[Well-differentiated neuroendocrine tumors of the digestive tract: Focus on pancreatic neuroendocrine tumors]. / Tumeurs neuroendocrines digestives bien différenciées: focus sur les tumeurs pancréatiques.

Pancreatic neuroendocrine tumors are rare tumors showing a rising incidence. They are well-differentiated tumors, classified by grade according to their Ki67 index value (grade 1 to 3). Pancreatic neuroendocrine tumors are mainly sporadic tumors but about 10% arise within endocrine tumor syndromes such as multiple endocrine neoplasia type 1. They can be responsible for functional syndromes or non-specific clinical symptoms depending on tumor extension. However, there is also an increase of incidental diagnoses of nonfunctional pancreatic neuroendocrine tumors with the widespread use of high-quality imaging techniques. About 50 % of pancreatic neuroendocrine tumors are diagnosed at a metastatic stage, with metastases often located in the liver. Chromogranin A, CT-scan and often an abdominal MRI, and functional imaging should be performed for tumor staging and follow-up. Imaging with PET/CT with 68Ga-labeled somatostatin analogues has the highest sensitivity for the diagnosis of pancreatic neuroendocrine tumors, while 18fluorodeoxyglucose PET/CT can sometimes be useful. Overall, they are rather indolent tumors with prolonged survival. Surgery is the recommended treatment in the localized setting, with the exception of small<2cm nonfunctional tumors that can be monitored with imaging techniques. For advanced tumors, there are several available treatments such as somatostatine analogues, chemotherapy, targeted therapies (sunitinib, everolimus), locoregional ablative therapies and Peptide Receptor Radiolabelled Therapy. The treatment strategy will depend on the initial tumor staging, tumor grade, aggressiveness and patient's choice.

[MEN for multiple endocrin neoplasms: When evokate MEN? Update 2022]. / Mise au point sur les néoplasies endocriniennes multiples.

Multiple endocrine neoplasia (MEN) are genetic predisposition syndromes to endocrine tumors including MEN1, MEN2 and exceptionally MEN4. MEN are transmitted in an autosomal dominant fashion with a high penetrance. Classically, there is no genotype/phenotype correlation for NEM1 whereas this is the case for NEM2. Patients with NEM1, linked to an inactivating mutation of the menin gene, may present with: primary hyperparathyroidism, pituitary adenoma, duodeno-pancreatic neuroendocrine tumors (NETs), bronchial tumors with an increased risk of thymoma, adrenal cortical tumors, an increased risk of breast cancer and characteristic skin involvement such as collagenomas, lentiginomas and an increased risk of skin cancer. These patients require at least annual follow-up. Screening of children is proposed from the age of 5 years. Patients with NEM2, linked to an activating mutation of the RET proto-oncogene, all present with medullary thyroid carcinoma (MTC) at a variable age depending on the genotype. Some patients present a pheochromocytoma (50 %) and hyperparathyroidism (20 %). Pediatric forms with aggressive CMT, ganglioneuromatosis and marfanoid syndrome exist (rare NEM2B). Some mutations are associated with a risk of aggressive CMT, justifying prophylactic thyroidectomy before 6 months of age. The age of genetic testing depends on the mutation subtype in the NEM2 parent. NEM4, related to a mutation in the CDKN1B gene, are rare, with a less well-known pathogenesis and their follow-up is not well codified.

[Inherited tumor syndromes of gastroenteropancreatic and thoracic neuroendocrine neoplasms]. / Syndromes de prédisposition aux tumeurs neuroendocrines gastro-entéro-pancréatiques et thoraciques.

About 5% of gastroenteropancreatic and thoracic neuroendocrine neoplasms (NENs) arise in the context of an inherited tumour syndrome. The two most frequent syndromes are: multiple endocrine neoplasia type 1 (MEN1), associated with a large spectrum of endocrine and non endocrine tumours, including duodenopancreatic, thymic and bronchial NENs, and the von Hippel-Lindau syndrome VHL, associated with pancreatic NENs. Two inherited syndromes have a low incidence of NENs: neurofibromatosis type 1 (NF1), associated with duodenal somatostatinomas, and tuberous sclerosis (TSC), associated with pancreatic NENs. Two rare syndromes have a high incidence of NENs: multiple endocrine neoplasia type 4 (MEN4), with a tumour spectrum similar to that of MEN1, and glucagon cell hyperplasia neoplasia (GCHN), involving only the pancreas. It is likely that other syndromes remain to be characterized, especially in familial small-intestinal NENs. The diagnosis is usually raised because of the suggestive clinical setting: young age at diagnosis, multiple tumours in multiple organs, familial history. Except in VHL and NF1, tumours themselves do not show specific pathological features; they usually are well differentiated and of low histological grade; their prognosis is good, except for MEN1-associated thymic NENs. The most suggestive pathological feature is their combination with various endocrine and/or non endocrine lesions in the adjacent tissue. Pathological examination is important, for a correct diagnosis and for an accurate management of the patients and their families, who must be referred to expert centers.

Receptor radionuclide targeting for neuroendocrine tumors (NET) diagnostic and therapy.

Neuroendocrine tumors (NET) represent a heterogeneous group of tumors originating from cells of neuroendocrine origin, which express somatostatin receptors (SSTR). This property allowed the successful development of radionuclides for diagnostic and peptide radionuclide radiation therapy (PRRT). This is the paradigm for the theragnostic concept in NET personalized medicine. The only phase III study to date (NETTER-1) clearly demonstrated the ability of 177Lutetium-based PRRT to improve progression-free survival in advanced intestinal NETs. In clinical practice, the indications are limited to G1-G2 well-differentiated NETs with high expression of SSTR. NETs with a low tumor burden and slow progression are probably the optimal indication. This treatment is now available in France. However, its precise position in the treatment algorithm remains to be explored. We provide an overview of receptor radionuclide utilization and mechanism in diagnostic and pretherapeutic imaging and we focus on PRRT for endocrine tumors.

Lung and digestive neuroendocrine neoplasms. From WHO classification to biomarker screening: Which perspectives?

The recent classifications of lung and digestive neuroendocrine neoplasms (NENs) make a fundamental distinction between well- and poorly-differentiated neoplasms. Well-differentiated NENs are termed carcinoids in the lung and neuroendocrine tumors in the gastroenteropancreatic sphere; their risk of malignancy is highly variable; histological grading is used to stratify patients into prognostically significant groups. Poorly-differentiated NENs are termed neuroendocrine carcinoma in both the lung and the digestive sphere; they constantly are of high grade of malignancy; two types are recognized on the basis of tumor cell morphology, the small cell and the large cell types. Recent studies have largely uncovered the genetic landscape of several subsets of well-differentiated NENs (lung, pancreas, small intestine) and of poorly-differentiated NENs. Some molecular markers may help to the differential diagnosis between highly proliferative neuroendocrine tumors and neuroendocrine carcinomas, especially in the pancreas. In well-differentiated tumors, MGMT status is proposed as a predictive marker of the response to temozolomide, but remains to be validated. In poorly-differentiated neoplasms, large cell neuroendocrine carcinoma has been shown to be a heterogeneous category, with some cases presenting the same molecular signature than small cell carcinoma and others the same signature than adenocarcinomas of the same body site. Rb protein has been recently shown to be a potential marker of response to platinum salts in neuroendocrine carcinoma. Much remains to be done to translate the rapid progress in the molecular understanding of NENS into diagnostic, prognostic or predictive markers.

Transplantable zebrafish models of neuroendocrine tumors.

Neuroendocrine tumors (NETs) are rare neoplasms whose incidence is increasing. NETs constitute a heterogeneous group of tumors. Their clinical features, functional properties, and clinical course are different on the basis of their site of origin. Due to the heterogeneity of these tumors, a coordinated multidisciplinary approach is required in these patients. However, medical doctor encounters many difficulties when providing care for patients with NETs. This review provides an overview of the state of the art of zebrafish model in the cancer research with a main focus on NETs.

[Classification of pancreatic neuroendocrine tumours: Changes made in the 2017 WHO classification of tumours of endocrine organs and perspectives for the future]. / Classification des tumeurs neuroendocrines pancréatiques : nouveautés introduites par la classification OMS 2017 des tumeurs des organes endocrines et perspectives.

The WHO classification of the tumors of endocrine organs, published in July 2017, has introduced significant changes in the classification of pancreatic neuroendocrine tumors, the previous version of which has appeared in 2010, within the WHO classification of the tumors of the digestive system. The main change is the introduction of a new category of well-differentiated neoplasms, neuroendocrine tumors G3, in addition to the previous categories of neuroendocrine tumors G1 and G2. The differential diagnosis between neuroendocrine tumors G3 (well-differentiated) and neuroendocrine carcinomas (poorly-differentiated) might be difficult; the authors of the WHO classification therefore suggest the use of a number of immunohistochemical markers to facilitate the distinction between the two entities. The other changes are: (a) the modification of the threshold between neuroendocrine tumors G1 and G2, now set at 3%; (b) the terminology used for mixed tumors: the previous term mixed adeno-neuroendocrine carcinoma (MANEC) is substituted by the term mixed neuroendocrine-non neuroendocrine neoplasm (MiNEN). Finally, the recommendations for Ki-67 index evaluation are actualized. Even if these changes only concern, stricto sensu, the neuroendocrine tumors of pancreatic location, they will probably be applied, de facto, for all digestive neuroendocrine tumors. The revision of the histological classification of pancreatic neuroendocrine tumors coincides with the revision of their UICC TNM staging; significant changes have been made in the criteria for T3 and T4 stages. Our professional practices have to take into account all these modifications.

[Digestive neuroendocrine tumors]. / Tumeurs neuroendocrines digestives.

Digestive neuroendocrine tumors (NETs) are a group of rare tumors with increasing incidence. Pathological analysis is critical to establish the diagnosis and evaluate tumor grade that relies on differentiation and proliferation index. NETs are mostly diagnosed at an advanced stage because of late occurrence of nonspecific symptoms, and can be associated with hormone hypersecretion. Chromogranin A is the main biochemical marker of NETs. Extension workup relies on conventional imaging (CT-scan, MRI) and isotopic imaging including somatostatin-receptor scintigraphy, which should be soon replaced by positron-emitting scintigraphy. The main prognostic factors include tumor stage, metastatic volume, histological differentiation and grade. Hormonal syndromes and poorly differentiated tumors are the two therapeutic emergencies. The treatment of localized well-differentiated tumors relies on endoscopic or surgical resection depending on the location and aggressiveness. Surgical removal is the only potentially curative treatment of metastatic NETs but is rarely feasible and is associated with almost constant relapse. Other antitumor therapies include somatostatin analogs, systemic chemotherapy, liver trans-arterial chemo-embolization, targeted therapies and peptide-receptor radionuclide therapy. Management strategy relies on primary tumor location, tumor aggressiveness, metastatic volume and the presence of extra-hepatic metastases. It must take into account the risk of cumulated toxicity in patients whose survival is often prolonged.

[TENpath network, an expertise pathology network dedicated to sporadic and inherited adult neuroendocrine tumors: first evaluation and first lessons]. / Le réseau TENpath, réseau d'expertise anatomopathologique des tumeurs neuroendocrines malignes de l'adulte, sporadiques et familiales : premier bilan et premières leçons.

TENpath is a network for the expert pathological diagnosis of malignant neuroendocrine tumors of the adult, both familial and sporadic, created by the French National Institute of Cancer in 2010. After 3years of activity, a first evaluation can be made. The perimeter of the network includes all neuroendocrine tumors (except small cell carcinomas of the lung), medullary carcinomas of the thyroid and extra-adrenal paragangliomas. The objectives of the network are not only the pathological review of all newly diagnosed cases of neuroendocrine tumors, but also the epidemiological surveillance, the training of pathologists, the production of recommendations and the initiation of research projects. The organisation of the network includes a database in which all referred cases are declared and a virtual expert system making it possible collegial expertises in line. Twenty-two expert centers are currently participating to TENpath. A total of 1350 cases have been referred in 2011 and 1518 in 2012. Major discrepancies amounted up to 5.9% in 2011 and to 2.9% in 2012. They mainly involved problems of differential diagnosis and wrong evaluations of the differentiation status of the tumor. The lessons to draw from the first years of TENpath are: (a) the long-standing underestimation of the actual number of patients with neuroendocrine tumors in France, (b) a better delineation, based on objective data, of the cases raising actual problems of diagnosis, (c) the existence of cases raising problems of classification even to experts and justifying a particular effort of research. These informations will be important to discuss the future evolution of TENpath.

[Gastroenteropancreatic neuroendocrine tumors: what must the pathologist know and do in 2014?]. / Tumeurs neuroendocrines du tube digestif et du pancréas : ce que le pathologiste doit savoir et doit faire en 2014.

The diagnostic management of a possible case of gastroenteropancreatic neuroendocrine tumor has much changed in the last 10 years. It is now made of four successive steps. The first step is the positive diagnosis, i.e. the definitive identification of the neuroendocrine nature of the tumor: it relies on morphological and immunohistochemical arguments; several national and international recommendations have now clarified the immunohistochemical arguments necessary for, and sufficient to make a diagnosis of gastroenteropancreatic neuroendocrine tumor. The second step is the determination of the grade, essential for the evaluation of the risk of progression: it relies on the determination of the proliferative capacities, according to the proposals of the European NeuroEndocrine Tumor Society (ENETS), later adopted by WHO in 2010. The third step is the histoprognostic classification, which must use a standardized terminology: it is required to use the specific classification proposed in 2010 by WHO in the framework of the revision of the classifications of digestive tumors. The last step is staging, which relies on the use of one of the existing TNM classifications, that, official, proposed by UICC/AJCC or that proposed by ENETS. The minimal informations, which must be present in the pathological report have been stated by the Société Française de Pathologie, at the request of the French National Cancer Institute.

Tumor neuroendocrino de la mama: a propósito de un caso / Neuroendocrine tumor of the breast: a purpose of a case

Los tumores neuroendocrinos en la glándula mamaria, representan menos del 2 por ciento de las lesiones malignas que se presentan en la mama, un 30 por ciento pueden ser metastásicos, principalmente de tumores carcinoides intestinales. Se presenta el caso de una paciente femenina 64 años con el antecedente de carcinoma de mama izquierda pT1N1Mo Estadio II A, se le practicó en el año 2000 cirugía preservadora, recibió tratamiento sistémico y radioterapia, presentando recaída local, histológicamente y por inmuhistoquímica, como tumor neuroendocrino, en mayo de 2008 se le realiza mastectomía simple izquierda. Actualmente viva y sin enfermedad. Los tumores neuroendocrinos pueden presentarse en localizaciones extra intestinales. El diagnóstico debe realizarse por histología y confirmado con técnicas de inmunohistoquímica, son tumores de baja agresividad biológica, no se presentan síntomas sistémicos por liberación de hormonas como en otras localizaciones, y el tratamiento debe basarse en el estadio clínico de la enfermedad al momento del diagnóstico.

Neuroendocrines in the mammary gland tumors represent less than 2 percent of malignant injuries, which 30 percent can be source metastatic, mainly tumors intestinal carcinoid. The clinical of a female patient case 64 years old are presented with the antecedent of pT1N1Mo Stadium II A left breast carcinoma who was practiced in the year 2000 sparing surgery, received systemic therapy and radiotherapy, featuring local relapse, histological and inmuhistochemestry, as neuroendocrines, practicing it in May of 2008 mastectomy left, currently living and without disease tumor. Neuroendocrines tumors can occur in extra intestinal in lung, uterine and less common in the mammary gland neck locations. The diagnosis must be made by histology and confirmed with Immunohistochemistry techniques, are tumors of low biological aggression, not have systemic symptoms by release of hormones as in other locations, and treatment must be based on the clinical stage of the disease at the time of diagnosis.