Classification Of Neuroendocrine Tumors Research Articles

Interpretation on the update of 2022 WHO classification of neuroendocrine tumors

The 5th edition of the WHO Endocrine and Neuroendocrine Oncology Blue Book, released in 2022, contained some changes in the classification of neuroendocrine tumors. A brief summary of the main changes has been provided in this section. Mainly summarized as changes in naming, differentiation and classification of neuroendocrine tumors, and tumor grading systems related to anatomical locations, morphological characteristics of neuroendocrine tumors in different locations, auxiliary diagnostic and prognostic/therapeutic markers, differential diagnosis and diagnostic difficulties of neuroendocrine tumors.

Changes in categorization or nomenclature within neuroendocrine tumors.

The 5th edition of the World Health Organization (WHO) classification of neuroendocrine neoplasms (NENs) is built to achieve a uniform terminology and to define a similar diagnostic scheme across different anatomic locations. Since the 4th edition, a chapter discussing NENs in nonneuroendocrine organs has been introduced, which proposes a binary system for classification segregating well-differentiated neoplasms, termed neuroendocrine tumors (NETs), and poorly differentiated neoplasms, termed neuroendocrine carcinomas (NECs). A grading system for NETs is based on mitotic index and/or Ki-67 index and/or necrosis, depending on the different locations. Although this approach has been already well established in the digestive system, it modifies and homogenizes the classification of NENs in the urinary tract, in female genital organs, and in the male genital system. In the lung and thymus, the double terminology of carcinoid/NET, already introduced in the 5th edition of the WHO classification of thoracic tumors, is endorsed. This approach undoubtedly helps the multidisciplinary approach for the diagnosis and clinical management of patients affected by these neoplasms, without losing site-specific characteristics that influence the clinical and biological behavior of tumors in different anatomical sites. Other major advances of the new WHO scheme are the homogenization of epidemiological data and the correct integration of data from prospective future studies aimed at the definition of molecular profiles and at the identification of tumor type-specific and patient-specific therapeutic approaches.

An Illustrated Review of the Recent 2019 World Health Organization Classification of Neuroendocrine Neoplasms: A Radiologic and Pathologic Correlation.

Recent advances in molecular pathology and an improved understanding of the etiology of neuroendocrine neoplasms (NENs) have given rise to an updated World Health Organization classification. Since gastroenteropancreatic NENs (GEP-NENs) are the most common forms of NENs and their incidence has been increasing constantly, they will be the focus of our attention. Here, we review the findings at the foundation of the new classification system, discuss how it impacts imaging research and radiological practice, and illustrate typical and atypical imaging and pathological findings. Gastroenteropancreatic NENs have a highly variable clinical course, which existing classification schemes based on proliferation rate were unable to fully capture. While well- and poorly differentiated NENs both express neuroendocrine markers, they are fundamentally different diseases, which may show similar proliferation rates. Genetic alterations specific to well-differentiated neuroendocrine tumors graded 1 to 3 and poorly differentiated neuroendocrine cancers of small cell and large-cell subtype have been identified. The new tumor classification places new demands and creates opportunities for radiologists to continue providing the clinically most relevant report and on researchers to design projects, which continue to be clinically applicable.

Clinical value of multi-gene testing in distinguishing benign and malignant thyroid nodules.

The newly released 2022 WHO Classification of Neuroendocrine Neoplasms (version 5) and a recent update on thyroid tumor classifications have emphasized genetic testing to an unprecedented level. Fine needle aspiration (FNA) has been widely applied for the preoperative diagnosis of thyroid nodules. However, it is limited mainly to testing for a single gene-BRAFV600E, whereas multi-gene testing data are scarce, especially in the Asian population. This study aimed to explore the clinical value of multi-gene testing in the differential diagnosis of benign and malignant thyroid nodules based on the 2023 Bethesda System for Reporting Thyroid Cytopathology (BSRTC). A total of 615 thyroid nodules underwent ultrasound-guided fine-needle aspiration cytology (FNAC) were collected from Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. The next-generation sequencing platform was applied for multi-gene testing. A panel of well-recognized commonly mutated genes in thyroid cancer were analyzed, including BRAFV600E, KRAS, NRAS, HRAS, TERT, TP53, PAX8/PPARG, CCDC6/ RET and NCOA4/ RET. Gene mutations were identified in 324 nodules (52.7%), with BRAFV600E being the most prevalent driver gene alteration observed in this cohort (233/324; 79.1%), followed by RAS (77/324, 23.8%). The overall malignancy rate of gene mutations was 89.7% in our cohort, of which the lymph node metastasis rate was 45.3%. The combination of multi-gene testing and cytology resulted in 89.3% sensitivity, 95.2% specificity, 98.9% positive predictive value, 64.5% negative predictive value and 90.3% accuracy, which were significantly higher than those from mere cytology (sensitivity 68.6%, specificity 87.5%, positive predictive value 95.9%, negative predictive value 39.8%, accuracy 72.2%). Multi-gene testing could substantially enhance the detection rate of malignant thyroid nodules and protect patients with benign nodules from unnecessary surgeries. Multi-gene testing provides a valuable reference for individualized preoperative decision-making, which may serve as a crucial method for postoperative treatment and prognosis assessment.

Updates on lung neuroendocrine neoplasm classification.

Lung neuroendocrine neoplasms (NENs) are a heterogeneous group of pulmonary neoplasms showing different morphological patterns and clinical and biological characteristics. The World Health Organisation (WHO) classification of lung NENs has been recently updated as part of the broader attempt to uniform the classification of NENs. This much-needed update has come at a time when insights from seminal molecular characterisation studies revolutionised our understanding of the biological and pathological architecture of lung NENs, paving the way for the development of novel diagnostic techniques, prognostic factors and therapeutic approaches. In this challenging and rapidly evolving landscape, the relevance of the 2021 WHO classification has been recently questioned, particularly in terms of its morphology-orientated approach and its prognostic implications. Here, we provide a state-of-the-art review on the contemporary understanding of pulmonary NEN morphology and the potential contribution of artificial intelligence, the advances in NEN molecular profiling with their impact on the classification system and, finally, the key current and upcoming prognostic factors.

Site-specific trends in gastroenteropancreatic neuroendocrine neoplasms in Bavaria, Germany.

Neuroendocrine neoplasms (NEN) are rare and heterogeneous epithelial tumors, occurring throughout the body. For gastroenteropancreatic (GEP)-NEN, rising incidence rates were reported for the last decades, with underlying causes remaining largely unexplained. We evaluated NEN trends stratifying by their histologic subtypes. Incident cases of GEP-NEN diagnosed between 2005 and 2019 were retrieved from the prospective, population-based Bavarian Cancer Registry. GEP-NEN were divided in their histologic subtypes, that is, neuroendocrine tumors (NET) G1, NET G2/G3, other NET versus small-cell neuroendocrine carcinoma (NEC), large-cell NEC, and other NEC. We calculated annual age-standardized incidence rates (ASIRs) per 100,000 persons for the total of GEP-NEN, NEN histologic subtypes, and tumor sites. We used an annual percentage change (APC) approach including a joinpoint analysis to investigate NEN incidence trends. ASIR of GEP-NEN rose from 2.2 in 2005 to 4.8 in 2019, characterized by a significant increase until 2012 (APC 2005-2012: 10.1%), followed by modest rise (APC 2012-2019: 1.5%). In the last decade, this increase was mainly driven by the rise of NET G1 and G2/G3, while incidence for NEC declined. Over the study period, ASIR increased significantly for all GEP-sites except the colon. APCs were largest for the stomach, the appendix, the pancreas, and the rectum. This study found a significant increase in the incidence of GEP-NET. Though this development may partially be attributable to the increased use of advanced detection techniques and changes in NEN classification, further research should also focus on the identification of NEN risk factors.

Gastric Neuroendocrine Tumors According to the 2019 World Health Organization Grading System: A Single-Center, Retrospective Study.

Although gastric neuroendocrine tumors (NETs) are uncommon neoplasms, their prevalence is increasing. The clinical importance of the World Health Organization (WHO) classification of gastric NETs, compared with NETs in other organs, has been underestimated. This study aimed to systematically evaluate the clinical and pathologic characteristics of gastric NETs based on the 2019 WHO classification and to assess the survival outcomes of patients from a single-center with a long-term follow-up. The medical records of 427 patients with gastric NETs who underwent endoscopic or surgical resection between January 2000 and March 2020 were retrospectively reviewed. All specimens were reclassified according to the 2019 WHO classification. The clinicopathologic characteristics, treatment, and oncologic outcomes of 139 gastric NETs were analyzed. The patients' median age was 53.0 years (interquartile range [IQR], 46.0 to 63.0 years). The median follow-up period was 36.0 months (IQR, 15.0 to 63.0 months). Of the patients, 92, 44, and 3 had grades 1, 2, and 3 NETs, respectively. The mean tumor size significantly increased as the tumor grade increased (p=0.025). Patients with grades 2 and 3 gastric NETs more frequently had lymphovascular invasion (29.8% vs 10.9%, p=0.005) and deeper tissue invasion (8.5% vs 0%, p=0.012) than those with grade 1 tumors. The overall disease-specific survival rate was 100%. Two patients with grades 2-3 gastric NETs experienced extragastric recurrence. Although gastric NETs have an excellent prognosis, grade 2 or grade 3 gastric NETs are associated with a larger size, deeper invasion, and extragastric recurrence, which require active treatment.

Cauda Equina Neuroendocrine Tumors: Distinct Epithelial Neuroendocrine Neoplasms of Spinal Origin.

The tumor formerly known as "cauda equina paraganglioma" was recently renamed as cauda equina neuroendocrine tumor (CENET) based on distinct biological and genetic properties. Nevertheless, it remains insufficiently understood. For this study, we retrieved CENETs (some previously reported), from the pathology files of 3 institutions; we examined their immunohistochemical profile, including common neuroendocrine tumor-associated hormones and transcription factors. We identified 24 CENETs from 7 female and 17 male adult patients, with a median age of 47 years. Six included neurofilament-positive ganglion cells. All tumors tested were positive for INSM1, synaptophysin, chromogranin A, SSTR2, and CD56 as well as at least 1 keratin (AE1/AE3, CAM5.2); CK7 and CK20 were negative. Glial fibrillary acidic protein was negative, except for peripheral nontumoral elements. S100 protein was variable but mainly expressed in scattered sustentacular cells. All but 1 tumor tested were positive for HOXB13; several stained for SATB2, and all tumors were consistently negative for GATA3. All tumors tested were negative for transcription factors found in various other epithelial neuroendocrine neoplasms including TTF1, CDX2, PIT1, TPIT, SF1, and PAX8; staining for T-brachyury was negative. Four of 5 CENETs tested had at least focal tyrosine hydroxylase reactivity. Serotonin expression was detected in all 21 tumors tested; it was diffusely positive in 5 and had variable positivity in the remainder. A few tumors had scattered cells expressing gastrin, calcitonin, pancreatic polypeptide, and peptide YY, while glucagon, adrenocorticotropic hormone, and monoclonal carcinoembryonic antigen were negative. PSAP expression was found focally in 4 of 5 tumors examined. SDHB was consistently intact; ATRX was intact in 14 tumors and showed only focal loss in 3. The median Ki-67 labeling index was 4.5% (range: 1% to 15%). We conclude that CENET represents a distinct neuroendocrine neoplasm; the subset with ganglion cells qualifies for designation as composite gangliocytoma/neuroma-neuroendocrine tumor (CoGNET) as defined in the 2022 WHO classification of neuroendocrine neoplasms. In addition to INSM1, chromogranin, synaptophysin, and keratins, the most characteristic finding is nuclear HOXB13 expression; a subset also express SATB2. Serotonin is the most common hormone expressed. The cytogenesis and pathogenesis of these lesions remains unclear.

Mixed neuroendocrine and non-neuroendocrine neoplasia (MiNEN) of the stomach

From the latest WHO classification of neuroendocrine neoplasms (NENs), the term MiNENs refers to mixed neuroendocrinenon-neuroendocrine tumors. A neuroendocrine component coexists with a non-neuroendocrine one in them. They are morphologically and/or immunohistochemically validated. The non-neuroendocrine component implicates adenocarcinoma, apart from other histological subtypes of carcinomas, such as squamous cell carcinoma. The neuroendocrine component can be represented by a high-grade tumour (HGNEC) in addition to neuroendocrine cancer. Gastric NENs also have subgroups of MiNENs such as mixed adenoneuroendocrine carcinoma (Mixed-adenocarcinoma-NEC), which includes both, small or large cell type, neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine tumor (Mixed-adenocarcinoma-NET). Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) is a rare disease. Based on the available data, neuroendocrine component has a highly aggressive biological behaviour represented by a low-differentiated neuroendocrine tumor in the majority of MiNENs cases. The treatment is based on the principles of neuroendocrine tumour therapy. The foregoing shows that it is not possible to provide precise epidemiological data, prognosis and approve treatment strategies.

EP14.01-012 A Case Report of Lung Large Cell Neuroendocrine Carcinoma with Carcinoid Morphology

This entity was recognised in the 2017 World Health Organisation classification of neuroendocrine neoplasms of the pancreas, and it is new entity in 2021 WHO classification of the neuroendocrine neoplasms of the lung.

Cytologic diagnosis of neuroendocrine neoplasms including carcinoid tumours- A retrospective study

The classification of neuroendocrine neoplasms has evolved substantially over time but remains a topic of controversy and debate. Cytology has become one of the mainstays of diagnosis for these tumors, and the treatment may be entirely based on the FNA report.: This is a retrospective study which aims to describe the cytological features found in different groups of Neuroendocrine neoplasms. We have also tried to enumerate the not so typical features which we have seen in our cases. Cases of Neuroendocrine neoplasms diagnosed by cytology in the year 2018 were included in this study. The slides of these cases were retrieved, cytological features reviewed, and clinicopathological features evaluated. Histopathological correlation was done wherever possible. In this retrospective study, there were 43 cases which included FNA (n=38), Fluid cytology(n=3), Bronchial washings and Brushings(n=2). FNA sites included lung, cervical lymph nodes, scalp, liver, pancreas, and mesentery with the cytological diagnoses of Small cell carcinoma (n=22) Neuroendocrine tumor (n=7), Large cell Neuroendocrine carcinoma (n=3) and Poorly differentiated carcinoma with neuroendocrine features (n=11). Features that are of help include scanty cytoplasm, fine or coarse granular chromatin, nuclear moulding and streaking, cells adhering to vessels, inconspicuous nucleoli, nuclear debris in small cell carcinomas; larger cell size, a moderate amount of cytoplasm, coarse granular chromatin in large cell neuroendocrine carcinomas; uniformity of cell size, round to plasmacytoid cells with stippled chromatin and rosette formation in carcinoid tumors. The identification of neuroendocrine morphology in cytology specimens is crucial as this would be the initial step towards using the appropriate markers for confirmation, which in turn has got therapeutic and prognostic significance.

Neuroendocrine Tumors: a Relevant Clinical Update.

The field of neuroendocrine oncology has changed much since the time of Oberndorfer first described and coined the term carcinoid. The purpose of this review is to summarize recent findings and highlight clinically relevant updates in the management of NENs, particularly those that are practice changing. Neuroendocrine tumors (NETs) have replaced carcinoid tumor, for the most part. The classification of neuroendocrine neoplasms (NENs) improved, and the epidemiological understanding of this disease group also expanded with global collaborations and maturation of large tumor registries. Clarity in the utility of some NET biomarkers continues to be evolving. Knowledge of molecular drivers of tumorigenesis increases, and scientific/technological advancements lead the way to multiple drug approvals for the treatment of advanced NETs. The incidence and prevalence of NENs continue to increase, and patients are living longer. Better understanding of molecular drivers and further understanding of the role of immunotherapy in NENs will further elevate the level of care and transform care for all patients with NENs.

Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms.

In this review, we detail the changes and the relevant features that are applied to neuroendocrine neoplasms (NENs) in the 2022 WHO Classification of Endocrine and Neuroendocrine Tumors. Using a question-and-answer approach, we discuss the consolidation of the nomenclature that distinguishes neuronal paragangliomas from epithelial neoplasms, which are divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The criteria for these distinctions based on differentiation are outlined. NETs are generally (but not always) graded as G1, G2, and G3 based on proliferation, whereas NECs are by definition high grade; the importance of Ki67 as a tool for classification and grading is emphasized. The clinical relevance of proper classification is explained, and the importance of hormonal function is examined, including eutopic and ectopic hormone production. The tools available to pathologists for accurate classification include the conventional biomarkers of neuroendocrine lineage and differentiation, INSM1, synaptophysin, chromogranins, and somatostatin receptors (SSTRs), but also include transcription factors that can identify the site of origin of a metastatic lesion of unknown primary site, as well as hormones, enzymes, and keratins that play a role in functional and structural correlation. The recognition of highly proliferative, well-differentiated NETs has resulted in the need for biomarkers that can distinguish these G3 NETs from NECs, including stains to determine expression of SSTRs and those that can indicate the unique molecular pathogenetic alterations that underlie the distinction, for example, global loss of RB and aberrant p53 in pancreatic NECs compared with loss of ATRX, DAXX, and menin in pancreatic NETs. Other differential diagnoses are discussed with recommendations for biomarkers that can assist in correct classification, including the distinctions between epithelial and non-epithelial NENs that have allowed reclassification of epithelial NETs in the spine, in the duodenum, and in the middle ear; the first two may be composite tumors with neuronal and glial elements, and as this feature is integral to the duodenal lesion, it is now classified as composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET). The many other aspects of differential diagnosis are detailed with recommendations for biomarkers that can distinguish NENs from non-neuroendocrine lesions that can mimic their morphology. The concepts of mixed neuroendocrine and non-neuroendocrine (MiNEN) and amphicrine tumors are clarified with information about how to approach such lesions in routine practice. Theranostic biomarkers that assist patient management are reviewed. Given the significant proportion of NENs that are associated with germline mutations that predispose to this disease, we explain the role of the pathologist in identifying precursor lesions and applying molecular immunohistochemistry to guide genetic testing.

Differential Diagnosis of High-grade Neuroendocrine Neoplasms in the Digestive System

The current World Health Organization classification of neuroendocrine neoplasms of the digestive system separates these tumors into two major categories: well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. These two groups are considered fundamentally different tumors, with different molecular abnormalities, prognoses, and treatment strategies. The cornerstone of the classification is proliferative rate of the tumor cells, as assessed by mitotic rate and Ki-67 labeling index. However, the range of mitotic rate and Ki-67 labeling index overlaps between high-grade, well-differentiated neuroendocrine tumor and poorly differentiated neuroendocrine carcinoma. In order to accurately separate these two entities, a systematic approach is necessary, which includes attention to the morphology, accurate assessment of the proliferative rate, review of any additional pathology materials, judicial use of immunohistochemistry, and correlation with clinical features. With this approach, the majority of tumors can be correctly classified as either high-grade, well-differentiated neuroendocrine tumor or poorly differentiated neuroendocrine carcinoma.

ENETS standardized (synoptic) reporting for neuroendocrine tumour pathology.

In recent years the WHO classification of neuroendocrine neoplasms (NEN) has evolved. Nomenclature as well as thresholds for grading have changed leading to potential confusion and lack of comparability of tumour reports. Therefore, the European Neuroendocrine Tumour Society (ENETS) has set‐up an interdisciplinary working group to develop templates for a pathology data set for standardised reporting of NEN. Experts of various disciplines, members of the ENETS Advisory Board, formed a taskforce that discussed and decided on the structure, content and the number of templates needed for reporting the most common NEN. The selection of the required items was based on the WHO classification of digestive system tumours, the WHO classification of tumours of the lung and mediastinum and on “ENETS standard of care” reports. The final proposal of the working group was approved by the ENETS Advisory Board. Templates for synoptic reporting were created for the seven most common NEN primary sites, that is, stomach, duodenum, jejunum‐ileum, appendix, colon‐rectum, pancreas, lung and mediastinum. In addition, a general template for reporting biopsies was designed. The templates allow the recording of the essential items on differentiation, proliferation (Ki‐67 and mitosis), neuroendocrine features (positivity for chromogranin A and synaptophysin) and stage as well as several optional markers especially helpful for the distinction of neuroendocrine tumours (NET) from neuroendocrine carcinomas (NEC). In summary, this paper presents the content and development of synoptic reports for most sites of NEN by a multidisciplinary team of international experts in the field, which could help to improve unambiguous reporting of NEN.

Biomarker Landscape in Neuroendocrine Tumors With High-Grade Features: Current Knowledge and Future Perspective.

Neuroendocrine tumors (NETs) are classified based on morphology and are graded based on their proliferation rate as either well-differentiated low-grade (G1) to intermediate (G2–G3) or poorly differentiated high-grade neuroendocrine carcinomas (NEC G3). Recently, in gastroenteropancreatic (GEP) NETs, a new subgroup of well-differentiated high-grade tumors (NET G3) has been divided from NEC by WHO due to its different clinical–pathologic features. Although several mutational analyses have been performed, a molecular classification of NET is an unmet need in particular for G3, which tends to be more aggressive and have less benefit to the available therapies. Specifically, new possible prognostic and, above all, predictive factors are highly awaited, giving the basis for new treatments. Alteration of KRAS, TP53, and RB1 is mainly reported, but also druggable alterations, including BRAF and high microsatellite instability (MSI-H), have been documented in subsets of patients. In addition, PD-L1 demonstrated to be highly expressed in G3 NETs, probably becoming a new biomarker for G3 neuroendocrine neoplasm (NEN) discrimination and a predictive one for immunotherapy response. In this review, we describe the current knowledge available on a high-grade NET molecular landscape with a specific focus on those harboring potentially therapeutic targets in the advanced setting.

The classification of neuroendocrine neoplasms of the lung and digestive system according to WHO, 5th edition: similarities, differences, challenges, and unmet needs.

Neuroendocrine neoplasms (NENs) are a group of disease entities sharing common morphological, ultrastructural and immunophenotypical features, yet with distinct biological behavior and clinical outcome, ranging from benign to frankly malignant. Accordingly, a spectrum of therapeutic options for each single entity is available, including somatostatin analogues (SSA), mTOR-inhibitors, peptide receptor radionuclide therapy (PRRT), non-platinum and platinum chemotherapy. In the last few decades, several attempts have been made to better stratify these lesions refining the pathological classifications, so as to obtain an optimal correspondence between the scientific terminology and, the predictive and prognostic features of each disease subtype, and achieve a global Classification encompassing NENs arising at different anatomical sites. The aim of this review was to analyze, compare and discuss the main features and issues of the latest WHO Classifications of NENs of the lung and the digestive system, in order to point out the strengths and limitations of our current understanding of these complex diseases.

Modern view on the classification of neuroendocrine neoplasms of stomach

Neuroendocrine neoplasms (NEN) of the stomach include a heterogeneous group of neoplasms characterized by different pathogenetic mechanisms, metastatic potential, and prognosis. The incidence of gastric NAN has increased 15-fold over the past few decades. It is necessary to clearly distinguish between well-differentiated neuroendocrine neoplasms (NETs) of the stomach and neuroendocrine cancer (NECs) of the stomach, as well as mixed neuroendocrine-non-neuroendocrine neoplasms. To date, there are three classifications that are used in clinical practice: clinicopathological classification, WHO classification, and UICC TNM classification. It should be noted that over the past five years, these classifications have undergone important changes. In the clinicopathological classification, in addition to the existing three types, a number of authors proposed to add the 4th type (developing as a result of inadequate functioning of the proton pump) and the 5th type (developing in patients who receive long-term therapy with proton pump inhibitors). In the 2019 WHO classification, an important change is the acceptance that well-differentiated NETs can have a high degree of malignancy – Grade III. The main changes in the 8th edition of the TNM classification concerned the differentiation of the M symbol. Thus, to date, the classification of gastric NENs allows us to accurately characterize tumor staging, the pathogenesis underlying their development, and prognosis. They form the basis for choosing an adequate treatment strategy that makes possible to achieve the most favourable result.

The classification of neuroendocrine neoplasms of the breast and its clinical relevance.

Neuroendocrine neoplasms of the breast (Br-NENs) are rare tumors of the mammary gland. Their definition and classification have been a matter of discussion for more than half a century, as they present some degree of overlap with other malignancies in the mammary gland. The recent evolutions in the understanding of the pathogenesis of neuroendocrine neoplasms (NENs) as well as the novel tools in the diagnostic arsenal of the pathologists, and a better correlation with clinical data, have led to improved classification schemes for these entities, beginning from those arising in digestive and thoracic organs. These new classification concepts have been recently expanded to NENs arising in every anatomical site, with the proposal of a common classification framework that has been applied in the 5th edition of the WHO classification of tumors. These concepts include the recognition of two distinct families of NENs (neuroendocrine tumors, NETs, and neuroendocrine carcinomas, NECs), the identification of mixed neuroendocrine/non-neuroendocrine neoplasms, and the application of definite morphological and immunohistochemical criteria for the diagnosis of NENs. The last WHO classification of Br-NENs, however, still seems to leave several unanswered questions and unmet needs in the understanding of diagnostic and clinical features of these entities. This review will critically revise the current classification of Br-NENs, underlining its lights and shadows and focusing on the identification of diagnostic histopathological criteria that can help the univocal recognition of Br-NET, Br-NEC, and Br-MiNEN.

Making Sense of a Complex Disease: A Practical Approach to Managing Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) are a heterogeneous clinical entity with a broad range of grade, pace of disease, functional status, and primary sites. Pathologic classification, diagnostic modalities, and therapeutic options for NETs have evolved considerably in the past decade. In part driven by these advances, incidence and prevalence of NETs are rising in the United States and the practicing oncologist is likely to encounter these in the clinic. However, there are no clear lines of therapy for unresectable or metastatic NETs, and sequencing of systemic therapies depends on consideration of patient and tumor characteristics including extent of disease, grade, pace of growth, functional status, primary site, somatostatin receptor status, performance status, and comorbidities. Familiarity with ongoing clinical trials will guide therapeutic decision making as well. In this review, we seek to provide a framework to formulate and tailor an individualized treatment plan for each patient with a NET.