Frediano Inzani

The 2010 WHO Classification of Digestive Neuroendocrine Neoplasms: a Critical Appraisal four years after Its Introduction

This paper briefly illustrates the basis, rules of application, and present outcome of the current World Health Organization (WHO) classification for neuroendocrine neoplasms. Established in 2010 upon the proposal from the European Neuroendocrine Tumor Society (ENETS), the WHO 2010 fostered some definitional changes (most notably the use of neuroendocrine tumor (NET) instead of carcinoid) and indicated the tools of grading and staging. Specific rules for its application were also defined. The data generated from the use of WHO 2010 classification substantially endorsed its rules and prognostic efficacy. In addition, the application demonstrated some issues, among which are the possible re-definition of the cutoff for grading G1 vs G2, as well as the possible identification of cases with somewhat different clinical behavior within the G3 neuroendocrine cancer class. Overall, since the recent introduction of WHO 2010 grading and staging, it appears wise to keep the current descriptors to avoid unnecessary confusion and to generate comparable data. Homogenous data on large series are ultimately needed to solve such issues.

25 Years of Neuroendocrine Neoplasms of the Gastrointestinal Tract

This paper provides a personal pathologist’s view of how neuroendocrine tumors (NET) were perceived and defined in the last quarter of a century. In years when the Helicobacter pylori, omeprazole and the adenoma–carcinoma sequence in colon carcinogenesis significantly impacted on gastrointestinal (GI) pathology daily practice, neuroendocrine neoplasms of the GI tract passed from the original carcinoid definition to the current NET and neuroendocrine carcinoma (NEC) definitions. The development of different concepts, basic tumor biology knowledge, tools for pathology diagnosis and the various World Health Organization (WHO) classifications from 1980 through 2010 are briefly reviewed and discussed.

Cyto-histology in NET: what is necessary today and what is the future?

The carcinoid as originally described is part of the relatively large family of neuroendocrine neoplasia found in almost every organ. Historical reasons back their current definitions. Neuroendocrine cancer is most frequently observed in the lung and the digestive tract. In the lung is defined as carcinoid (typical and atypical) for well differentiated, low to intermediate grade, and small cell and large cell neuroendocrine carcinoma for poorly differentiated, high grade. In the digestive system are respectively defined as neuroendocrine tumor (NET) and neuroendocrine carcinoma (NEC) of small and large cell types. Grading and staging are developed for their clinical classification by the World Health Organization (WHO) and the American Joint Committee on Cancer (AJCC). In both anatomical sites the morphological features are overlapping, with bland histology for carcinoid and NET, and aggressive features with extensive necrosis, severe atypia and abundant, atypical mitoses for high grade cancer types. Such features are also essential diagnostic clues in cytological preparations. The confirmation of the neuroendocrine signature by immunohistochemistry is mandatory for the diagnosis; a minimum panel comprising chromogranin A and synaptophysin is recommended in the digestive system. In addition, the application of grading requires the mitotic count and or spotty necrosis assessment for lung, or the mitotic count and the Ki67 assessment in the digestive system.

Masking effect of chronic pancreatitis in the interpretation of somatostatin receptor positron emission tomography in pancreatic neuroendocrine tumors.

To the Editor: W e present the rare occurrence of a concurrent pancreatic neuroendocrine tumor (pNET) and pancreatic ductal adenocarcinoma (PDAC) in a patient with multiple endocrine neoplasia 1 (MEN1) syndrome. It is important for clinicians to consider the possibility of PDAC in patients with MEN1 because aggressive early surgical intervention provides the only chance of cure. Multiple endocrine neoplasia 1 is characterized by parathyroid adenomas, pNETs, and anterior pituitary tumors. Multiple endocrine neoplasia 1Yassociated pNETs are usually slowly progressive and associated with low malignant potential. In the context of MEN1, pancreatic NET size correlates with prognosis and the presence of metastases,2 and lesions of more than 2 cm are associated with greater genetic instability and malignant behaviour. The European Neuroendocrine Tumour Society recommendations for management of pancreatic lesions in a patient with MEN1 state that early diagnosis and surgical excision of MEN1-related pNET improve survival, preventing or delaying the development of distant metastases.4 It is mandatory to operate on MEN1-related nonfunctioning pancreatic tumors with metastases, size of more than 2 cm, or yearly increased size of more than 0.5 cm. Management of pNETs of less than 2 cm is controversial, current recommendation being intensive surveillance to avoid repeated intervention where lesions are typically multiple and behave in an indolent fashion.

Human cardiac progenitor cells with regenerative potential can be isolated and characterized from 3D-electro-anatomic guided endomyocardial biopsies

AIMS In the present study, we aimed to develop a percutaneous approach and a reproducible methodology for the isolation and expansion of Cardiac Progenitor Cells (CPCs) from EndoMyocardial Biopsies (EMB) in vivo. Moreover, in an animal model of non-ischemic heart failure (HF), we would like to test whether CPCs obtained by this methodology may engraft the myocardium and differentiate. METHODS AND RESULTS EMB were obtained using a preformed sheath and a disposable bioptome, advanced via right femoral vein in 12 healthy mini pigs, to the right ventricle. EMB were enzymatically dissociated, cells were expanded and sorted for c-kit. We used 3D-Electro-Anatomic Mapping (3D-EAM) to obtain CPCs from 32 patients affected by non-ischemic cardiomyopathy. The in vivo regenerative potential of CPCs was tested in a rodent model of drug-induced non-ischemic cardiomyopathy. c-kit positive CPCs replicative capacity was assessed in 30 patients. Telomere length averaged 7.4±0.4kbp and telomerase activity was present in all preparations (1.7×105 copies). The in situ hybridization experiments showed that injected human CPCs may acquire a neonatal myocyte phenotype given the expression of the alpha-sarcomeric actin together with the presence of the Alu probe, suggesting a beneficial impact on LV performance. CONCLUSIONS The success in obtaining CPCs characterized by high regenerative potential, in vitro and in vivo, from EMB indicates that harvesting without thoracotomy in patients affected by either ischemic or non-ischemic cardiomyopathy is feasible. These initial results may potentially expand the future application of CPCs to all patients affected by HF not undergoing surgical procedures.

Classification of Neuroendocrine Neoplasms

Neuroendocrine neoplasms (NENs) are made by transformed cells producing hormone/mediators and characterized by the shared expression of some neural-specific antigens. NENs may arise in nerve structures, endocrine organs, and in the diffuse neuroendocrine system at various organs and apparata. The rarity, complexity, and diversity of NENs impaired the development of shared definition and classification. Organ-specific classifications have been historically developed and are in use and formalized under the World Health Organization authority. Common classification themes however do exist including common morphology features for most well-differentiated low-grade tumors and for high-grade, poorly differentiated carcinomas, though with diverse prevalence at different anatomical sites. Common features and specific classifications schemes are briefly discussed here.

Clinicopathological analysis of mixed endometrial carcinomas: clinical relevance of different neoplastic components

Mixed endometrial carcinomas (MECs) refer to tumors characterized by 2 or more distinct histotypes mostly that comprised endometrioid (EC) and serous/clear cell carcinomas (SC/CC). The specific quantification of these distinct components represents a challenging and critical point for both prognosis and management. Herein, we analyze a large series of MEC and compare them with EC and SC/CC. We evaluated a series of 69 MECs between January 2002 and December 2015. We compared the MEC series with 186 ECs (including 117 endometrioid G3), 31 SCs, and 38 CCs. The prognostic implication of the percentage of each component was analyzed. Among the 69 MECs, those patients older than 45 years represent the significant population, with 52.2% of them with stage III-IV disease. A similar result was found among pure SC. The comparative analysis of some prognostic parameters (multifocality, vascular invasion, and lymph node metastasis) underlined that MECs with a type II component larger than 5% represent a more aggressive entity. However, relapse, disease-free survival, mortality, and overall survival are statistically significant (P<.05) in EC-SC (SC<5%or >5%) and in EC-CC (CC<5%or >5%), whereas they are not significant (P>.05) in SC-CC (SC/CC<%or >5%). MECs, including also cases with less than 5% of SC/CC, show features as aggressive as those of pure SC/CC. In this perspective, MEC should be followed by personalized and tailored managements. The presence of different components suggests different pathogenic and metastatic processes when compared with pure carcinomas.

A Challenging Case Of Ventricular Arrhythmia In A Patient With Myocarditis: ICD Yes/No After Ablation

In patients with myocarditis, early diagnosis and appropriate therapy are mandatory, as well as close clinical follow-up with particular regard to progression of disease and ventricular arrhythmia recurrences. The management of ventricular arrhythmias should follow current guidelines for ICD implantation, but new therapeutic options could be evaluated in these patients, such as combined epicardial/endocardial ablation and external wearable defibrillator. Particularly, depressed left ventricular ejection fraction (LVEF) represents the only risk marker for sudden cardiac death currently used in myocarditis, although the use of a single risk factor has limited utility. On this regard, combined analysis of myocardial tissue structure by cardiac magnetic resonance (CMR) and endomyocardial biopsy, in association with resting cardiac systolic function, could improve predictive accuracy for SCD in patients with myocarditis.

One-Step Nucleic Acid Amplification (OSNA): A fast molecular test based on CK19 mRNA concentration for assessment of lymph-nodes metastases in early stage endometrial cancer

Introduction The aim of the current study is to evaluate the detection rate of micro- and macro-metastases of the One-Step Nucleic Acid Amplification (OSNA) compared to frozen section examination and subsequent ultra-staging examination in early stage endometrial cancer (EC). Material and methods From March 2016 to June 2016, data of 40 consecutive FIGO stage I EC patients were prospectively collected in an electronic database. The sentinel lymph node mapping was performed in all patients. All mapped nodes were removed and processed. Sentinel lymph nodes were sectioned and alternate sections were respectively examined by OSNA and by frozen section analysis. After frozen section, the residual tissue from each block was processed with step-level sections (each step at 200 micron) including H&E and IHC slides. Results Sentinel lymph nodes mapping was successful in 29 patients (72.5%). In the remaining 11 patients (27.5%), a systematic pelvic lymphadenectomy was performed. OSNA assay sensitivity and specificity were 87.5% and 100% respectively. Positive and negative predictive values were 100% and 99% respectively, with a diagnostic accuracy of 99%. As far as frozen section examination and subsequent ultra-staging analysis was concerned, we reported sensitivity and specificity of 50% and 94.4% respectively; positive and negative predictive values were 14.3% and 99%, respectively, with an accuracy of 93.6%. In one patient, despite negative OSNA and frozen section analysis of the sentinel node, a macro-metastasis in 1 non-sentinel node was found. Conclusions The combination of OSNA procedure with the sentinel lymph node mapping could represent an efficient intra-operative tool for the selection of early-stage EC patients to be submitted to systematic lymphadenectomy.

Classification and Staging of Pancreatic Neuroendocrine Neoplasms

The cancer classification reflects the current status of the knowledge on the type of tumor for which it is built. In the case of neuroendocrine neoplasms, the current classification here detailed is the latest produced by the World Health Organization (WHO) in 2010. The WHO 2010 classification, besides the usual morphological ground on which is based, utilizes the instruments of grading and staging to formally define the malignancy of neuroendocrine neoplasm. Grading is based on proliferation as defined by mitotic count and Ki67 in a three-tier system with G1 (mitotic count 20; Ki67 >20 %). The rules of application require the count of mitoses in areas of highest mitoses presence and for Ki67 in areas of highest nuclear labeling, counting mitoses in at least 50 HPF and then normalizing to 10 HPF, and for Ki67 counting the % of labeled cells in 400–2,000 cells. The grading tool proved to be an effective prognostic instrument separating patients for progressive death risk in three statistically significant different groups. The staging tool is based on current staging parameters including tumor (T), lymph node (N), and metastasis (M). However, two staging systems are currently available: the one endorsed by major agencies including the International Union for Cancer Control (Union Internationale Contre le Cancer, UICC), the American Joint Committee on Cancer (AJCC), and the WHO, which is the very same as the one adopted for the pancreatic adenocarcinoma, and the other proposed by the European Neuroendocrine Tumor Society (ENETS). Both systems are equally effective, though at direct comparison the ENETS system better described the neuroendocrine neoplasm disease.