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Necrolytic Migratory Erythema


Glucagonoma syndrome


Glucagon-secreting tumors, usually malignant and

located principally in the pancreas


MEN I syndrome, Zollinger-Ellison syndrome


Rash—erythematous, scaly patches intertriginous and

acral area; angular chelitis, diabetes mellitus, diarrhea


Mild epidermal acanthosis with confluent parakeratosis

and vacuolar degeneration of the superficial epithelial


IHC repertoire:





Overall 5-year survival ~ 50%

Adverse variables:

Malignant pancreatic tumor, weight loss, metastases

Necrolytic migratory erythema (NME), referred to as the glucagonoma syndrome, is a rare paraneoplastic syndrome consisting of the classic triad of diarrhea, diabetes mellitus, and rash associated with serum hyperglucagone-mia (1-3). The most common etiology involves the elaboration of glucagons from an islet cell tumor of the pancreas but may rarely follow the metabolic consequences of cirrhosis, pancreatic insufficiency, or celiac disease. There is no ethnic or gender predilection and age of onset is usually in the sixties. NME is associated with type 1 multiple endocrine neoplasia syndrome (MEN I) sequence and/or Zollinger-Ellison hypergastrinemia syndrome in a minority of the cases (4-6).

The cutaneous and systemic manifestations follow the metabolic consequences of glucagon elaboration. These consist of insulin antagonism with resulting hyperglyce-mia and hypoaminoacidemia. It is thought that the hypoaminoacidemia results in decreased available substrate for peptide synthesis that consequentially manifests in rapidly cycling tissues such as the skin, gut, and bone marrow. These profound metabolic disturbances underlie the clinical disorders of diabetes mellitus, rash, and diarrhea observed in this syndrome.

The rash consists of an expanding erythematous and scaly patch typically observed within the intertriginous areas including the inguinal creases, nasolabial sulcus, and popliteal fossae (Figure 23.1) (7). Other frequently involved areas include acral sites and the perineum. In time, the patches develop into blistering plaques with peri-lesional pustules. Lesional pain and intense pruritus are commonly observed. The rash typically waxes and wanes cyclically with concurrent lesions showing different levels of healing. Approximately 30% of patients develop angular chelitis and glossitis.

Other systemic manifestations that commonly accompany this syndrome include diabetes mellitus, weight loss, diarrhea, neuropsychiatric disorders, thromboembolic disease, and a host of laboratory abnormalities. Diabetes mellitus develops in approximately 85% of patients with NME. The hyperglycemia results from the antagonistic effect of glucagons upon insulin, by increasing glu-coneogenesis in the liver and kidney, glycogenolysis in the liver and skeletal muscle and inhibiting glycogen synthesis in the liver (8). Glycemic management of patients with this syndrome can be difficult. Weight loss and tumor-associated cachexia is frequently observed and is particularly evident in the terminal stages of the disease. Diarrhea is observed in approximately one-third of patients and can be debilitating. Neuropsychiatric disturbances consist of depression, psychoses, as well as ataxia and visual disturbances. Thromboembolic complications are common and presumably due to tumor-associated hypercoaguability. Migratory thrombophlebitis (Tros-seau's syndrome), deep venous thrombosis of the leg with

Thrombophlebitis Pictures
Figure 23.1. Erythematous and focally scaly eruption involving genitalia and inguinal regions seen in necrolytic migratory erythema. Photo courtesy of Cleveland Clinic Foundation, Department of Dermatology.

attendant risk of pulmonary embolism, and cerebral artery thrombosis are observed. Laboratory abnormalities include spectacular elevation of the serum glucagon level, elevated erythrocyte sedimentation rate, normo-chromic normocytic anemia, hypoalbuminemia, and hypoaminoacidemia.

The diagnosis can be established by histologic criteria in the appropriate clinical setting, or with laboratory testing (9). The histologic features are distinctive though not pathognomonic of the disorder. The histologic features are entirely limited to the epithelium and consist of alterations in all of its layers. Overall, the epithelium shows acanthosis, and confluent parakeratosis with loss of the granular layer (Figure 23.2). At high-power examination, the keratinocytes, particularly in the middle portion of the stratum spinosum, show ballooning and vacuolar degeneration. Intraepidermal bullae and neutrophilic exocytosis may also be observed (Figure 23.3). Although the differential includes disorders capable of showing exo-cytosis of neutrophils, such as psoriasis, as well as disorders that may induce keratinocyte degeneration, such as sunburn or viral infection, seldom do they constitute a diagnostic dilemma after clinical correlation. The most important disorders that are capable of producing histo-logic alterations that may mimic NME include the nutritional deficiency states of pellagra and acrodermatitis enteropathica. Pellagra or niacin deficiency has distinctive clinical attributes that usually permit its distinction from NME. Pellagra is primarily observed in two clinical settings including children with an inherited disorder involving tryptophan metabolism (Hartnup disease) and among nutritionally impoverished adults (10,11). The cutaneous manifestations include photodistributed erythematous and burning patches that in time develop into scaly and fissured hyperpigmented plaques. The cutaneous manifestations are often accompanied by diarrhea and dementia that, if not corrected in time, eventuate in death.

Pellagra Rash
Figure 23.2. Low power photomicrograph depicting epidermal acanthosis with hyperkeratosis.
Vacuolar Degeneration
Figure 23.3. High power detail of stratum spinosum showing vacuolar alteration with loss of the granular layer and coarse parakeratosis typical of necrolytic erythema.

Additional settings in which niacin deficiency may be observed include the carcinoid syndrome in which the metabolic precursor of niacin, tryptophan, is usurped by the tumor. Niacin deficiency may follow impaired absorption or interaction with certain medications such as iso-niazid, mecaptopurine, 5-fluoruracil, the sulfonamides, anticonvulsants, and antidepressants. Acrodermatitis enteropathica consists of a distinctive acral and periorifical rash observed in infants and less commonly adults, who are deficient in zinc or other micronutrients (Figure 23.4) (12-14). The metabolic defect in infants often involves a defect in the zinc transporter genes. Among adults, this condition may be observed in patients receiving total par-enteral nutrition.

Laboratory confirmation can be achieved by measuring the serum level of glucagons. Levels are usually above 1000pg/ml (normal 100pg/ml). Although elevated serum glucagon levels are observed in 100% of cases, other causes of elevated serum glucagons include cirrhosis, renal failure, prolonged fasting, diabetic ketoacidosis, and with other islet cell tumors of the pancreas should be considered. Computerized tomography can be utilized to visualize the tumor that in the majority of cases resides within the pancreas. A minority of cases result from ectopic islet cell tumors located in the small intestine, stomach, or appendix. Selective celiac arteriography with serum sampling for glucagon also remains an important means of establishing the diagnosis.

In the largest study to date, approximately 50% of patients succumbed to their disease within 5 years of diagnosis (15). The majority of patients possess metastatic malignant islet cell tumors at the time of diagnosis. Early recognition of the disease is difficult as these tumors are rare and aggressive, and the clinical manifestations including the rash often develop following metastases. Adverse prognostic signs include the development of metastatic disease and weight loss. Treatment is aimed toward curative surgical extirpation of the tumor. Metastatic and unresectable disease may be palliated with various chemotherapeutic agents including streptzotocin and 5-fluoruracil. Clinical improvement of symptoms can in most instances be achieved with the administration of serotonin inhibitors such as octreotide.

Acrodermatitis Enteropathica
Figure 23.4. Acral distributed erythematous papules in child with acrodermatitis enteropathica because of zinc deficiency.

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