65 YEARS OF THE DOUBLE HELIX: Endocrine tumour syndromes in children and adolescents.

As medicine is poised to be transformed by incorporating genetic data in its daily practice, it is essential that clinicians familiarise themselves with the information that is now available from more than 50 years of genetic discoveries that continue unabated and increase by the day. Endocrinology has always stood at the forefront of what is called today 'precision medicine': genetic disorders of the pituitary and the adrenal glands were among the first to be molecularly elucidated in the 1980s. The discovery of two endocrine-related genes, GNAS and RET, both identified in the late 1980s, contributed greatly in the understanding of cancer and its progression. The use of RET mutation testing for the management of medullary thyroid cancer was among the first and one of most successful applications of genetics in informing clinical decisions in an individualised manner, in this case by preventing cancer or guiding the choice of tyrosine kinase inhibitors in cancer treatment. New information emerges every day in the genetics or system biology of endocrine disorders. This review goes over most of these discoveries and the known endocrine tumour syndromes. We cover key genetic developments for each disease and provide information that can be used by the clinician in daily practice.

65 YEARS OF THE DOUBLE HELIX: Classification of endocrine tumors in the age of integrated genomics.

The classification of human cancers represents one of the cornerstones of modern pathology. Over the last century, surgical pathologists established the current taxonomy of neoplasia using traditional histopathological parameters, which include tumor architecture, cytological features and cellular proliferation. This morphological classification is efficient and robust with high reproducibility and has served patients and health care providers well. The most recent decade has witnessed an explosion of genome-wide molecular genetic and epigenetic data for most cancers, including tumors of endocrine organs. The availability of this expansive multi-dimensional genomic data, collectively termed the cancer genome, has catalyzed a re-examination of the classification of endocrine tumors. Here, recent cancer genome studies of various endocrine tumors, including those of the thyroid, pituitary and adrenal glands, pancreas, small bowel, lung and skin, are presented with special emphasis on how genomic insights are impacting endocrine tumor classification.

[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.

Single-cell approaches for molecular classification of endocrine tumors.

PURPOSE OF REVIEW: In this review, we summarize recent developments in single-cell technologies that can be employed for the functional and molecular classification of endocrine cells in normal and neoplastic tissue. RECENT FINDINGS: The emergence of new platforms for the isolation, analysis, and dynamic assessment of individual cell identity and reactive behavior enables experimental deconstruction of intratumoral heterogeneity and other contexts where variability in cell signaling and biochemical responsiveness inform biological function and clinical presentation. These tools are particularly appropriate for examining and classifying endocrine neoplasias, as the clinical sequelae of these tumors are often driven by disrupted hormonal responsiveness secondary to compromised cell signaling. Single-cell methods allow for multidimensional experimental designs incorporating both spatial and temporal parameters with the capacity to probe dynamic cell signaling behaviors and kinetic response patterns dependent upon sequential agonist challenge. SUMMARY: Intratumoral heterogeneity in the provenance, composition, and biological activity of different forms of endocrine neoplasia presents a significant challenge for prognostic assessment. Single-cell technologies provide an array of powerful new approaches uniquely well suited for dissecting complex endocrine tumors. Studies examining the relationship between clinical behavior and tumor compositional variations in cellular activity are now possible, providing new opportunities to deconstruct the underlying mechanisms of endocrine neoplasia.

New horizons in diagnosis and management of endocrine tumors.

Endocrine tumors were considered relatively infrequent neoplasms. However, during the last decades, their frequency gradually increased. The use of imaging techniques, guided FNA biopsy, an endoscope camera in the investigation of endocrine lesions, permits early diagnosis. At the histological level, new applications such as non-biotin containing immunohistochemical detection systems, tyramide amplification method, in situ hybridization, FISH, CGH, and other molecular techniques have provided better knowledge on the protein and molecular background. The investigation of somatostatin and dopamine receptors assists targeted therapy of endocrine tumors. Novel treatment modalities have emerged for the management of pituitary and gastroenteropancreatic tumors respectively. Despite this progress, in some instances, the morphological diagnosis remains questionable. Similarities among normal elements, hyperplastic conditions and benign or malignant lesions can make separation difficult. The "gray zones" representing the overlapping in the sequence of normal parenchyma/ hyperplasia/ adenoma/ carcinoma signify a difficult and controversial diagnostic task, which merits special attention. Furthermore, in most endocrine tumors, the diagnosis of carcinoma is justified only in the presence of local or distant metastases. More precise guidelines are needed, by improving the currently available criteria, to minimize the "gray zones", leading to a more accurate separation of such endocrine lesions.

[Outstanding problems of normal and pathological morphology of the diffuse endocrine system].

The diffuse endocrine system (DES)--a mosaic-cellular endoepithelial gland--is the biggest part of the human endocrine system. Scientists used to consider cells of DES as neuroectodermal. According to modem data cells of DES are different cytogenetic types because they develop from the different embryonic blastophyllum. So that any hormone-active tumors originated from DES of the digestive, respiratory and urogenital system shouldn't be considered as neuroendocrinal tumors. The basic problems of DES morphology and pathology are the creation of scientifically substantiated histogenetic classification of DES tumors.

Endocrine tumours of the pancreas.

Verbeke C S (2010) Histopathology 56, 669-682 Endocrine tumours of the pancreas Histopathology reporting of pancreatic endocrine neoplasms is complex. The tumours can exhibit a variety of morphological appearances, which often require careful differential diagnostic consideration. Prediction of tumour behaviour and clinical outcome is based on the World Health Organization classification and TNM staging and grading system, which share some criteria and premises, but differ significantly in others. Clinicopathological correlation through discussion at multidisciplinary team meetings is of paramount importance. In this review special emphasis is given to the items of information that can and should be provided by the pathologist to allow optimal patient management. The review further discusses areas of current controversy and uncertainty, of which pathologists participating in multidisciplinary discussions should be aware.

Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution.

PURPOSE: Unequivocal pathologic markers for the prognosis of pancreatic endocrine tumors are often lacking. Suggestions for prognostic guidance include the WHO classification. Recently, a tumor-node-metastasis (TNM) staging system was proposed. We evaluate this system, as well as assess other potential prognostic factors such as tumor Ki67, size, endocrine syndrome, heredity, body mass index (BMI), and plasma chromogranin A, in a large patient material treated at a single institution. EXPERIMENTAL DESIGN: A total of 324 patients with pancreatic endocrine tumor, consecutively diagnosed and treated at a tertiary referral center, were retrospectively evaluated. Median follow-up was 54 months (range, 1-423 months). Patient and tumor data were extracted from medical records. Univariate and multivariate analyses were done to recognize factors of prognostic value. RESULTS: The median overall survival was 99 months (95% confidence interval, 81-117). Five- and 10-year survival rates were 64% and 44%, respectively. In univariate analysis, TNM stage, radical surgery, WHO classification, nonfunctioning tumor, Ki67 > or = 2%, chromogranin A > or = 3 times the upper normal limit, BMI < 20 kg/m2, sporadic tumor, tumor size, and referral from our primary uptake area had a significant prognostic effect. In multivariate analysis, TNM stage, WHO classification, radical surgery, and Ki67 > or = 2% retained their significance. Having a nonfunctioning tumor was not an independent marker of poor prognosis and neither was heredity. CONCLUSIONS: The recently suggested TNM staging system emerged as a useful clinical tool.

Transcriptome analysis of endocrine tumors: clinical perspectives.

There is considerable interest in the application of DNA microarrays to the pathologic evaluation of endocrine neoplasms. Improvements in tumor classification and prognostication, prediction of response to therapy, and comprehensive assessment of tumoral hormone production represent the major anticipated benefits. Here, some of the microarray studies that support the clinical use of transcriptome profiling for endocrine tumors are reviewed. In addition, some of the barriers to clinical implementation are discussed.

CT and MR imaging findings of endocrine tumor of the pancreas according to WHO classification.

The pancreatic endocrine tumors are rare neuroendocrine tumors of the pancreas originating from totipotential stem cells or differentiated mature endocrine cells within the exocrine gland. Endocrine tumors are usually classified into functioning and non-functioning tumors and presents with a range of benignity or malignancy. In this article, we present the various CT and MR imaging findings of endocrine tumors of pancreas according to recent WHO classification.

[A TNM classification for digestive endocrine tumors of midgut and hindgut: proposals from the European Neuroendocrine Tumor Society (ENETS)]. / Une classification TNM pour les tumeurs endocrines digestives de l'intestin moyen et postérieur: propositions de l'European Neuroendocrine Tumor Society (2007).

The recent proposals for a TNM classification of midgut and hindgut endocrine tumors made by the European Neuroendocrine Tumor Society (ENETS) are presented and commented. Certain particular points, such as the evaluation of the risk of malignancy of an endocrine tumor discovered fortuitously after appendicectomy and the indication of an additional surgical treatment, are developed. Finally, other questions frequently asked about digestive endocrine tumors are addressed.

Criteria for malignancy in gastrointestinal endocrine tumors.

In contrast with the large amount of data generated from endocrine tumors of the pancreas, sparse and mostly unconfirmed data are available on the criteria for the assessment of malignancy risk and patient outcome in endocrine tumors of the gastrointestinal tract. In these conditions the 2000 WHO classification with its standardized scheme of pathologic report constitutes a framework facilitating the assessment of tumor malignancy and has been regarded as useful for clinical purposes, providing the basis for proper management of the patients and for the design of treatment protocols. The classification is based on a combination of pathological and clinical features with parameters specific for each organ in which the endocrine tumors originate. Three main categories, one further subdivided into two subgroups, are considered: (1) well-differentiated endocrine tumors, further subdivided into tumors with benign and with uncertain behavior; (2) well-differentiated endocrine carcinomas, low grade; and (3) poorly differentiated endocrine carcinomas, high grade. In this review the differential tumor characteristics between the different categories are summarized. Moreover, the relevance of additional features with respect to tumor prognostication, chiefly the Ki-67 proliferation index and malignancy-associated genetic changes, is discussed with emphasis on the discrepancies emerging between tumors of foregut and of midgut origin.

The grey zone between pure (neuro)endocrine and non-(neuro)endocrine tumours: a comment on concepts and classification of mixed exocrine-endocrine neoplasms.

Terms such as "mixed endocrine-exocrine carcinoma" (MEEC) and "adenocarcinoma with neuroendocrine (NE) differentiation" (ADC-NE) identify tumours belonging to the spectrum of neoplasms with divergent exocrine and (neuro)endocrine differentiation. These tumours display variable quantitative extent of the two components, potentially ranging from 1 to 99%, and variable structural patterns, ranging from single scattered NE cells to a well-defined NE tumour cell population organized in organoid, trabecular or solid growth patterns. In the present report, the grey zone of tumours/carcinomas with mixed NE and non-NE features is explored for various organs. From a practical point of view, MEECs differ from carcinomas with focal NE differentiation by (1) the extension of each component (more than 30%) and (2) the structural pattern of the NE component, either organoid for well-differentiated or solid/diffuse for poorly differentiated cases. In MEECs, the most aggressive cell population drives the clinical behaviour. Conversely, ADC-NE generally do not show a different clinical outcome, compared to the corresponding conventional forms, except for prostatic adenocarcinoma, in which NE cells are a negative prognostic factor. The recognition of MEECs may be of relevance for a targeted therapeutic strategy, foreseeing the use of biotherapies similar to those proposed for pure NE tumours.

[Mixed endocrine tumors]. / Les tumeurs mixtes endocrines.

Mixed endocrine tumors are tumors composed of at least two distinct tumor populations, one of which is endocrine. Because of their rarity and unusual presentation, endocrine mixed tumors raise many problems of diagnosis, management and therapy. Three main types of endocrine mixed tumors are recognized: The existence of these various types has been confirmed by recent molecular studies, even if the same studies have also shown that the histogenesis of a mixed endocrine tumor cannot be predicted from its histological features. Composite tumors are the less rare mixed tumors. The recent WHO classification recommends to restrict the term of composite endocrine tumor to the epithelial tumors containing at least 30% of obviously tumoral endocrine cells; some authors recommend to use higher thresholds, of at least 50%, in order to avoid overdiagnosis. The endocrine component is usually well differentiated, easily identified by its suggestive histological features; the endocrine nature of tumor cells is confirmed by the immunodetection of specific endocrine and neuro-endocrine markers (such as chromogranin A and synaptophysin). In some cases, the endocrine component is poorly differentiated: the demonstration of neuro-endocrine markers is necessary to confirm the diagnosis. Mixed tumors can occur in every anatomical site; they are more frequent in organs containing endocrine cells in the normal state (especially the digestive tract and the pancreas), but they can also be observed in organs devoid of endocrine cells (such as the mammary gland). The management of mixed endocrine tumors must take into account the more aggressive component. Mixed tumors containing a well differentiated endocrine component and an adenocarcinomatous component are to be treated like adenocarcinomas. Mixed tumors containing a poorly differentiated endocrine component must be considered as poorly differentiated endocrine carcinomas.

The phenotype of gut endocrine tumours.

Endocrine tumours of gut and pancreas tract are rare entities originating from cells of the diffuse endocrine system. The endocrine phenotype is assessed by the expression of general and specific endocrine markers. General endocrine markers associate to organelles like large dense core vesicles (e.g. chromogranin A) and small synaptic-like vesicles (e.g. synaptophysin), or to the cytosol, like neuron specific enolase and protein gene product 9.5 (PGP9.5). The specific markers correspond to the hormones produced by tumour cells. Two major categories of endocrine tumours are identified as (i) well-differentiated and (ii) poorly differentiated neoplasms. Well-differentiated tumours/carcinomas (also known as carcinoids) express all general markers of endocrine differentiation and various hormones. Poorly differentiated endocrine carcinomas lack large dense core vesicles markers (chromogranin A), while widely express synaptophysin and cytosol endocrine markers. The clinical behaviour of endocrine tumours spans from benign to low-grade malignant for well-differentiated tumours/carcinomas to high grade malignant for poorly differentiated carcinomas. The Multiple Endocrine Neoplasia type 1 syndrome (MEN1) gene is involved in the genesis of a proportion of both well- and poorly differentiated sporadic tumours. p53 gene abnormality appears as restricted to poorly differentiated endocrine carcinomas.