-
Tomography (Ann Arbor, Mich.) Jan 2023Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) comprise a heterogeneous group of neoplasms, which derive from cells of the diffuse neuroendocrine system that... (Review)
Review
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) comprise a heterogeneous group of neoplasms, which derive from cells of the diffuse neuroendocrine system that specializes in producing hormones and neuropeptides and arise in most cases sporadically and, to a lesser extent, in the context of complex genetic syndromes. Furthermore, they are primarily nonfunctioning, while, in the case of insulinomas, gastrinomas, glucagonomas, vipomas, and somatostatinomas, they produce hormones responsible for clinical syndromes. The GEP-NEN tumor grade and cell differentiation may result in different clinical behaviors and prognoses, with grade one (G1) and grade two (G2) neuroendocrine tumors showing a more favorable outcome than grade three (G3) NET and neuroendocrine carcinoma. Two critical issues should be considered in the NEN diagnostic workup: first, the need to identify the presence of the tumor, and, second, to define the primary site and evaluate regional and distant metastases. Indeed, the primary site, stage, grade, and function are prognostic factors that the radiologist should evaluate to guide prognosis and management. The correct diagnostic management of the patient includes a combination of morphological and functional evaluations. Concerning morphological evaluations, according to the consensus guidelines of the European Neuroendocrine Tumor Society (ENETS), computed tomography (CT) with a contrast medium is recommended. Contrast-enhanced magnetic resonance imaging (MRI), including diffusion-weighted imaging (DWI), is usually indicated for use to evaluate the liver, pancreas, brain, and bones. Ultrasonography (US) is often helpful in the initial diagnosis of liver metastases, and contrast-enhanced ultrasound (CEUS) can solve problems in characterizing the liver, as this tool can guide the biopsy of liver lesions. In addition, intraoperative ultrasound is an effective tool during surgical procedures. Positron emission tomography (PET-CT) with FDG for nonfunctioning lesions and somatostatin analogs for functional lesions are very useful for identifying and evaluating metabolic receptors. The detection of heterogeneity in somatostatin receptor (SSTR) expression is also crucial for treatment decision making. In this narrative review, we have described the role of morphological and functional imaging tools in the assessment of GEP-NENs according to current major guidelines.
Topics: Humans; Positron Emission Tomography Computed Tomography; Syndrome; Neuroendocrine Tumors; Prognosis; Radiologists
PubMed: 36828370
DOI: 10.3390/tomography9010018 -
Endocrine-related Cancer Dec 2016Worldwide, the syndromes of paraganglioma (PGL), somatostatinoma (SOM) and early childhood polycythemia are described in only a few patients with somatic mutations in...
Worldwide, the syndromes of paraganglioma (PGL), somatostatinoma (SOM) and early childhood polycythemia are described in only a few patients with somatic mutations in the hypoxia-inducible factor 2 alpha (HIF2A). This study provides detailed information about the clinical aspects and course of 7 patients with this syndrome and brings into perspective these experiences with the pertinent literature. Six females and one male presented at a median age of 28 years (range 11-46). Two were found to have HIF2A somatic mosaicism. No relatives were affected. All patients were diagnosed with polycythemia before age 8 and before PGL/SOM developed. PGLs were found at a median age of 17 years (range 8-38) and SOMs at 29 years (range 22-38). PGLs were multiple, recurrent and metastatic in 100, 100 and 29% of all cases, and SOMs in 40, 40 and 60%, respectively. All PGLs were primarily norepinephrine-producing. All patients had abnormal ophthalmologic findings and those with SOMs had gallbladder disease. Computed tomography (CT) and magnetic resonance imaging revealed cystic lesions at multiple sites and hemangiomas in 4 patients (57%), previously thought to be pathognomonic for von Hippel-Lindau disease. The most accurate radiopharmaceutical to detect PGL appeared to be [F]-fluorodihydroxyphenylalanine ([F]-FDOPA). Therefore, [F]-FDOPA PET/CT, not [Ga]-(DOTA)-[Tyr3]-octreotate ([Ga]-DOTATATE) PET/CT is recommended for tumor localization and aftercare in this syndrome. The long-term prognosis of the syndrome is unknown. However, to date no deaths occurred after 6 years follow-up. Physicians should be aware of this unique syndrome and its diagnostic and therapeutic challenges.
Topics: Adolescent; Adrenal Gland Neoplasms; Adult; Child; Cohort Studies; Disease Progression; Female; Humans; Male; Middle Aged; Neoplasms, Multiple Primary; Pancreatic Neoplasms; Paraganglioma; Polycythemia; Retrospective Studies; Somatostatinoma; Syndrome; Young Adult
PubMed: 27679736
DOI: 10.1530/ERC-16-0231 -
Neurology. Genetics Jun 2020To investigate the effect of somatic, postzygotic, gain-of-function mutation of Endothelial Per-Arnt-Sim (PAS) domain protein 1 () encoding hypoxia-inducible factor-2α...
OBJECTIVE
To investigate the effect of somatic, postzygotic, gain-of-function mutation of Endothelial Per-Arnt-Sim (PAS) domain protein 1 () encoding hypoxia-inducible factor-2α (HIF-2α) on posterior fossa development and spinal dysraphism in gain-of-function syndrome, which consists of multiple paragangliomas, somatostatinoma, and polycythemia.
METHODS
Patients referred to our institution for evaluation of new, recurrent, and/or metastatic paragangliomas/pheochromocytoma were confirmed for gain-of-function syndrome by identification of the gain-of-function mutation in resected tumors and/or circulating leukocytes. The posterior fossa, its contents, and the spine were evaluated retrospectively on available MRI and CT images of the head and neck performed for tumor staging and restaging. The transgenic mouse model underwent Microfil vascular perfusion and subsequent intact ex vivo 14T MRI and micro-CT as well as gross dissection, histology, and immunohistochemistry to assess the role of in identified malformations.
RESULTS
All 8 patients with gain-of-function syndrome demonstrated incidental posterior fossa malformations-one Dandy-Walker variant and 7 Chiari malformations without syringomyelia. These findings were not associated with a small posterior fossa; rather, the posterior fossa volume exceeded that of its neural contents. Seven of 8 patients demonstrated spinal dysraphism; 4 of 8 demonstrated abnormal vertebral segmentation. The mouse model similarly demonstrated features of neuraxial dysraphism, including cervical myelomeningocele and spinal dysraphism, and cerebellar tonsil displacement through the foramen magnum. Histology and immunohistochemistry demonstrated incomplete mesenchymal transition in the mutant but not the control mouse.
CONCLUSIONS
This study characterized posterior fossa and spinal malformations seen in gain-of-function syndrome and suggests that gain-of-function mutation in HIF-2α results in improper mesenchymal transition.
PubMed: 32337341
DOI: 10.1212/NXG.0000000000000414 -
Case Reports in Gastrointestinal... 2019Somatostatinoma is a rare neuroendocrine tumor with an incidence rate of 1 in 40 million people. It presents mostly as asymptomatic tumor diagnosed incidentally on...
Somatostatinoma is a rare neuroendocrine tumor with an incidence rate of 1 in 40 million people. It presents mostly as asymptomatic tumor diagnosed incidentally on imaging or surgery when evaluating or treating possible causes of abdominal pain. It also can present with vague symptoms, or as a clinical triad of glucose intolerance, steatorrhea, and achlorhydria. The majority of somatostatinomas are present in the pancreatic head, followed by the duodenum, the pancreatic tail, and rarely the ampulla of Vater. The prognosis is poor as more than 77% of cases present as advanced disease with local invasion or distant metastasis. Surgical resection is the main treatment for early stage disease. Other treatment options include somatostatin analogue, molecular targeted therapy, and cytotoxic chemotherapy. The scarcity of somatostatinoma cases led to the lack of fully formulated treatment options. Herein, we present a 43-year old male patient who was referred by his primary care physician to our gastroenterology clinic due to elevated liver function test and double-duct sign on CT scan. We performed an ERCP, which revealed 2 cm ampullary lesion with upstream obstruction. Biopsies were taken and histopathology was unrevealing. He underwent a laparoscopic pancreaticoduodenectomy with histopathology revealed stage IIb somatostatinoma. Treating physicians should hold a high index of suspicion and maintain a broad differential diagnosis of elevated liver enzymes.
PubMed: 31210994
DOI: 10.1155/2019/9506405 -
Haematologica Jun 2023Gain-of-function mutations in the EPAS1/HIF2A gene have been identified in patients with hereditary erythrocytosis that can be associated with the development of...
Gain-of-function mutations in the EPAS1/HIF2A gene have been identified in patients with hereditary erythrocytosis that can be associated with the development of paraganglioma, pheochromocytoma and somatostatinoma. In the present study, we describe a unique European collection of 41 patients and 28 relatives diagnosed with an erythrocytosis associated with a germline genetic variant in EPAS1. In addition we identified two infants with severe erythrocytosis associated with a mosaic mutation present in less than 2% of the blood, one of whom later developed a paraganglioma. The aim of this study was to determine the causal role of these genetic variants, to establish pathogenicity, and to identify potential candidates eligible for the new hypoxia-inducible factor-2 α (HIF-2α) inhibitor treatment. Pathogenicity was predicted with in silico tools and the impact of 13 HIF-2b variants has been studied by using canonical and real-time reporter luciferase assays. These functional assays consisted of a novel edited vector containing an expanded region of the erythropoietin promoter combined with distal regulatory elements which substantially enhanced the HIF-2α-dependent induction. Altogether, our studies allowed the classification of 11 mutations as pathogenic in 17 patients and 23 relatives. We described four new mutations (D525G, L526F, G527K, A530S) close to the key proline P531, which broadens the spectrum of mutations involved in erythrocytosis. Notably, we identified patients with only erythrocytosis associated with germline mutations A530S and Y532C previously identified at somatic state in tumors, thereby raising the complexity of the genotype/phenotype correlations. Altogether, this study allows accurate clinical follow-up of patients and opens the possibility of benefiting from HIF-2α inhibitor treatment, so far the only targeted treatment in hypoxia-related erythrocytosis disease.
Topics: Humans; Polycythemia; Mutation; Paraganglioma; Basic Helix-Loop-Helix Transcription Factors; Hypoxia
PubMed: 36700397
DOI: 10.3324/haematol.2022.281698 -
Annals of Oncology : Official Journal... 2001Gastroenteropancreatic (GEP) neoplasms originate from any of the various cell types belonging to the neuroendocrine system. A general characteristic of GEP endocrine... (Review)
Review
Gastroenteropancreatic (GEP) neoplasms originate from any of the various cell types belonging to the neuroendocrine system. A general characteristic of GEP endocrine tumours is that the vast majority produce and secrete a multitude of peptide hormones and amines. Many patients with malignant metastasising tumours present clinical symptoms related to hormone hyperproduction. These include the so-called carcinoid syndrome, characterised by flushing, diarrhoea, wheezing and right heart disease, which is predominantly associated with the serotonin- and tachykinins-producing carcinoids of the midgut. Several types of syndrome associated with GEP endocrine tumors are caused by overproduction of a specific hormone. For instance, the well-known Zollinger-Ellison syndrome is gastrin-mediated. The so-called 'insulinoma syndrome' depends on excessive production of insulin and proinsulin, resulting in hypoglycemia. The 'glucagonoma syndrome' is characterised by necrolytic migratory erythema, diabetes and diarrhoea. The Verner-Morrison syndrome, which is brought about by high circulating levels of vasointestinal peptide (VIP). produces severe secretory diarrhoea. Finally the 'somatostatinoma syndrome' involves gallbladder dysfunction and gallstones, diarrhoea with or without steatorrhea, and impaired glucose tolerance. The biochemical diagnosis of endocrine digestive tumors is based on general and specific markers. The best general markers are chromogranin A (CgA) and pancreatic polypeptide (PP). Specific markers for endocrine tumors include insulin, gastrin, glucagon, vaso intestinal polypeptide (VIP), somatostatin and the primary cathabolic product of serotonin, 5-hydroxyndoleacetic acid (5-HIAA). Localisation procedures commonly applied, in the diagnosis of endocrine tumours include ultrasound (US), computed tomography (CT) and somatostatin receptor scintigraphy (SRS).
Topics: Biomarkers, Tumor; Chromogranin A; Chromogranins; Humans; Incidence; Malignant Carcinoid Syndrome; Neoplasm Metastasis; Neuroendocrine Tumors; Pancreatic Neoplasms; Pancreatic Polypeptide; Radionuclide Imaging; Receptors, Somatostatin; Stomach Neoplasms; Zollinger-Ellison Syndrome
PubMed: 11762360
DOI: 10.1093/annonc/12.suppl_2.s95 -
Journal of Nuclear Medicine : Official... Aug 2017Pheochromocytoma/paraganglioma (PPGL) syndromes associated with polycythemia have previously been described in association with mutations in the von Hippel-Lindau gene....
Pheochromocytoma/paraganglioma (PPGL) syndromes associated with polycythemia have previously been described in association with mutations in the von Hippel-Lindau gene. Recently, mutations in the prolyl hydroxylase gene () 1 and 2 and in the hypoxia-inducible factor 2 α () were also found to be associated with multiple and recurrent PPGL. Such patients also presented with PPGL and polycythemia, and later on, some presented with duodenal somatostatinoma. In additional patients presenting with PPGL and polycythemia, no further mutations have been discovered. Because the functional imaging signature of patients with PPGL-polycythemia syndromes is still unknown, and because these tumors (in most patients) are multiple, recurrent, and metastatic, the goal of our study was to assess the optimal imaging approach using 4 different PET radiopharmaceuticals and CT/MRI in these patients. Fourteen patients (10 women, 4 men) with confirmed PPGL and polycythemia prospectively underwent Ga-DOTATATE (13 patients), F-FDG (13 patients), F-fluorodihydroxyphenylalanine (F-FDOPA) (14 patients), F-fluorodopamine (F-FDA) (11 patients), and CT/MRI (14 patients). Detection rates of PPGL lesions were compared between all imaging studies and stratified between the underlying mutations. F-FDOPA and F-FDA PET/CT showed similar combined lesion-based detection rates of 98.7% (95% confidence interval [CI], 92.7%-99.8%) and 98.3% (95% CI, 90.9%-99.7%), respectively. The detection rates for Ga-DOTATATE (35.3%; 95% CI, 25.0%-47.2%), F-FDG (42.3; 95% CI, 29.9%-55.8%), and CT/MRI (60.3%; 95% CI, 48.8%-70.7%) were significantly lower ( < 0.01), irrespective of the mutation status. F-FDOPA and F-FDA are superior to F-FDG, Ga-DOTATATE, and CT/MRI and should be the radiopharmaceuticals of choice in this rare group of patients.
Topics: Adolescent; Adult; Child; Female; Humans; Male; Middle Aged; Multimodal Imaging; Paraganglioma; Polycythemia; Young Adult
PubMed: 28336782
DOI: 10.2967/jnumed.116.187690 -
JAMA Ophthalmology Feb 2020Patients with the EPAS1 gain-of-function mutation syndrome (or Pacak-Zhuang syndrome) present with multiple paragangliomas or pheochromocytomas, duodenal...
IMPORTANCE
Patients with the EPAS1 gain-of-function mutation syndrome (or Pacak-Zhuang syndrome) present with multiple paragangliomas or pheochromocytomas, duodenal somatostatinoma, polycythemia, headaches, and sometimes diminished visual acuity at an early age. The characteristic phenotype and known genetic cause of the syndrome provide an opportunity to study the role of hypoxia-inducible factor 2α (HIF-2α) in oxygen sensing, development in regions of physiologic hypoxia, and other pathological processes.
OBJECTIVES
To describe the ocular lesions in EPAS1 gain-of-function mutation syndrome and to establish whether early-onset diminished visual acuity is developmental or associated with long-term physiologic sequelae of the syndrome.
DESIGN, SETTING, AND PARTICIPANTS
This clinical case series with a transgenic murine model study was conducted from July 2013 to June 2019. Participants were 3 patients referred by their primary care physicians to the National Institutes of Health for evaluation of recurrent and metastatic paragangliomas or pheochromocytomas accompanied by polycythemia. The syndrome and somatic mosaicism in patients were confirmed by the identification of gain-of-function mutations in the EPAS1 gene in resected tumors and other tissues.
MAIN OUTCOMES AND MEASURES
Ocular findings in patients with EPAS1 gain-of-function mutation syndrome.
RESULTS
A total of 3 patients (mean [SD] age, 29 [6.2] years) with confirmed ocular abnormalities were included in the study. Increased contrast accumulation at the posterior aspect of the globe was seen bilaterally on magnetic resonance imaging scans in all patients. Ophthalmoscopy images demonstrated fibrosis overlying the optic disc, tortuous and dilated retinal vessels, and retinal pigment epithelium changes. Optic disc edema and retinal exudates were also seen. Fluorescein angiography images showed leakage of dye from postcapillary venules surrounding the optic disc and highlighted aberrant retinal vascular patterns. Enhanced-depth imaging optical coherence tomography images showed substantial thickening of the choroid and dilation of choroidal vessels. The ocular features of the syndrome were confirmed with a transgenic model of mice with gain-of-function Epas1A529V mutation.
CONCLUSIONS AND RELEVANCE
In this case series, HIF-2α and hypoxia signaling was found to have a role in vessel development within the choroid and retina, indicating that the marked permanent choroidal thickening and tortuous and dilated veins seen in the choroid and retina in patients with EPAS1 gain-of-function mutation syndrome were suggestive of the persistence of venous elements within the developing mesenchyme. These findings may explain other eye and vascular abnormalities whose pathogenesis remains unclear.
Topics: Adult; Animals; Basic Helix-Loop-Helix Transcription Factors; Choroid; Disease Models, Animal; Female; Gain of Function Mutation; Humans; Male; Mice; Retina; Tomography, Optical Coherence
PubMed: 31876943
DOI: 10.1001/jamaophthalmol.2019.5244 -
Annals of the Royal College of Surgeons... Jul 2011Somatostatinomas are rare neuroendocrine tumours with an annual incidence of 1 in 40 million. They arise in the pancreas or periampullary duodenum. Most are clinically...
BACKGROUND
Somatostatinomas are rare neuroendocrine tumours with an annual incidence of 1 in 40 million. They arise in the pancreas or periampullary duodenum. Most are clinically non-secretory and do not cause the somatostatinoma syndrome. Many are metastatic at presentation and their management is typically multimodal.
CASE HISTORIES
Four cases of somatostatinoma are described. Two patients with periampullary disease presented with biliary obstruction, one with frank jaundice and one with incidental bile duct obstruction on investigation of hepatitis B. Each patient had type 1 neurofibromatosis and resection of the somatostatinoma by means of a pylorus-preserving proximal pancreaticoduodenectomy has resulted in long-term survival. Another two patients with metastatic pancreatic somatostatinomas presented with abdominal pain. Contrasting management illustrates current treatment strategies that are dependent in part on the distribution of the disease.
DISCUSSION
The pathophysiology, presentation, clinical associations and role of diagnostic imaging are discussed for periampullary and pancreatic neuroendocrine tumours. Operative treatment has an important role in both the curative and palliative settings in conjunction with appropriate medical treatments and these are described. Management options depend on the extent of the disease and the cases are used to illustrate the rationale of such strategies.
Topics: Abdominal Pain; Adult; Aged; Ampulla of Vater; Cholangiopancreatography, Endoscopic Retrograde; Cholestasis; Common Bile Duct Neoplasms; Diagnosis, Differential; Female; Humans; Incidental Findings; Jaundice, Obstructive; Male; Middle Aged; Neurofibromatosis 1; Pancreatic Neoplasms; Pancreaticoduodenectomy; Somatostatinoma; Tomography, X-Ray Computed
PubMed: 21943457
DOI: 10.1308/003588411X582681 -
In Vivo (Athens, Greece) 2020Somatostatinomas (SSomas) constitute a rare neuroendocrine tumor. The purpose of this study was to evaluate the current published literature about pancreatic SSomas and...
BACKGROUND/AIM
Somatostatinomas (SSomas) constitute a rare neuroendocrine tumor. The purpose of this study was to evaluate the current published literature about pancreatic SSomas and report epidemiologic and clinicopathologic data for this entity.
PATIENTS AND METHODS
A combined automated and manual systematic database search of the literature was performed using electronic search engines (Medline PubMed, Scopus, Ovid and Cochrane Library), until February 2020. Statistical analysis was performed using the R language and environment for statistical computing.
RESULTS
Overall, the research revealed a total of 36 pancreatic SSoma cases. Patient mean age was 50.25 years. The most common pancreatic location was the pancreatic head (61.8%). The most frequent clinical symptom was abdominal pain (61.1%). Diagnostic algorithm most often included Computed Tomography and biopsy; surgical resection was performed in 28 cases. Out of the 36 cases, 22 had been diagnosed with a metastatic tumor and metastasectomy was performed in 6 patients with a worse overall survival (OS) (p=0.029). In total, OS was 47.74 months.
CONCLUSION
Patients with metastatic disease did not benefit from metastasectomy, but the sample size was small to reach definite conclusions. However, further studies with longer follow-up are needed for a better evaluation of these results.
Topics: Humans; Metastasectomy; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Somatostatinoma; Tomography, X-Ray Computed
PubMed: 33144470
DOI: 10.21873/invivo.12201