Characteristics and treatment options of glucagonomas: a national study from the French Group of Endocrine Tumors and ENDOCAN-RENATEN network.

OBJECTIVE: Glucagonoma is a very rare functional pancreatic neuroendocrine tumor (PanNET). We aimed to provide data on the diagnosis, prognosis, and management of patients with glucagonoma. DESIGN AND METHODS: In this retrospective national cohort, we included all patients with glucagonoma, defined by at least 1 major criterion (necrolytic migratory erythema [NME] and/or recent-onset diabetes, and/or weight loss ≥ 5 kg) associated with either glucagonemia > 2 × upper limit of normal or positive glucagon immunostaining. Antisecretory efficacy was defined as partial/complete resolution of glucagonoma symptoms. Antitumor efficacy was assessed according to the time to next treatment (TTNT). RESULTS: Thirty-eight patients were included with median age 58.7 yo, primary PanNET located in the tail (68.4%), synchronous metastases (63.2%). Median Ki-67 index was 3%. Most frequent glucagonoma symptoms at diagnosis were NME (86.8%), weight loss (68.4%), and diabetes (50%). Surgery of the primary PanNET was performed in 76.3% of cases, mainly with curative intent (61.5%). After surgery, complete resolution of NME was seen in 93.8% (n = 15/16). The secretory response rates were 85.7%, 85.7%, 75%, and 60% with surgery of metastases (n = 6/7), chemotherapy (n = 6/7), liver-directed therapy (n = 6/8), and somatostatin analogs (n = 6/10), respectively. All lines combined, longer TTNT was reported with chemotherapy (20.2 months). Median overall survival (OS) was 17.3 years. The Ki-67 index > 3% was associated with shorter OS (hazard ratio 5.27, 95% CI [1.11-24.96], P = .036). CONCLUSION: Patients with glucagonoma had prolonged survival, even in the presence of metastases at diagnosis. Curative-intent surgery should always be considered. Chemotherapy, peptide receptor radionuclide therapy, or liver-directed therapy seems to provide both substantial antitumor and antisecretory efficacies.

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.

European Neuroendocrine Tumor Society 2023 guidance paper for functioning pancreatic neuroendocrine tumour syndromes.

This ENETS guidance paper aims to provide practical advice to clinicians for the diagnosis, treatment and follow-up of functioning syndromes in pancreatic neuroendocrine tumours (NET). A NET-associated functioning syndrome is defined by the presence of a clinical syndrome combined with biochemical evidence of inappropriately elevated hormonal levels. Different hormonal syndromes can be encountered in pancreatic NET patients, including insulinoma, gastrinoma as well as the rare glucagonoma, VIPoma, ACTHoma, PTHrPoma, carcinoid syndrome, calcitoninoma, GHRHoma and somatostatinoma. The recommendations provided in this paper focus on the biochemical, genetic and imaging work-up as well as therapeutic management of the individual hormonal syndromes in well-differentiated, grade 1-3, functioning NET with the primary tumour originating in the pancreas, and for specific subtypes also in the duodenum.

Supportive therapy in gastroenteropancreatic neuroendocrine tumors: Often forgotten but important.

Neuroendocrine tumors (NETs) are a group of rare and heterogeneous malignancies that can develop in various organs. A significant number of gastroenteropancreatic neuroendocrine tumours (GEP-NETs) is functionally active and presents with symptoms related to the secretion of biologically active substances, leading to the development of distinct clinical syndromes. There are various therapeutic approaches for GEP-NETs, including curative surgery, palliative surgery, local-ablative and loco-regional therapies as well as systemic therapeutic options including peptide receptor radionuclide therapy, cytotoxic therapy, and molecularly targeted therapies. Specific supportive therapy of patients with NETs includes management or prevention of hormone-related clinical syndromes and paraneoplastic states. Supportive therapy plays a key role in NET treatment. Supportive therapy includes debulking surgery and interventional radiologic techniques to reduce tumour bulk or load, as well as systemic medical treatment options to manage or prevent hypersecretion syndromes and treatment-related side effects. Supportive therapies are a type of of comprehensive treatment addressing the patient as a whole person throughout the process of NET treatment. Therefore, supportive therapy also encompasses psychosocial support, expert nursing, nutritional support and management of cancer related pain.

A Case Series of Molecular Imaging of Glucagonoma After Initial Therapy-68Ga-DOTATATE PET/CT Reveals Similar Results as in Neuroendocrine Tumors of Other Origin in Follow-up and Re-evaluation.

Glucagonoma is an extremely rare, glucagon-secreting neuroendocrine tumor of the pancreas. Only sparse data are available about the characteristics of this tumor in somatostatin receptor imaging and only for the situation of initial diagnosis. We present a series of 3 glucagonoma patients who underwent at least 1 Ga-DOTATATE PET/CT scan. All patients were diagnosed by either histology and/or elevated serum levels of glucagon. The presented cases suggest that somatostatin receptor-based imaging can probably be used for re-evaluation of disease status in patients with glucagonoma in a similar way as it is already established for neuroendocrine tumors of other origin.

A review of cutaneous manifestations within glucagonoma syndrome: necrolytic migratory erythema.

Necrolytic migratory erythema (NME) is a rare skin disorder that is a cutaneous manifestation of the glucagonoma syndrome. It presents with annular eruptions of migrating erythematous papules and plaques with superficial epidermal necrosis, central flaccid bullae, and crusted erosions located primarily in the intertriginous areas. Treatment with the long-acting somatostatin analog Octreotide is a potential therapy to help ameliorate skin symptoms. We present a case of a patient with a 1-year history of a pancreatic glucagonoma that developed an ulcerated, plaque-like, weeping rash over multiple areas of their body despite current treatment with Octreotide and stable pancreatic tumor staging. The patient had a similar rash when initially diagnosed with a glucagonoma, and it quickly improved after Octreotide treatment. Clinical examination and biopsy were consistent with necrolytic migratory erythema due to an underlying glucagonoma. This rare case adds to our understanding of the clinical presentation of NME, as well as highlights the relapsing and remitting course, even if the underlying pancreatic tumor is stable and the patient is undergoing treatment.

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.

[Neuroendocrine well-differentiated pancreatic tumors]. / Tumeurs neuro-endocrines bien différenciées du pancreas.

Neuroendocrine pancreatic tumors are rare tumors which require specific diagnosis and management. They are characterized by complex histopathologic criteria, large differences in secretory profile and évolutivity, and be associated to hereditary endocrine disease as NEM1 or VHL. Therapeutic strategy is currently discussed throught the regional or national pluridisciplinary workups organized by the 17 experts centers of the French RENATEN network. Treatment of these tumors requires the optimal control of hormonal secretory features for functioning neuroendocrine tumors while antiproliferative treatments are indicated for metastatic large or/and progressive tumors. Their optimal treatment may include locoregional procedures as chemoembolization, radiopeptidé therapy, chemotherapy, targeted therapies and clinical trials.

A tale of two tumors: treating pancreatic and extrapancreatic neuroendocrine tumors.

Despite their perceived rarity, gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rising in incidence and prevalence. The biology, natural history, and therapeutic options for GEP-NETs are heterogeneous: NETs arising in the pancreas can be distinguished from those arising elsewhere in the gastrointestinal tract, and therapy is dichotomized between these two groups. Somatostatin analogues are the mainstay of oncologic management of bowel NETs; everolimus, streptozocin, and sunitinib are approved to treat pancreatic NETs. There are significant differences in molecular genetics between pancreatic and extrapancreatic NETs, and studies are evaluating whether additional NET patients may benefit from targeted agents. We discuss the distinguishing features of these two groups of tumors, as well as the therapeutic implications of the distinction. We also examine the evolving therapeutic landscape and discuss the likelihood that treatment will be developed independently for pancreatic and extrapancreatic gastrointestinal NETs, with novel therapeutics effective for newly identified pathologically or molecularly defined subgroups.

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 associated with glucagonoma syndrome diagnosed by 68Ga-DOTANOC PET-CT.

Necrolytic migratory erythema (NME) is a rare dermatological condition which presents a diagnostic challenge. Repeated negative skin biopsies and non-detection of any pancreatic tumor in conventional imaging modalities like a computed tomography (CT) scan and ultrasonogram (USG) make the diagnosis more difficult. By the time the diagnosis is made, the patient usually presents with metastasis. We present a rare case of difficult to diagnose NME, as repeated skin biopsies and conventional imaging modalities like CT and USG could not detect the underlying glucagonoma. A (68)Ga-DOTANOC positron emission tomography PET-CT was able to detect the underlying cause of NME as glucagonoma of the pancreas and the same investigation confirmed the absence of any metastasis elsewhere in the body. The tumor was excised and patient dramatically improved, and all skin lesions disappeared.

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.

Hyperthermic isolated liver perfusion with melphalan and bevacizumab.

Whereas surgical resection is the only curative treatment for liver tumors, effective treatment for isolated unresectable lesions when there is tumor progression in spite of several lines of chemotherapy remains to be found. We report herein two cases of patients treated by a 1-hour Hyperthermic Isolated Liver Perfusion (HILP) with a combination of melphalan and bevacizumab leading to complete response. The first patient had liver metastases secondary to previously resected malignant glucagonoma and the second, recurrent hepatocellular carcinoma. We used bevacizumab in association with melphalan for HILP because of the additional effect of an anti-VEGF antibody in these highly vascularized tumors and its locally restricted delivery to the isolated hepatic vascular compartment despite of its classic contraindication in association with surgery. The protocol was approved by the Ethics Committee. Enhanced CT scans during follow-up showed complete tumor necrosis as early as the second postoperative day. Patients had 27 and 7 months disease-free survival and 48 and 41 months overall survival after HILP, for neuroendocrine liver metastases and HILP plus liver transplantation for HCC respectively. Under very specific conditions, bevacizumab in HILP can provide excellent tumor response in hopeless clinical cases of liver tumors.

Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances.

Pancreatic neuroendocrine tumors (pNETs) comprise with gastrointestinal carcinoids, the main groups of gastrointestinal neuroendocrine tumors (GI-NETs). Although these two groups of GI-NETs share many features including histological aspects; over-/ectopic expression of somatostatin receptors; the ability to ectopically secrete hormones/peptides/amines which can result in distinct functional syndromes; similar approaches used for tumor localization and some aspects of treatment, it is now generally agreed they should be considered separate. They differ in their pathogenesis, hormonal syndromes produced, many aspects of biological behaviour and most important, in their response to certain anti-tumour treatment (chemotherapy, molecular targeted therapies). In this chapter the clinical features of the different types of pNETs will be considered as well as aspects of their diagnosis and medical treatment of the hormone-excess state. Emphasis will be on controversial areas or recent advances. The other aspects of the management of these tumors (surgery, treatment of advanced disease, tumor localization) are not dealt with here, because they are covered in other chapters in this volume.

[Diagnostics and treatment in functional pancreatic neuroendocrine tumours]. / Diagnostik und Therapie bei funktionell aktiven pankreatischen neuroendokrinen Tumoren.

Pancreatic neuroendocrine tumours (PNET) are rare entities with an annual incidence of < 100,000. About 1 - 2 % of pancreatic neoplasias are neuroendocrine tumours. About one third of these tumours secrete biologically active substances that lead to development of specific clinical syndromes. PNET may occur sporadically or in association with hereditary syndromes, such as multiple endocrine neoplasia type 1 (MEN1). Among the functional PNET, insulinomas and gastrinomas are the most common entities. In contrast, vasoactive intetinale peptide (VIP)-secreting tumours, glucagonomas, serotonin-secreting carcinoid tumors, and tumours with secretion of ectopic hormones, such as calcitonin, are extremely rare. Once diagnosis has been established on the basis of clinical and laboratory findings, localization of the source of pathologic hormone secretion is warranted. Imaging methods frequently used for localization of PNET comprise anatomical imaging modalities, computed tomography, and magnetic resonance imaging, endoscopic ultrasound, selective arterial catheterization with hepatic venous sampling, DTPA-octreotid scintigraphy and DOTA-D-Phe(1)-Tyr(3)-octreotid positron emission tomography. Therapy is based on the specific tumour entity and the extent of the disease. In the majority of patients, even in the case of malignant disease, a surgical approach is warranted, eventually combined with a medical treatment.

Tumores neuroendocrinos del páncreas / Pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors are infrequent and slow-growing neoplasms. They are classified basedon their clinical presentation as functioning and nonfunctioning tumors. The most common functionaltumors are the insulinoma and gastrinoma. They can be sporadic or be part of hereditary forms as MEN-1.The diagnosis is based on the detection of the specific clinical syndrome in association of high levels of the substance secreted by the tumor and conventional imaging studies or others such as stimulation tests, somatostatin receptor scintigraphy and endoscopic ultrasound. In general, these tumors have a better prognosis than the pancreatic adenocarcinoma and they can show metastasis to the liver and infrequently, in bones. The treatment can be managed medically diminishing the inappropriate secretion of the substances by the tumor using, for example, the somatostatin analogs. Surgery should be always considered, especially in case of insulinomas, small non-functioning tumors, and small gastrinomas that can be managed with surgery enucleation. More advanced resective surgery, such as Whipple resection, are not routinely recommended and they should be limited to selected patients. In advanced tumors, there are other treatment alternatives, for example, hepatic resection, radiofrequency, chemotherapy and new agents such as sunitinib and everolimus.

Los tumores neuroendocrinos pancreáticos son infrecuentes y de crecimiento lento. Se clasifican en tumores funcionantes o no funcionantes (TNEP-NF), de acuerdo a la presentación clínica. Los tumores funcionantes más frecuentes son los insulinomas y los gastrinomas. Pueden ocurrir en forma esporádica o asociados a síndromes hereditarios como la NEM- 1, entre otros. El diagnóstico se basa en la detección del síndrome clínico específico asociado a la demostración de niveles elevados de la sustancia secretada y exámenes imagenológicos convencionales u otros más específicos como de estimulación, cintigrafía de receptores de somatostatina y endosonografía. En general, tienen mejor pronóstico que los adenocarcinomas pancreáticos y pueden dar metástasis hepáticas y con menor frecuencia, óseas. El tratamiento puede ser médico disminuyendo la secreción inapropiada de las sustancias producidas por el tumor como los análogos de somatostatina. La cirugía siempre debe ser considerada, especialmente en caso de insulinomas, pequeños TNEP-NF, y gastrinomas pequeños, que pueden ser tratados con enucleación quirúrgica. Las cirugías resectivas más avanzadas, como la operación de Whipple no están recomendadas en forma rutinaria y sólo deben ser utilizadas en pacientes seleccionados. En casos de tumores avanzados, existen alternativas de tratamiento, como la resección hepática, radiofrecuencia, quimioterapia, y terapia con nuevos agentes en estudio como el sunitinib y everolimus.