Necrolytic Migratory Erythema & Glucagon: Case Report

Rare Pancreatic Tumor Presents with Distinctive Skin Rash: A Case Study of Glucagonoma and Necrolytic Migratory Erythema

A rare and often misdiagnosed condition, glucagonoma syndrome, manifested in a 41-year-old male with a distinctive skin rash known as necrolytic migratory erythema (NME), highlighting the importance of recognizing dermatological signs as potential indicators of underlying systemic disease.

The Significance of NME as a Diagnostic Clue

NME is a rare disorder linked to several conditions, including glucagonoma, chronic pancreatitis, nutritional deficiencies, liver disease, and inflammatory bowel disease. Approximately 70% of individuals with glucagonoma present with NME, making it a crucial visual indicator for early diagnosis and timely intervention. Glucagonoma itself is an unusual neuroendocrine tumor originating from the pancreatic alpha cells, affecting an estimated 1 in 20 million people, most commonly those in their 50s. The syndrome’s hallmark symptoms include weight loss, NME, diabetes, diarrhea, anemia, and neuropsychiatric disturbances.

Case Presentation: A Diagnostic Journey

A 41-year-old male presented with erythema and erosions on both lower limbs, accompanied by malnutrition and mild itching that had persisted for three years. Initially diagnosed with “eczema” and treated with topical corticosteroids, his condition saw temporary improvement but frequently recurred. One month prior to evaluation at the Dermatology Hospital of Southern Medical University in 2024, the lesions spread across his body, developing into crusted papules and polycyclic plaques with a map-like appearance, primarily affecting his face, groin, buttocks, and extremities. Notably, his tongue exhibited a beefy red and fissured appearance. No abnormalities were observed in his nails.

Laboratory analysis revealed a significantly elevated serum glucagon level – exceeding 128 pmol/L, well above the normal range of 2 to 18 pmol/L. Tests for anti-bp180 and anti-bp230 antibodies, and cortisol levels, were negative. A skin biopsy revealed parakeratosis, inflammatory crust, spongiosis, localized necrosis in the upper epidermis, lymphocytes infiltrating peri-follicular and peri-vascular areas, and eosinophilic infiltration. A contrast-enhanced abdominal computed tomographic (CT) scan subsequently identified an enhancing mass in the pancreatic body tail, along with liver metastases.

Diagnostic Confirmation and Treatment Challenges

The clinical presentation was characteristic of NME, confirmed by histopathological examination of the skin biopsy. The elevated serum glucagon levels, coupled with the CT scan revealing a pancreatic neuroendocrine tumor, definitively established the diagnosis of glucagonoma combined with NME. Treatment initially involved microelements such as zinc, Vitamin B, folic acid, antihistamines, and topical corticosteroids, resulting in slight improvement of the rash. However, the patient declined surgical intervention due to financial constraints.

Understanding Glucagonoma and NME

Glucagonoma is characterized by the excessive proliferation of α-cells in the pancreas, often leading to metastasis. The resulting overproduction of glucagon causes glucagonoma syndrome, manifesting in symptoms like NME, weight loss, diabetes, diarrhea, anemia, and neuropsychiatric symptoms. NME itself presents as scaly, erosive, ring-shaped erythema, often accompanied by pustules and blisters, and can also involve nail dystrophy, cheilitis, and stomatitis.

Due to its rarity, NME is often misdiagnosed, frequently mistaken for eczema. Diagnostic criteria proposed in 2018 by Xuechen Cao and Yan Lu include: (1) imaging revealing a pancreatic mass, (2) elevated plasma glucagon levels (>1000 ng/L), (3) typical NME manifestations, and (4) a history of multiple endocrine neoplasia. Secondary criteria include new-onset diabetes, low serum zinc levels and hypoaminoacidemia, unexplained weight loss and diarrhea, and cheilitis or glossitis. In this case, the patient met the primary criteria of (1), (2), and (3), as well as the secondary criterion of (4), solidifying the diagnosis.

Differentiating NME from Similar Conditions

Several conditions can mimic NME, necessitating careful differential diagnosis. These include Acrodermatitis Enteropathica (AE), a rare, zinc metabolism disorder typically presenting in infancy; pemphigus erythematosus (PE), characterized by erythematous patches and vesicles; drug eruptions; essential fatty acid deficiency; vitamin deficiency-related dermatitis; and pseudoglucagonoma syndrome. AE typically presents with low serum zinc levels, while PE often exhibits superficial epidermal acantholysis on histopathology. Drug eruptions usually have a clear history of medication exposure and respond to corticosteroids.

The underlying cause of NME remains unclear, but hyperglucagonemia is believed to play a significant role. Excessive glucagon secretion disrupts amino acid metabolism, leading to hypoaminoacidemia and impaired epidermal protein synthesis. Surgical removal of glucagonomas or the use of somatostatin analogs can effectively control the skin rash. Nutritional support and zinc supplementation can also improve symptoms. Surgical resection remains the only curative treatment, although over half of glucagonomas are metastatic at diagnosis.

The Importance of Interdisciplinary Collaboration

NME often presents a chronic and debilitating rash, significantly impacting a patient’s quality of life. The lesions, easily mistaken for other dermatological conditions, underscore the importance of considering underlying pancreatic tumors in persistent, unexplained skin eruptions. Given that NME may be the sole early indicator of this tumor, accurate diagnosis is paramount. This requires a collaborative approach involving dermatologists, endocrinologists, gastroenterologists, and oncologists to ensure timely diagnosis and effective management. This case emphasizes the critical role of recognizing NME as a dermatologic marker for systemic malignancies, necessitating collaborative care for optimal patient outcomes.

beyond the Surface: Exploring the Broader Implications of Glucagonoma and NME

The case of the 41-year-old male with necrolytic migratory erythema (NME) and glucagonoma provides a compelling illustration of how dermatological manifestations can be a window into complex, underlying systemic diseases. While the initial focus is on the skin rash, understanding the full scope of glucagonoma and related conditions requires a deeper dive into the metabolic and physiological processes at play, as well as the implications for patient care and future research.

The metabolic landscape of Glucagonoma Syndrome: A Closer Look

The overproduction of glucagon, the key hormone in this syndrome, triggers a cascade of metabolic disruptions. Primarily, glucagon works to increase blood glucose levels, but its excessive presence in glucagonoma syndrome pushes the body into an altered state of metabolism. this metabolic chaos results in the telltale symptoms: NME, weight loss, diabetes, diarrhea, anemia, and also, neuropsychiatric disturbances. The mechanisms behind each of these symptoms is equally fascinating and complex.

• NME and Amino Acid Imbalance: As mentioned, the skin rash, NME, is a direct result of impaired amino acid metabolism[[1]]. The excess glucagon causes the liver to break down more amino acids, leading to hypoaminoacidemia. The subsequent deficiency of amino acids results in the inhibition of epidermal protein synthesis,and results in those distinctive skin lesions.
• Diabetes and Insulin Resistance: High glucagon levels oppose insulin, which results in hyperglycemia and, frequently, full-blown diabetes. Many patients show signs of insulin resistance, creating further complications in the management of their conditions.
• Weight Loss and Nutritional Deficits: Malabsorption from diarrhea, combined with the catabolic effects of glucagon, fuel weight loss. This loss of nutrition, is more acute when the condition is advanced.
• Anemia: Consequently of multiple nutritional deficiencies, particularly iron and vitamin B12, anemia can develop.
• Neuropsychiatric Symptoms: Patients may also experience symptoms of depression, anxiety, and cognitive dysfunction. These symptoms might be influenced by electrolyte imbalances, nutritional deficits, or the direct effects of the tumor or its byproducts on the central nervous system.

Prognosis and Treatment Strategies

The treatment of glucagonoma, like the case study highlights, presents a multifaceted challenge.While surgery may offer a cure if the tumor is localized, the frequently enough-delayed diagnosis, along with the metastatic nature of the disease at its diagnosis, often makes complete resection difficult. Success rates increase dramatically when proper collaborative interventions occur early. Moreover,treatment goes well beyond treating the tumor itself; it is focused on symptom management.

• Tumor Resection: Whenever possible, surgical removal of the glucagonoma is the definitive treatment.
• Somatostatin Analogs: Medications like octreotide and lanreotide can help to decrease glucagon levels, helping to control the rash, diabetes, and diarrhea.
• Nutritional Support: Replenishing nutrients such as zinc, essential fatty acids, and vitamins is crucial.
• Diabetes Management: Implementing proper diabetic care, including diet, exercise, and insulin or other diabetes medications is crucial to manage blood glucose levels.
• Symptom Management: Depending on the presenting symptoms, treatment is often given to manage anemia, correct electrolyte imbalances, or treat any neuropsychiatric symptoms.

Practical Tips for Patients and Healthcare Professionals

The identification and management of glucagonoma require a proactive strategy. If you or a loved one is affected by NME or suspected of having related conditions:

• Seek early and thorough dermatological evaluation: early recognition through routine dermatology check-ups is essential in preventing misdiagnosis. Ensure that you receive comprehensive skin exams to determine any underlying conditions.
• Thoroughly document yoru symptoms: Keep track of any skin rashes, changes in bowel habits, weight changes, or any neurological symptoms. This detailed history can be quite valuable for accurate diagnosis.
• Insist on a comprehensive diagnostic workup: This ought to include a serum glucagon level test and imaging to discover any pancreatic abnormalities.
• Seek a multidisciplinary approach: Get dermatologists, endocrinologists, gastroenterologists, and oncologists communicating with each other.
• Explore clinical trials: If standard treatments are ineffective, ask about clinical trials and potential treatment options.

The Road ahead: future Directions in research

The underlying cause of NME is not well understood, but high glucagon levels are believed to play a significant role. Although glucagonoma is a rare tumor, ongoing research continues to unravel the specific mechanisms involved and to find additional effective therapies to combat the condition.Emerging areas of interest include:

• Targeted Therapies: Development of new drugs that specifically target glucagon receptors.
• immunotherapy: Immunological approaches to use the immune system to recognize and destroy cancer cells.
• Early detection Methods: Search for more sensitive methods for detecting glucagonoma at an early stage.
• Genetic and Molecular Profiling: Studying the genetic and molecular characteristics of glucagonoma to find new therapeutic targets.

Is NME always caused by a glucagonoma? No, NME can be associated with various conditions, including malnutrition, liver disease, and inflammatory bowel disease, although it’s often associated with glucagonoma.

What’s the best way to diagnose glucagonoma? Diagnosis typically requires assessment of the skin, elevated serum glucagon levels, and imaging to detect a pancreatic mass.