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Introduction

NME is a rare disorder associated with multiple diseases, including glucagonoma, chronic pancreatitis, nutritional deficiency, liver diseases, and inflammatory bowel disease. About 70% of cases of glucagonoma may present with NME, therefore NME is an important visual clue for the diagnosis, enabling timely intervention.

Glucagonoma is an unusual neuroendocrine tumor, derives from the pancreatic alpha cells with an estimated incidence of 1 in 20 million,¹ most commonly affecting people in their 50s.² The main manifestations are weight loss, NME, diabetes, diarrhea, anemia, and neuropsychiatric symptoms. NME is a crucial characteristic of glucagonoma. However, many primary dermatologists lack sufficient knowledge about the disorder, leading to potential misdiagnosis and missed diagnosis. Consequently, we report a case of typical NME combined with glucagonoma diagnosed in 2024 at Dermatology Hospital of Southern Medical University, designed to strengthen the diagnosis and differentiation ability of dermatologists.

Case Presentation

The patient was a 41-year-old male who presented with erythema with erosions on both lower limbs, accompanied by malnutrition and mild itching for the past three years. The patient was diagnosed with “eczema” in the local hospital. He had been treated with topical corticosteroids for years with improvement but frequently recurred. One month ago, the lesions gradually spread all over the body, with crusted papules and polycyclic plaques with a map-like margin mainly involving the face, groin, buttocks, and extremities. And his tongue appeared beefy red and fissuring (Figure 1). No nail abnormality was found.

Figure 1 Clinical appearance. (a) Scattered erythematous seborrheic plaques on the face. (b) Bright red, swollen tongue; multiple fissures; beefy tongue appearance. (c) Well-defined erythema with raised borders and yellow crusting on both inguinal areas and scrotum. (d and e) Multiple erythema and erosion on the buttocks and knees. (f) Well-defined erythema with raised borders and yellow crusting on both ankles.

Laboratory analysis found a serum glucagon level of more than 128 pmol/L (normal range, 2 to 18 pmol/L). Anti-bp180 and anti-bp230, cortisol levels were negative. A skin biopsy was performed and showed parakeratosis, inflammatory crust, spongiosis, localized necrosis in the upper epidermis, lymphocytes infiltrating peri-follicular and peri-vascular areas, and eosinophilic infiltration (Figure 2). A contrast-enhanced abdominal computed tomographic scan revealed an enhancing pancreatic body tail mass and liver metastases (Figure 3).

Figure 2 Histological findings of plaque on the left thigh. Parakeratosis, spongiosis, localized necrosis in the upper epidermis. (HE, x 400).

Figure 3 Enhanced abnormal computed tomography scan. Showing a pancreatic body tail mass (right arrow) and intrahepatic mass (left arrow), confirming glucagonoma.

Diagnostic Evaluation

The clinical presentation was characteristic of NME, confirmed by histopathological examination of skin biopsy. In accordance with the known correlation between NME and glucagonoma, serum glucagon levels were found to be significantly elevated. Subsequent abdominal CT demonstrated a pancreatic neuroendocrine tumor, establishing the definitive diagnosis of glucagonoma. Therefore, the diagnosis of NME combined with glucagonoma was made.

Treatment with microelements such as zinc, Vitamin B, folic acid, antihistamines, and topical corticosteroids. The rash reduced slightly. However, the patient refused surgical treatment for financial reasons.

Discussion

Glucagonoma is a neuroendocrine tumor characterized by excessive proliferation of α-cells in the pancreas, with a higher prevalence in women than men. The tumor typically grows slowly and can metastasize. Due to the excessive secretion, glucagonoma syndrome occurs, which may present with NME, weight loss, diabetes, diarrhea, anemia, and neuropsychiatric symptoms.³ NME manifests as scaly, erosive, ring-shaped erythema with the formation of pustules and large blisters. Other manifestations may include nail dystrophy, cheilitis, and stomatitis.

Given the rarity of NME, reports on the condition are few both nationally and internationally, and a standardized diagnostic criterion has not yet been made. In 2018, Xuechen Cao and Yan Lu reviewed and summarized previous cases and proposed diagnostic criteria for glucagonoma.⁴ The primary diagnostic criteria(Table-1) include (1) Imaging revealing a pancreatic mass, (2) Elevated plasma glucagon levels (>1000 ng/L), (3) Typical NME manifestations, (4) A history of multiple endocrine neoplasia. Secondary criteria include (1) New-onset diabetes (fasting plasma glucose, oral glucose tolerance test), (2) low serum zinc levels and hypoaminoacidemia, (3) Unexplained weight loss and diarrhea, (4) 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), confirming the diagnosis of NME associated with glucagonoma.

Table 1 the Diagnostic Criteria and Differential Diagnosis

Given its rarity and prolonged clinical course, NME is frequently misdiagnosed as eczema. In such cases, dermatologists should maintain a high clinical suspicion for associated systemic diseases. Several conditions can present with NME-like skin rashes, including Acrodermatitis Enteropathica (AE), pemphigus erythematosus(PE), drug eruption, essential fatty acid deficiency, vitamin deficiency-related dermatitis, and pseudoglucagonoma syndrome.

AE: it is a rare, recessively inherited disorder associated with zinc metabolism abnormalities, typically presenting in infancy with symptoms such as eczema-like dermatitis, crusting, bullae, and pustules, commonly affecting the extremities and perioral areas.⁵ Additional symptoms include hair loss, diarrhea, stomatitis, photophobia, nail dystrophy, abnormal hair texture, growth retardation, and emotional disorders. Especially common in artificially fed infants, with few in adulthood.⁶ The serum zinc level is always low.⁷

PE: the lesions appear as erythematous patches, often found on the face, neck, chest, and other areas, and may have an irregular shape with unclear borders. It may also present in a linear or ring-shaped pattern, with associated vesicles and bullae. Mucosal involvement, such as oral ulcers, throat pain, and ocular inflammation, may also occur. The disease progresses rapidly, with vesicles easily rupturing to form ulcers, and lesions may spread to adjacent skin, occasionally accompanied by secondary infections. Hematoxylin-eosin stain (HE) typically shows superficial epidermal acantholysis, usually located in the granular layer or upper epidermis. Spongiosis and dermal eosinophilic infiltration can be observed, and DIF typically reveals antibodies between epidermal keratinocytes as well as scattered granular deposits of antibodies along the basement membrane zone (BMZ).⁸

Drug Eruption: it manifests in various clinical forms, with severe reactions presenting as generalized erythema, vesicles, and erosion. Drug eruption usually has a clear history of drug exposure before the onset of the rash, typically resulting from a non-anticipated inflammatory response affecting the skin and/or mucous membranes as a result of drugs entering the body through oral ingestion, inhalation, injection, suppositories, or topical absorption.² It often shows a clear response to corticosteroid therapy.

The pathogenesis of NME remains unclear. Hyperglucagonemia is believed to play a significant role, because excessive glucagon secretion induces amino acid metabolic dysregulation, culminating in hypoaminoacidemia and consequent impairment of epidermal protein synthesis. And surgical removal of glucagonomas or somatostatin analogs can control the skin rash.^6,9 Additionally, hypoaminoacidemia, micronutrient depletion, and deficiencies in essential fatty acids and zinc should also be considered, as nutritional support and topical zinc therapy have been used to improve symptoms.¹⁰ Surgical resection is considered the only curative treatment.¹¹ If left untreated, glucagonomas may metastasize to distant organs such as the liver and lungs, leading to progressive clinical deterioration and ultimately life-threatening complications. Surgical options include simple excision (for tumors <2 cm) with regional lymphadenectomy, pancreaticoduodenectomy with regional lymphadenectomy, distal pancreatectomy, and splenectomy. However, over half of glucagonomas are metastatic at diagnosis, with liver metastasis being the most common.¹² Liver transplantation is considered a potential treatment for patients with liver metastasis. Transarterial chemoembolization (TACE), radiofrequency ablation, and surgery combined may offer advantages in resecting isolated metastatic tumors. Pharmacological treatments for glucagonoma include chemotherapy, somatostatin analogs, and targeted molecular therapies.¹³ Molecular targeted therapy: Agents such as sunitinib and everolimus inhibit specific molecular aberrations within tumors, thereby significantly prolonging progression-free survival (PFS).¹⁴

Conclusion

NME mainly presents a chronic course, but the recurrent rash seriously affects the patient’s quality of life. The lesions in our case are characterized by generalized erythema with erosions, which are easily misdiagnosed as pemphigus, eczema, and drug eruption, highlighting the importance of precise imaging to exclude pancreatic tumors, when facing similar conditions. Since NME might be the only clue for the early detection of this tumor, it is very important to correctly diagnose. This requires collaborative efforts from dermatologists, endocrinologists, gastroenterologists, and oncologists. This interdisciplinary approach is essential for the timely diagnosis and management of this rare condition. All in all, this case underscores the importance of recognizing NME as a dermatologic marker for systemic malignancies, necessitating collaborative care for timely diagnosis and treatment.

Ethics Statement

The publications of images were included with the patient’s consent.

Consent Statement

The patient had given written informed consent for the publication of his clinical details. Institutional approval is not required for this case study.

Acknowledgments

The authors would like to thank the patient for participation in this study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This work was supported by The “Set Sail” Program for Young PhD Researchers in Basic and Applied Medical Research (SL2023A04J02432).

Disclosure

The authors report no conflicts of interest in this work.

References

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2. Yang WJ, Hu HH, Guo H, Li JH. Generalized migratory erythema in an elderly woman Necrolytic migratory erythema. J Dtsch Dermatol Ges. 2022;20(2):231–234. doi:10.1111/ddg.14664

3. Liu JW, Qian YT, Ma DL. Necrolytic migratory erythema. JAMA Dermatol. 2019;155(10):1180. doi:10.1001/jamadermatol.2019.1658

4. Cao X, Yan L. 坏死松解性游走性红斑临床研究进展. 中华医学杂志. 2018;98(33):2694–2696. doi:10.3760/cma.j.issn.0376-2491.2018.33.019

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6. van Beek AP, de Haas ER, van Vloten WA, Lips CJ, Roijers JF, Canninga-van Dijk MR. The glucagonoma syndrome and necrolytic migratory erythema: a clinical review. Eur J Endocrinol. 2004;151(5):531–537. doi:10.1530/eje.0.1510531

7. Zou P, Du Y, Yang C, Cao Y. Trace element zinc and skin disorders. Front Med Lausanne. 2022;9:1093868. doi:10.3389/fmed.2022.1093868

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Cystectomy is a major surgery that requires the removal of the bladder and the creation of a urinary diversion. It’s a component of treatment for many patients with bladder cancer and may be an option for patients with other conditions, like neurogenic bladder and fistula repair. Now, surgeons at Cleveland Clinic are increasingly using nerve-sparing techniques for cystectomy that preserve sexual function and quality of life without compromising cancer treatment.

“There’s been a shift in the urologic cancer community in terms of prioritizing quality-of-life outcomes without compromising cancer treatment,” says Nima Almassi, MD. “Historically, cystectomy has been performed with a wide resection to maximize oncologic treatment and avoid positive margins and cancer recurrence.”

Prospective studies have shown that patients generally report positive quality-of-life outcomes across most domains following cystectomy, with a few exceptions. Body image, especially for patients who need a stoma, urinary function, and sexual function tend to be areas where patients report a decreased quality of life. For men undergoing cystectomy, a wide (non-nerve sparing) resection will cause severe erectile dysfunction. Nerve-sparing cystectomy represents one method of potentially improving quality of life outcomes for men undergoing surgery.

Postoperative sexual outcomes in men and women

Urologic oncologists like Dr. Almassi say that many patients don’t need to sacrifice their sexual function because of treatment. For male patients undergoing cystectomy, erectile dysfunction (ED) is a very common side effect, but nerve-sparing cystectomy can help temper it.

The Cleveland Clinic team has also been focused on improving the bladder cancer experience in women, which includes evaluating similar nerve-sparing and organ-sparing techniques to preserve reproductive anatomy and obviate surgical menopause and sexual dysfunction. Prospective studies ongoing at Cleveland Clinic have shown that women who undergo vaginal-sparing cystectomy appear to have less prolapse than women, but the data are still early when it comes to sexual function.

Patient selection is key

Patients eligible for this type of surgery have a good baseline ED and are motivated to preserve it. Additionally, they must be free of specific disease characteristics that could complicate oncologic control, such as cancer abutting or involving the neurovascular bundle. Preoperative MRI imaging can guide patient selection.

Similarly, aggressive subtypes of bladder cancer with high risk of being locally advanced may not be suitable for a nerve-sparing surgical approach. “In this case, we would not recommend nerve-sparing out of concern it could compromise cancer control,” says Dr. Almassi.

A positive institutional experience

Nerve-sparing cystectomy requires the surgeon to dissect the neurovascular bundles off the bladder and prostate. “We have found that this has yielded much better erectile function in patients after surgery without compromising oncologic outcomes. For all patients who we’ve deemed eligible for this, we have not had positive surgical margins,” notes Dr. Almassi.

Using validated questionnaires, patients report their erectile function about every three months for a year. The team is finding that around six months postoperatively, most patients experience only mild ED, and that remains consistent. Even three months following the surgery, he says, patients typically are recovering well but are often not yet sexually active at this time.

“Most patients’ erectile function ends up returning to within three points on a 25-point scale from their preoperative baseline, suggesting erectile function can recover to similar levels to what it was before surgery.”

Part of the center’s protocol is starting patients on tadalafil, and they may still be using it when function is assessed postoperatively, Dr. Almassi remarks.

The Cleveland Clinic team opts for a robotic approach, owing to better visualization and access to the neurovascular bundle. However, performing this technique with open surgery is also achievable in experienced hands. “The way the field has transitioned, fewer surgeons in high volume centers perform open cystectomy,” he explains.

A call for screening candidates

“Optimizing quality of life for our patients is a major focus for our group. Studies show that sexual function declines after cystectomy. We have an opportunity to safely personalize a surgical technique in select patients to help preserve functional outcomes,” says Dr. Almassi. “We certainly encourage our colleagues to consider screening patients who may be good candidates.”

Due to time constraints and surging patient volumes, elderly emergency department patients are not routinely screened for delirium. A Cleveland Clinic geriatrician is making a case for why that should change, however, showing that even a 60-second test can accurately detect confused patients who may otherwise slip through the cracks.

Although delirium screenings are routine for older patients being admitted to the hospital or ICU, they are not yet commonplace in emergency departments, explains Saket Saxena, MD, Codirector of the geriatric emergency department at Cleveland Clinic. “Unfortunately, elderly patients who present with acute conditions often wait hours or days to be fully screened for delirium,” he says, “However, we know that recognizing the disorder early can significantly improve patient care.”

Dr. Saxena is the principal author of a recent study that evaluated 4AT, a bedside screening tool for delirium in emergency department patients. The study found that 4AT, which takes around one minute to complete, can detect delirium with a positivity rate of 14%, a number that is consistent with the general population. Interestingly, about 7% of those determined to have delirium did not initially present with a complaint of altered mental status.

Combatting diagnostic challenges

When people imagine delirium, he notes, they often think of patients who are agitated or even aggressive – getting out of bed, struggling or pulling out their lines. However, a significant number of these patients have hypoactive delirium, a condition that prompts a quiet, docile demeanor. Although these patients may not appear obviously confused, they will sleep a lot, eat little and decline to actively participate in conversations or therapies.

“That is the type of delirium that often gets missed when patients are transitioned from emergency to inpatient care,” explains Dr. Saxena.

Although hypoactive delirium can be particularly difficult to identify because it can easily be explained away by simple fatigue or “not being hungry,” the disorder can have a significant impact on patient outcomes.

“Nutritional status cannot be maintained if the patient isn’t eating,” explains Dr. Saxena. “And if the patient isn’t getting out of bed, the chances of debilitation rise; muscular strength is lost, and the risk of blood clots in the legs increases. All of these factors play a role in how these patients perform during hospitalization and beyond.” In fact, studies have found that patients with delirium have a length of stay that’s twice as long as those without, he notes.

Historically, Cleveland Clinic has used the Confusion Assessment Method to screen patients for delirium in the hospital or ICU; however, no method has been used to formally assess delirium in the emergency department. In preparation for the study, Dr. Saxena worked with triage nurses to identify the delirium screening tool they were most comfortable using in an emergency setting. The 4AT method, which was deemed easy to learn and administer, was chosen as the preferred rapid delirium test. Patients were flagged for screening if they were over 65 years old and medically complex, and all patients over age 80 were screened.

Clinical implications

The rapid test begins by asking the person accompanying the patient if they are concerned about or have noticed any changes in the patient’s mental status. If the caregiver answers yes, the assessment is completed by asking the patient “orientation” questions that evaluate their ability to understand today’s date, where they are, and their date of birth and age. Their attention span is measured by asking the patient to name the months of the year backwards.

Any patient who receives a score of four or more is flagged for delirium.

Dr. Saxena said the study demonstrates that while detecting delirium in the acute setting is challenging, it can be done quickly and accurately using a rapid test like the 4AT method. Among Dr. Saxena’s future goals are improving interdepartmental communication about high-risk geriatric patients. “This approach helps ensure continuity of care throughout the hospital stay by making subsequent caregivers aware of any diagnoses – including delirium – that were made in the emergency department.

Despite the rising incidence of rheumatoid arthritis (RA), extra-articular manifestations have become rare in the era of modern treat-to-target therapy. However, they still present clinical challenges — particularly in the case of rheumatoid nodules. In addition to the need to rule out serious differential diagnoses and address potential complications, especially those involving the lungs, these recurrent inflammatory granulomas can affect daily life not only cosmetically but also functionally.

Christopher Edwards, MD, professor of rheumatology at University Hospital Southampton in Southampton, England, discussed the clinical relevance and management of rheumatoid nodules during the 2025 Annual Meeting of the European Alliance of Associations for Rheumatology.

When Edwards began his career in rheumatology, the presence of rheumatoid nodules was considered a key diagnostic criterion for RA. If not found on the hands, clinicians often examined the elbows and Achilles tendons, which are also common sites. Histologically, rheumatoid nodules are granulomatous inflammatory lesions that evolve through multiple stages. While often subcutaneous, they can also be found on the sclera, larynx, heart valves, and — most significantly — in the lungs.

Biopsy When Malignancy Is Suspected

Pulmonary nodules can present diagnostic difficulties. “I’ve seen patients who were initially told they had lung metastases,” Edwards recalled. Waiting for further imaging and biopsy can be highly distressing for patients. Granulomatosis with polyangiitis can also resemble rheumatoid nodules, further complicating the diagnosis.

It is especially important to distinguish these nodules from infections such as tuberculosis. Patients with RA are at increased risk for infection due to both the underlying disease and immunosuppressive treatment. Like tuberculomas, pulmonary rheumatoid nodules can undergo central necrosis when exposed to tumor necrosis factor-alpha inhibitors, leading to cavitation or even pneumothorax. “Any cavity in the lung can become infected,” Edwards cautioned.

Diagnosing Peripheral Nodules

Diagnosing peripheral rheumatoid nodules is usually straightforward. These nodules typically feel rubbery on palpation and are movable relative to the underlying tissue. Important differential diagnoses include gouty tophi, lipomas, epidermoid cysts, infectious granulomas, sarcoidosis, and neoplastic lesions.

Imaging tools such as ultrasound or fine-needle aspiration can help clarify the diagnosis, particularly when gout is suspected. “Biopsy is rarely required — only if there’s concern about a neoplastic or malignant process,” Edwards explained.

Better Disease Control, Fewer Nodules

“In my practice, I see very few nodules these days,” said Edwards. Epidemiological data support this trend: The 10-year cumulative incidence of subcutaneous nodules in RA patients decreased from 30.9% between 1985 and 1999 to 15.8% between 2000 and 2014.

Multiple factors likely contributed to this decline, including the earlier initiation of more effective therapies and a reduction in smoking rates. Smoking remains a major risk factor for nodule development, along with long-standing, severe RA, male sex, and seropositivity for rheumatoid factor or anti-cyclic citrullinated peptide antibodies. “Patients with nodules are almost always seropositive,” Edwards noted.

These findings suggest that maintaining tight control of disease activity is more critical for preventing nodules than concerns about drug-induced nodulosis.

Little Reason to Discontinue Methotrexate

“There was a time when we worried that methotrexate might be causing nodules,” Edwards said, referring to anecdotal reports of increased nodulosis after initiating methotrexate (MTX). “But now we’re using more MTX and seeing fewer nodules.”

He emphasized that the presence of nodules alone should not prompt discontinuation of MTX. “It wasn’t a reason to stop methotrexate back then, and it’s not a reason now — though in some cases, it may justify a more aggressive treatment approach.”

Other medications — particularly tumor necrosis factor inhibitors like etanercept — have also been linked to nodule development, though Edwards suggested this may reflect reporting bias. “It might not be causal,” he said.

Often, treatment isn’t necessary. “Sometimes it’s just a matter of observation,” Edwards noted. Painful or functionally limiting nodules may be managed with local glucocorticoid injections to reduce discomfort and soften the nodules. However, he admitted he had never personally injected a rheumatoid nodule.

He also cautioned against injections over the elbow. “There’s something about the skin and the olecranon bursa that makes infections more likely in that area. I saw one patient who needed plastic surgery after an infection left a significant wound.”

Rheumatoid nodules also have a tendency to recur.

When to Consider Surgery

“Surgery can benefit some patients,” Edwards said. Surgical removal may be warranted for nodules that ulcerate, become infected, or impair function — such as large nodules on the thumb or fingertip that interfere with gripping. “Patients are usually happy to regain function, even if the nodule comes back a couple of years later.” Nodules that are consistently irritated by shoes or clothing straps may also merit removal.

Pulmonary rheumatoid nodules — unlike subcutaneous ones — often contain B cells and typically respond well to rituximab or abatacept. “These lung nodules tend to shrink or stabilize with rituximab, and certainly, no new ones seem to develop,” Edwards noted. Case reports and small series have also documented improvement with Janus kinase inhibitors.

This story was translated from Medscape’s German edition.