic migratory erythema, hyperglucagonaemia, and cirrhosis of the liver with no evidence of pancreatic tumour while alive or at autopsy. Serum glucagon levels during the period of observation and during an oral glucose tolerance test suggested that the hyperglucagonaemia was not due to an occult glucagon-producing tumour but may have been the result of advanced hepatic cirrhosis.
Necrolytic migratory erythema without glucagonoma in patients with liver disease. Marinkovich MP, Botella R, Datloff J, Sangueza OP. Department of Dermatology, Oregon Health Sciences University, Portland.	J Am Acad Dermatol 1995 Apr;32(4):604-9 Abstract quote BACKGROUND: Necrolytic migratory erythema (NME) is an uncommon inflammatory dermatosis with a distinct clinical and histologic appearance. NME is usually associated with glucagonoma. Only a few cases of NME in the absence of glucagonoma have been previously reported. OBJECTIVE: We sought to understand further the pathogenesis of NME by analyzing data from three patients. METHODS: Three patients were examined both clinically and histopathologically. RESULTS: Each patient had an extensive erythematous scaling eruption in intertriginous, perioral, and acral areas, and a markedly red, smooth tongue. Skin biopsy specimens showed confluent parakeratosis, epidermal pallor, papillary edema, and a lymphohistiocytic infiltrate. Two patients had alcoholic liver disease and one had liver dysfunction as a result of hemochromatosis. Serum albumin level was depressed, and liver enzyme values were increased in all three patients. Glucagonoma was undetectable in these patients. CONCLUSION: In the absence of glucagonoma, hepatocellular dysfunction and hypoalbuminemia appear to be the most common factors associated with NME.
ZINC DEFICIENCY
Necrolytic migratory erythema and zinc deficiency. Sinclair SA, Reynolds NJ. Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.	Br J Dermatol 1997 May;136(5):783-5 Abstract quote Necrolytic migratory erythema (NME) is an uncommon condition classically associated with high plasma levels of circulating glucagon and a glucagonoma. We report a patient with cirrhosis who showed clinical and histological features of NME. Investigation revealed normal glucagon levels without evidence of glucagonoma. Serum zinc levels were below the normal range and zinc supplementation resulted in rapid and complete resolution of the eruption.

 

PATHOGENESIS	CHARACTERIZATION
AMINO ACID DEFICIENCY
Amino acid deficiency and the skin rash associated with glucagonoma. Norton JA, Kahn CR, Schiebinger R, Gorschboth C, Brennan MF.	Ann Intern Med 1979 Aug;91(2):213-5 Abstract quote A 47-year-old white man had a malignant glucagonoma and severe necrolytic migratory erythema. His plasma glucagon levels were markedly elevated at 50 ng/mL and plasma amino acids diminished to 45% of normal. To test the hypothesis that the skin rash associated with a glucagonoma is secondary to an amino acid deficiency, we obtained 2 d of fasting baseline laboratory data from the patient while he consumed his usual diet. He was then given 3 L/d of supplemental intravenous amino acids for 3 d. His plasma amino acid levels increased slightly, and there was some improvement in his skin rash. Immediately thereafter, total parenteral nutrition was administered for 3 d without added zinc or fatty acids. During total parenteral nutrition, 14 of 17 plasma amino acids became normal, and the patient's skin rash rapidly disappeared. These findings suggest that the skin rash associated with a glucagonoma is most likely due to an amino acid deficiency and can be reversed by parenteral nutrition.

 

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
LABORATORY MARKERS
GLUCAGON
Metabolic studies and glucagon gel filtration pattern before and after surgery in a case of glucagonoma syndrome. von Schenck H, Thorell JI, Berg J, Bojs G, Dymling JF, Hallengren B, Ljungberg O, Tibblin S.	Acta Med Scand 1979;205(3):155-62 Abstract quote A case of glucagonoma syndrome with necrolytic migratory erythema, glossitis, anemia, hyperglucagonemia and a malignant, pancreatic A-cell tumour in a 68-year-old male is described. Gel filtration of the highly elevated circulating glucagon immunoreactivity (2200 pg/ml) demonstrated 60% pancreatic glucagon and 30% "proglucagon". Metabolic studies before operation demonstrated suppression of the total plasma glucagon concentration on oral glucose tolerance test, unchanged total plasma glucagon concentration during intravenous glucose tolerance test and insulin-induced hypoglycemia. Administration of arginine was followed by a rise in both the pancreatic glucagon and the "proglucagon", whereas alanine increased only the pancreatic glucagon. The plasma somatostatin level was immeasurable preoperatively. Somatostatin infusion completely suppressed the release of the pancreatic glucagon but did not significantly affect the "proglucagon". After removal of the tumour the skin lesions disappeared and the total plasma glucagon values fell to normal levels (120 pg/ml). Also, other abnormal laboratory findings returned to normal, including the preoperatively observed renal glucosuria.
LDH
Glucagonoma syndrome with increased lactate dehydrogenase isoenzymes: octreotide treatment. Siller GM, Strutton GM, Moore GA, Kanowski DM, Nedwich JA. Royal Brisbane Hospital.	Australas J Dermatol 1994;35(1):11-4 Abstract quote Glucagonoma Syndrome is a rare syndrome comprising hyperglucagonemia, diabetes mellitus, necrolytic migratory erythema and hypoaminoacidemia in the setting of a glucagon producing, alpha cell tumour of the pancreas. We report a case of Glucagonoma Syndrome palliatively treated successfully with octreotide. In addition to classical clinical and biochemical findings, this patient also had a Glomus Jugulare tumour, and Empty Sella Syndrome and demonstrated an unusual pattern of plasma lactate dehydrogenase isoenzymes, features not previously reported in this syndrome.

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
Necrolytic migratory erythema. Distinctive dermatosis of the glucagonoma syndrome. Kahan RS, Perez-Figaredo RA, Neimanis A	Arch Dermatol 1977 Jun;113(6):792-7 Abstract quote Glucagon-secreting tumors of the pancreatic islets (glucagonomas) produce a distinctive syndrome in which weight loss, diabetes mellitus, anemia,and prominent mucocutaneous findings occur. The cutaneous component-necrolytic migratory erythema--may be polymorphous, but most commonly manifests as erosions and crusts of the groin, perineum, buttocks, distal part of the extremities, and central area of the face. Alternatively, scaly papules and plaques may predominate in these areas. The eruption may resemble such dermatoses as pemphigus foliaceus, acrodermatitis enteropathica, chronic mucocutaneous candidiasis, psoriasis, and severe seborrheic dermatitis. Two patients with chronic, previously undiagnosed dermatoses had necrolytic migratory erythemia, which led to the discovery of glucagonomas present in each. In one patient surgical resection of the tumor resulted in total clearing of the rash within 48 hours. Awareness of this distinctive entity may lead to early diagnosis and, possibly, cure.
Delayed diagnosis of glucagonoma syndrome. Alkemade JA, van Tongeren JH, van Haelst UJ, Smals A, Steijlen PM, van de Kerkhof PC. Department of Dermatology, University Hospital Nijmegen St Radboud, The Netherlands.	Clin Exp Dermatol 1999 Nov;24(6):455-7 Abstract quote The classical presentations of necrolytic migratory erythema associated with alpha cell pancreatic tumour have been well documented. In addition, the occurrence of extracutaneous hallmarks of this disease such as weight loss, diabetes, anaemia, stomatitis and diarrhoea have been described in various reports. Here we report three cases with glucagonoma syndrome. Early detection is important in view of the malignant course of the disease. However, diagnosis is sometimes complicated by the fact that some patients may fail to show the characteristic feature of glucagonoma syndrome.
VARIANTS
WITHOUT GLUCAGONOMA
Necrolytic migratory erythema without glucagonoma. Goodenberger DM, Lawley TJ, Strober W, Wyatt L, Sangree MH Jr, Sherwin R, Rosenbaum H, Braverman I, Katz SI.	Arch Dermatol 1979 Dec;115(12):1429-32 Abstract quote Two patients with clinical and histologic findings consistent with necrolytic migratory erythema are presented. Unlike previously described patients with this disorder, neither patient had substantially elevated glucagon levels nor an associated pancreatic islet cell tumor. The cause of the skin disease in these patients remains unknown but may be related to the underlying small-bowel disorder present in both.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL	Hyperkeratosis, parakeratosis, formation of clefts in the upper epidermis, and scattered dyskeratotic cells.
VARIANTS
ACANTHOLYSIS
Suprabasal acantholysis--an unusual feature of necrolytic migratory erythema. Long CC, Laidler P, Holt PJ. Department of Dermatology, University Hospital of Wales, Heath Park, Cardiff, UK.	Clin Exp Dermatol 1993 Sep;18(5):464-7 Abstract quote A 67-year-old man with diabetes, weight loss and anaemia initially presented with a widespread scaling erythematous rash; a skin biopsy demonstrated marked suprabasal acantholysis. A subsequent biopsy showed localized upper epidermal necrolysis and the diagnosis of glucagonoma syndrome was later confirmed. Glucagonoma syndrome should be considered in patients with diabetes, weight loss and anaemia who present with a scaling rash, the histology of which shows suprabasal acantholysis. The extent of any upper epidermal necrolysis may be be very limited.
ANGIOPLASIA
Angioplastic necrolytic migratory erythema. Unique association of necrolytic migratory erythema, extensive angioplasia, and high molecular weight glucagon-like polypeptide. Franchimont C, Pierard GE, Luyckx AS, Gerard J, Lapiere CM.	Am J Dermatopathol 1982 Dec;4(6):485-95 Abstract quote A diabetic patient developed necrolytic migratory erythema with extensive angioplasia and high molecular weight glucagon-like polypeptide. There was no associated neoplasm such as glucagonoma. Lesions in the skin were studied by standard optical microscopy and by radioautography after incorporation of tritiated thymidine. Alterations in the skin begin as focal necrosis in the epidermis and in epithelial structures of adnexa, followed by marked angioplasia and a superficial and deep perivascular dermatitis.
DYSKERATOSIS
Necrolytic migratory erythema: dyskeratotic dermatitis, a clue to early diagnosis. Hunt SJ, Narus VT, Abell E. Department of Dermatology, University of Pittsburgh, PA 15221.	J Am Acad Dermatol 1991 Mar;24(3):473-7 Abstract quote A 57-year-old woman with a 6-year history of a dermatitis that evolved into typical necrolytic migratory erythema is reported. Four biopsy specimens were obtained in 5 years. The early lesions revealed superficial perivascular inflammation in the dermis, minor epidermal spongiosis, and scattered dyskeratotic cells in the upper epidermis. The differential diagnosis of this pattern of dyskeratotic dermatitis, particularly in a chronic eruption, should include consideration of hyperglucagonemia and the possibility of an associated pancreatic islet cell tumor.

 

SPECIAL STAINS/IMMUNOPEROXIDASE/ OTHER	CHARACTERIZATION
SPECIAL STAINS
IMMUNOPEROXIDASE
DIRECT IMMUNOFLUORESCENCE
Apoptosis with positive direct immunofluorescence findings in a patient with necrolytic migratory erythema. Perniciaro C, Rappaport KD, White JW Jr. Department of Dermatology, Mayo Clinic Jacksonville, Florida 32224, USA.	Cutis 1998 Sep;62(3):129-32 Abstract quote A 45-year-old man with a glucagonoma and necrolytic migratory erythema is described. Clinical, radiographic, and histologic features were typical for this syndrome. However, a skin biopsy specimen for direct immunofluorescence examination revealed apoptotic keratinocytes that stained positive with immunoglobulins, fibrinogen, and C3. These immunofluorescence findings were initially interpreted erroneously as showing erythema multiforme or a related disorder. We present a unique case of necrolytic migratory erythema with positive direct immunofluorescence findings reflecting immunoglobulin and complement deposition within dyskeratotic epithelial cells.
ELECTRON MICROSCOPY
Ultrastructural studies of necrolytic migratory erythema. Ohyama K, Kitoh M, Arao T.	Arch Dermatol 1982 Sep;118(9):679-82 Abstract quote Necrolytic migratory erythema is a disorder highly suggestive of glucagonoma syndrome. We carried out histologic and electron microscopic studies of the skin lesions in a 57-year-old woman with the glucagonoma syndrome. Light microscopic studies revealed hyperkeratosis, parakeratosis, formation of clefts in the upper epidermis, and scattered dyskeratotic cells. Ultrastructurally, the intercellular spaces were widened in the upper epidermis and desmosomes were reduced in number. The cytoplasm of affected cells showed vacuolar degeneration; the organelles were lysed or absent. There were scattered dark cells and dyskeratotic cells. These changes appear to represent a degenerative process of the keratinocytes.

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
Acrodermatitis enteropathica

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
GENERAL
Glucagonoma syndrome: survival 24 years following diagnosis. Nightingale KJ, Davies MG, Kingsnorth AN. Department of Dermatology, Derriford Hospital, Plymouth, UK.	Dig Surg 1999;16(1):68-71 Abstract quote The symptoms of necrolytic migratory erythema, diabetes, stomatitis, weight loss and diarrhoea represent the glucagonoma syndrome which has been recognized since the early 1970s. Because of its rarity (1 case/20-200 million population) late diagnosis is frequent which leads to a poor prognosis. The case described, originally reported in 1974, is the longest survivor to be documented in the literature, and is one of the original patients with a glucagonoma that helped to define the syndrome.
Glucagonomas/diabetico-dermatogenic syndrome (DDS): a statistical evaluation of 407 reported cases. Soga J, Yakuwa Y. College of Biomedical Technology, Niigata University, 2-746 Asahimachi-dohri, Niigata City 951-8518, Japan.	J Hepatobiliary Pancreat Surg 1998;5(3):312-9 Abstract quote Of the rare pancreatic endocrinomas, glu-cagonomas, either with or without diabetico-dermatogenic syndrome (DDS), are probably third in frequency after insulinomas and gastrinomas. This study was carried out to evaluate the present status of glucagonoma/DDS in a statistically reliable number of cases and to provide precise information to investigators actively working in this particular field of research. A total of 407 cases of glucagonoma were collected from the international literature and evaluated according to characteristic clinicopathologic features. Findings were: (1) The incidence of DDS was 57.2% (233/407). (2) The tail of the pancreas was predominantly involved, in 53.7% (213/397). (3) One-third of the tumors (80 of 276 for whom size was recorded; 29.0%) measured 20 mm or less. (4) Metastases occurred in 51.4% (209/407) and malignant tumors in 60.7% (247/407). (5) Multiplicity occurred in 11.8% (48/407), and associated multiple endocrine neoplasia type 1 in 13. 0% (53/407). (6) In the patients with DDS, the rates of hyperglucagonemia, necrolytic migratory erythema, diabetes mellitus, loss of weight, hypo-aminoacidemia, or anemia, as representative constituents of DDS, were all higher than rates in the overall series (P < 0.01). (7) The 10-year survival rate in the 233 patients with DDS was 51.6% in those with metastases and 64.3% in those without metastases (P < 0.001).
TREATMENT
GENERAL
Response of glucagonomas to surgical excision and chemotherapy. Report of two cases and review of the literature. Reyes-Govea J, Holm A, Aldrete JS. Department of Surgery, University of Alabama School of Medicine, Birmingham 35294.	Am Surg 1989 Aug;55(8):523-7 Abstract quote The glucagon-producing pancreatic tumors or glucagonomas are among the rarest forms of islet cell tumors; most are malignant and usually produce a definite clinical syndrome. Mild diabetes mellitus, weight loss, and anemia usually accompany the syndrome. However, only the presence of a peculiar cutaneous rash (necrolytic migratory erythema) and the finding of hyperglucagonemia on assay are reliable diagnostic features of the syndrome. Selective, celiac axis arteriography is the most valuable preoperative technique for localizing these neoplasms and their common liver metastases. Immunohistochemical and ultrastructural examinations are particularly helpful in defining the tumor cell nature (alpha-2 islet cell) and the peptide content (glucagon). When the tumor is benign (less than 30%), complete operative removal results in lasting cure; for malignant forms, surgical therapy is mainly palliative, and adjunctive chemotherapy should be administered. In this report, the importance of clinical recognition and operative and chemotherapeutic responses is illustrated in two patients. In each case, the characteristic dermatitis, diabetes mellitus, weight loss, anemia, and elevated plasmatic glucagon were present. Both patients had their tumors localized by selective angiography and underwent operative removal of the primary pancreatic lesion. In the case of benign glucagonoma, surgical excision was curative. In the malignant one, cytoreductive surgery plus adjunctive chemotherapy (dimethyltriazenomidazole-carboxamide resulted in prolonged survival and significant clinical improvement. Follow-up with serum glucagon assay has been useful in monitoring recurrence.
Treatment of necrolytic migratory erythema in glucagonoma syndrome. Shepherd ME, Raimer SS, Tyring SK, Smith EB. Department of Dermatology, University of Texas Medical Branch, Galveston 77550.	J Am Acad Dermatol 1991 Nov;25(5 Pt 2):925-8 Abstract quote The glucagonoma syndrome is characterized by elevated serum glucagon, a pancreatic alpha-cell tumor, anemia, hypoaminoacidemia, and necrolytic migratory erythema. Necrolytic migratory erythema may cause marked morbidity and is frequently misdiagnosed. A 42-year-old white woman with a 1 1/2-year history of refractory dermatitis (most severe on the lower extremities) had the glucagonoma syndrome. Her severe morbidity was markedly relieved with the administration of intravenous amino acids. This therapy was successful in controlling the necrolytic migratory erythema through recurrences after somatostatin (SMS 201-995), surgical debulking, and chemotherapy proved inadequate.
Rapid resolution of necrolytic migratory erythema after glucagonoma resection. Smith AP, Doolas A, Staren ED. Department of General Surgery, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA.	J Surg Oncol 1996 Apr;61(4):306-9 Abstract quote A 55-year-old man presented with an 11-year history of necrolytic migratory erythema and glossitis. After the patient's serum glucagon was demonstrated to be elevated, computed tomography scan revealed a mass involving the head of the pancreas. The patient underwent a Whipple-type pancreatico-duodenectomy and his rash resolved completely 6 days after tumor resection. He received no adjuvant treatment. A discussion of the varying theories regarding the pathogenesis and treatment of glucagon-associated necrolytic migratory erythema is presented.
Necrolytic migratory erythema, first symptom of a malignant glucagonoma: treatment by long-acting somatostatin and surgical resection. Report of three cases. El Rassi Z, Partensky C, Valette PJ, Berger F, Chayvialle JA. Department of Digestive Diseases, Hopital Edouard Herriot, Lyon, France.	Eur J Surg Oncol 1998 Dec;24(6):562-7 Abstract quote We report three cases of malignant glucagonoma with necrolytic migratory erythema as the first clinical symptom. Long-acting somatostatin analogue was the first step of a multimodal therapeutic strategy which included surgical resection of the primary tumour in every case. Liver metastases which were present in two patients were treated by hepatic arterial chemoembolization and systemic chemotherapy in one case and by liver resection for cytoreduction and hepatic arterial chemoembolization in another case. Skin lesions resolved in all three patients.
DACARBAZINE
Successful treatment of glucagonoma-related necrolytic migratory erythema with dacarbazine. van der Loos TL, Lambrecht ER, Lambers JC.	J Am Acad Dermatol 1987 Feb;16(2 Pt 2):468-72 Abstract quote A 63-year-old man with a glucagonoma syndrome is described. The diagnosis was confirmed by necrolytic migratory erythema, which is the most distinctive feature of the clinical syndrome. There was no chance of operative resection of the tumor because of liver metastases at the time of diagnosis. The patient was treated with dacarbazine. During this treatment the skin lesions disappeared completely.
OCTREOTIDE
Somatostatin analog-induced remission of necrolytic migratory erythema without changes in plasma glucagon concentration. Santangelo WC, Unger RH, Orci L, Dueno MI, Popma JJ, Krejs GJ.	Pancreas 1986;1(5):464-9 Abstract quote A 41-year-old woman with metastatic glucagonoma and the characteristic disabling rash, necrolytic migratory erythema, was treated with a synthetic somatostatin analog while waiting to undergo curative surgical resection. Plasma glucagon concentration (1,500-3,300 pg/ml, normal less than 200) remained elevated during analog therapy as the rash cleared. Only with surgical resection (partial pancreatectomy and partial hepatectomy) did glucagon levels return to normal. The therapeutic benefit caused by the analog in this syndrome differs from that in other endocrine tumor syndromes such as pancreatic cholera, carcinoid, or gastrinoma where circulating levels of tumor-produced agents are suppressed in conjunction with control of symptoms.
Octreotide (SMS 201-995) in the treatment of metastatic glucagonoma: report of one case and review of the literature. Rosenbaum A, Flourie B, Chagnon S, Blery M, Modigliani R. Service de Gastroenterologie, Hopital Saint-Lazare, Paris, France.	Digestion 1989;42(2):116-20 Abstract quote We report 1 patient with a necrolytic migratory erythema, a high plasma glucagon concentration and a metastatic pancreatic endocrine tumor who has now been treated effectively for 33 months with the somatostatin analogue octreotide (SMS 201-995) (400 micrograms/day). The results of SMS 201-995 in the treatment of glucagonoma syndrome are reviewed.
The long-acting somatostatin analogue octreotide alleviates symptoms by reducing posttranslational conversion of prepro-glucagon to glucagon in a patient with malignant glucagonoma, but does not prevent tumor growth. Jockenhovel F, Lederbogen S, Olbricht T, Schmidt-Gayk H, Krenning EP, Lamberts SW, Reinwein D. Abteilung fur Klinische Endokrinologie, Universitat, Essen, Germany.	Clin Investig 1994 Jan;72(2):127-33 Abstract quote A 52-year-old female with metastatic glucagonoma secreting glucagon and chromogranin A was treated with the somatostatin analogue octreotide for 2 years without any additional tumor-reducing interventions. Before therapy plasma glucagon was above 8 micrograms/l (normal < 0.2) and within 2 days 3 x 200 micrograms octreotide daily suppressed plasma glucagon to 2.2-2.5 micrograms/l. Concomitantly, chromogranin A dropped from 0.85 mg/l (normal < 0.1) to 0.2. After 3 weeks the preexisting disabling necrolytic migratory erythema had vanished completely, and weight loss was temporarily stopped. During therapy chromogranin A and plasma glucagon rose, exceeding pretreatment levels after 3 and 14 months, respectively. After 1 year the erythema recurred, responding only transiently to increasing doses of octreotide. The patient died after 2 years of therapy of tumor cachexy despite very high doses of octreotide (4 x 600 micrograms/day). Throughout treatment octreotide did not prevent tumor growth, as demonstrated by computed tomography and sonography. Determination of immunoreactive glucagon before and during octreotide therapy in fractions of plasma samples subjected to gel chromatography revealed a reduction in the ratio of glucagon to preproglucagon from 1.83 (before) to 0.56 (during therapy), indicating inhibition of posttranslational processing of preoproglucagon by octreotide, thereby reducing circulating bioactive glucagon. In summary, octreotide induced a remission of clinical symptoms by inhibiting posttranslational conversion of preproglucagon to glucagon but did not prevent tumor growth. Therefore, octreotide is a valuable therapy for rapid relief of clinical symptoms, thereby improving the possibilities for other tumor-reducing therapies.

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Congenital and Metabolic

Skin Rashes

Last Updated 2/7/2002