A novel likely pathogenetic variant p.(Cys235Arg) of the MEN1 gene in multiple endocrine neoplasia type 1 with multifocal glucagonomas.

PURPOSE: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary endocrine syndrome caused by pathogenic variants in MEN1 tumor suppressor gene. Diagnosis is commonly based on clinical criteria and confirmed by genetic testing. The objective of the present study was to report on a MEN1 case characterized by multiple pancreatic glucagonomas, with particular concern on the possible predisposing genetic defects. METHODS: While conducting an extensive review of the most recent scientific evidence on the unusual glucagonoma familial forms, we analyzed the MEN1 gene in a 35-year-old female with MEN1, as well as her son and daughter, using Sanger and next-generation sequencing (NGS) approaches. We additionally explored the functional and structural consequences of the identified variant using in silico analyses. RESULTS: NGS did not show any known pathogenic variant in the tested regions. However, a new non-conservative variant in exon 4 of MEN1 gene was found in heterozygosity in the patient and in her daughter, resulting in an amino acid substitution from hydrophobic cysteine to hydrophilic arginine at c.703T > C, p.(Cys235Arg). This variant is absent from populations databases and was never reported in full papers: its characteristics, together with the high specificity of the patient's clinical phenotype, pointed toward a possible causative role. CONCLUSION: Our findings confirm the need for careful genetic analysis of patients with MEN1 and establish a likely pathogenic role for the new p.(Cys235Arg) variant, at least in the rare subset of MEN1 associated with glucagonomas.

Necrolytic Migratory Erythema: A Forgotten Paraneoplastic Condition.

BACKGROUND: Necrolytic migratory erythema (NME) is most commonly a paraneoplastic condition. It is the dermatologic manifestation classically associated with glucagonoma pancreatic neuroendocrine tumour. Glucagonoma syndrome has been defined by the constellation of secreting tumour associated with overproduction by the α-cells in the pancreatic islets of Langerhans, abnormally elevated blood level of glucagon, and skin findings of NME. OBJECTIVE: Although rare, all dermatologists must know and recognise NME promptly to request useful investigations for the diagnosis of this characteristic neuroendocrine tumour. METHODS AND RESULTS: We report a case of a middle-aged woman seen in our dermatology clinic with longstanding skin findings suggestive of NME revealing a glucagonoma. Surgical removal was associated with complete resolution of the cutaneous and systemic features. CONCLUSION: NME is often the first clinical finding of an occult neuroendocrine pancreatic neoplasia. Dermatologists must be aware of this condition since they can be the first physician to suspect it and allow multidisciplinary management, which influences the prognostic value. Surgical removal is the first-line therapy if early diagnosis is done before liver metastases occur.

Glucagonoma syndrome: a review and update on treatment.

Glucagonoma syndrome is defined by the presence of an alpha-cell secreting tumour of the pancreas, elevated levels of glucagon, and a characteristic rash called necrolytic migratory erythema (NME). NME is usually a specific and often initial finding of glucagonoma syndrome, but it may occur in other settings unassociated with an alpha-cell pancreatic tumour (pseudoglucagonoma syndrome). Glucagonoma syndrome must be distinguished from pseudoglucagonoma syndrome. Prompt recognition of NME and subsequent workup for a glucagonoma can allow for an earlier diagnosis and enhance the chances of a favourable outcome. In particular, metastases occur late, so early recognition of glucagonoma syndrome before liver metastases can be life-saving. Surgical resection is the definitive treatment for glucagonoma syndrome, although chemotherapeutic agents, somatostatin analogues and radionuclide therapy are also employed. Herein, we offer an approach to workup after identifying NME and an update on its current treatment modalities.

Non-secreting benign glucagonoma diagnosed incidentally in a patient with refractory thrombocytopenic thrombotic purpura: report of a case.

Thrombotic thrombocytopenic purpura (TTP) is a rare hematologic disorder, which may be idiopathic or secondary to a variety of diseases. However, there are very few reports of TTP in the context of pancreatic neoplasms. We report a case of relapsing TTP after initial treatment with plasmapheresis, corticosteroids, and rituximab, in a 59-year-old woman. During diagnostic work-up, a pancreatic lesion 35 × 25 mm in size was discovered incidentally and splenopancreatectomy was performed. The pathological diagnosis was benign glucagonoma. The hematological symptoms resolved completely after the procedure and 3 years later, the patient is well with no sign of recurrence of TTP or glucagonoma. To our knowledge, this represents the first documented case of a non-secreting benign pancreatic neuroendocrine tumor (glucagonoma) associated with TTP that is refractory to standard treatment.

Necrolytic migratory erythema as the first manifestation of pancreatic neuroendocrine tumor.

Necrolytic migratory erythma (NME) is an obligatory paraneoplastic syndrome. Here we describe a woman admitted to the dermatology ward with NME which was later found to be associated with glucagonoma, a slow-growing, rare pancreatic neuroendocrine tumor. Even more rarely, the tumor was located in the pancreas head, while most of such lesions are located in the distal pancreas. The diagnosis of this rare tumor requires an elevated serum glucagon level and imaging confirming a pancreatic tumor. After surgical removal of the tumor, the patient's cutaneous and systemic features resolved. It is therefore imperative that clinicians recognize NME early in order to make an accurate diagnosis and to provide treatment for this rare tumor.

[Glucagonoma - a rare neuroendocrine tumor (NET) that typically originates in the pancreas]. / Nekrolytiskt migrerande erytem och glukagonom.

One of the primary indicators of this condition is a painful and migratory dermatitis. Additionally, early signs often include weight loss and diabetes. Patients with glucagonoma commonly first encounter general practitioners or dermatologists. Unfortunately, due to the nonspecific nature of symptoms such as eczema-like dermatitis, weight loss and diabetes, diagnosis is frequently delayed, often by 2-3 years. Consequently, by the time patients are diagnosed, the tumor has usually grown and metastasized, often spreading to the liver. As a result, surgical intervention is often not possible, and treatment options are usually limited to palliative care. However, with early diagnosis of glucagonoma, treatment can be curative. Therefore, it is crucial for medical professionals who initially meet these patients, including dermatologists, general practitioners, endocrinologists, and others, to be aware of this condition to ensure an early diagnosis. By recognizing the signs and symptoms early, doctors can potentially improve patient outcomes and save lives.

Putting the pieces together: necrolytic migratory erythema and the glucagonoma syndrome.

Glucagonomas are slow-growing, rare pancreatic neuroendocrine tumors. They may present with paraneoplastic phenomena known together as the "glucagonoma syndrome." A hallmark sign of this syndrome is a rash known as necrolytic migratory erythema (NME). In this paper, the authors describe a patient with NME and other features of the glucagonoma syndrome. The diagnosis of this rare tumor requires an elevated serum glucagon level and imaging confirming a pancreatic tumor. Surgical and medical treatment options are reviewed. When detected early, a glucagonoma is surgically curable. It is therefore imperative that clinicians recognize the glucagonoma syndrome in order to make an accurate diagnosis and refer for treatment.

Necrolytic migratory erythema and glucagonoma rising from pancreatic head.

Glucagonoma syndrome encompasses necrolytic migratory erythema (NME), hyperglucagonemia, diabetes mellitus, anemia, weight loss, glossitis, angular cheilitis, steatorrhea, diarrhea, venous thrombosis, and neuropsychiatric disturbance. Of all the symptoms, NME is a rare skin disorder which is pathognomonic for glucagonoma. We present a 61-year-old woman diagnosed initially as pancreatic head adenocarcinoma with liver metastasis prior to the skin eruption. From the dermatologic finding and other clues, glucagonoma was diagnosed finally.

Pancreatic glucagonoma with pancreatic calcification.

BACKGROUND: Glucagonoma is an uncommon type of pancreatic neuroendocrine tumor [NET] which is characterized by diabetes mellitus, necrolytic migratory erythema, depression and deep vein thrombosis. The typical rash is often misdiagnosed and the diagnosis is delayed by 7-8 years. Pancreatic NETs and other pancreatic tumors are known to show calcifications within the tumor but calcification of the remaining normal pancreas is very uncommon. It occurs when there is ductal obstruction leading to acute or chronic pancreatitis. CASE REPORT: We present a case of glucagonoma with coexistent pancreatic calcification. CONCLUSION: Glucagonoma should be suspected in a diabetic patient with migratory rash. Pancreatic tumor should be suspected in patient with idiopathic focal pancreatitis.

Vascular pancreatic lesions: spectrum of imaging findings of malignant masses and mimics with pathologic correlation.

The differential diagnosis of hypervascular pancreatic lesions is complex, and includes endocrine and exocrine tumors of the pancreas, metastases to the pancreas, and masses, or mass-like lesions, arising from the neurovascular networks traversing the pancreas. In this manuscript, we will discuss salient imaging findings of these masses, pertinent differential diagnoses, as well as review clinical symptomatology that may aid in the diagnosis of some of these lesions.

Pancreatic glucagonoma metastasising to the right ovary five years after initial surgery: a case report.

CONTEXT: Glucagonomas of the pancreas are neuroendocrine tumours (NETs) that arise from well-differentiated neuroendocrine cells within the pancreatic islets. They are considered to be aggressive NETs and often have metastases at initial presentation. In contrast localised glucagonoma without metastatic spread may have prolonged disease free survival with radical resectional surgery. CASE REPORT: The authors present a case of a glucagonoma that initially presented with classical necrolytic migratory erythema and a large solitary mass in the body and tail of the pancreas that was surgically resected. Five years after surgery the patient presented with increased serum glucagon levels and a mass in the right ovary. Pathology of the resected ovary after oophorectomy identified this as an isolated metastatic glucagonoma. CONCLUSION: Glucagonoma is a rare pancreatic NET that has significant malignant potential. This is the first case of a pancreatic glucagonoma metastasising to the ovary 5 years after radical distal pancreatosplenectomy.

Pancreatic neuroendocrine tumors: biology, diagnosis,and treatment.

Pancreatic neuroendocrine tumors (PNETs), a group of endocrine tumors arising in the pancreas, are among the most common neuroendocrine tumors. The genetic causes of familial and sporadic PNETs are somewhat understood, but their molecular pathogenesis remains unknown. Most PNETs are indolent but have malignant potential. The biological behavior of an individual PNET is unpredictable; higher tumor grade, lymph node and liver metastasis, and larger tumor size generally indicate a less favorable prognosis. Endocrine testing, imaging, and histological evidence are necessary to accurately diagnose PNETs. A 4-pronged aggressive treatment approach consisting of surgery, locoregional therapy, systemic therapy, and complication control has become popular in academic centers around the world. The optimal application of the multiple systemic therapeutic modalities is under development; efficacy, safety, availability, and cost should be considered when treating a specific patient. The clinical presentation, diagnosis, and treatment of specific types of PNETs and familial PNET syndromes, including the novel Mahvash disease, are summarized.

Synchronous Insulinoma and Glucagonoma: A Review of the Literature.

BACKGROUND/AIM: Pancreatic neuroendocrine tumors (PNETs) are pancreatic neoplasms with neuroendocrine features, divided into functioning and non-functioning. The non-functioning PNETs are the largest group, and their morbidity is the result of their potential to invade surrounding tissues and metastasize. The functioning PNETs produce hormonal symptoms due to over-secretion of specific hormones. They constitute 1% to 2% of all pancreatic tumors. The use of novel imaging methods has rendered their detection more frequent. Insulinoma, the most common functioning PNET, comprises 35-40% of all functioning PNETs. Its clinical presentation is due to hyperinsulinemia and the subsequent hypoglycemia. Glucagonoma accounts for 5% of all PNETs and is the fourth most frequent functioning PNET, following insulinoma, gastrinoma, and vipoma. Its symptoms are due to the massive secretion of glucagon and ensuing hyperglycemia. The co-existence of two PNETs is a very rare entity. This report aimed to describe cases of concomitant insulinomas and glucagonomas. MATERIALS AND METHODS: A review of the literature was performed using the PubMed database and Cochrane library aiming to identify reported cases of concomitant pancreatic insulinoma and glucagonoma. Specifically, the research was conducted using the keywords, separately and in various combination, including insulinoma, glucagonoma, cystic, pancreatic neuroendocrine tumors and hypoglycemia. Only publications in English were included in the present study. RESULTS: A total of 8 cases of concomitant pancreatic insulinoma and glucagonoma were identified, corresponding to the period 1992-2021. CONCLUSION: Concomitant insulinoma and glucagonoma are rare and challenging. A multidisciplinary approach is necessary for diagnosis, prognosis, and therapy.