Are Markers of Systemic Inflammatory Response Useful in the Management of Patients With Neuroendocrine Neoplasms?

Given the increasing incidence of neuroendocrine neoplasms (NENs) over the past few decades, a more comprehensive knowledge of their pathophysiological bases and the identification of innovative NEN biomarkers represents an urgent unmet need. There is still little advance in the early diagnosis and management of these tumors, due to the lack of sensible and specific markers with prognostic value and ability to early detect the response to treatment. Chronic systemic inflammation is a predisposing factor for multiple cancer hallmarks, as cancer proliferation, progression and immune-evading. Therefore, the relevance of inflammatory biomarkers has been identified as critical in several types of tumours, including NENs. A bidirectional relationship between chronic inflammation and development of NENs has been reported. Neuroendocrine cells can be over-stimulated by chronic inflammation, leading to hyperplasia and neoplastic transformation. As the modulation of inflammatory response represents a therapeutic target, inflammatory markers could represent a promising new key tool to be applied in the diagnosis, the prediction of response to treatment and also as prognostic biomarkers in NENs field. The present review provides an overview of the pre-clinical and clinical data relating the potentially usefulness of circulating inflammatory markers: neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), cytokines and tissue inflammatory markers (PD-1/PD-L1), in the management of NENs. (1) NLR and PLR have both demonstrated to be promising and simple to acquire biomarkers in patients with advanced cancer, including NEN. To date, in the context of NENs, the prognostic role of NLR and PLR has been confirmed in 15 and 4 studies, respectively. However, the threshold value, both for NLR and PLR, still remains not defined. (2) Cytokines seem to play a central role in NENs tumorigenesis. In particular, IL-8 levels seems to be a good predictive marker of response to anti-angiogenic treatments. (3) PD-1 and PD-L1 expression on tumour cells and on TILs, have demonstrated to be promising predictive and prognostic biomarkers in NENs. Unfortunately, these two markers have not been validated so far and further studies are needed to establish their indications and utility.

Pathology Reporting in Neuroendocrine Neoplasms of the Digestive System: Everything You Always Wanted to Know but Were Too Afraid to Ask.

During the 5th NIKE (Neuroendocrine tumors Innovation in Knowledge and Education) meeting, held in Naples, Italy, in May 2019, discussions centered on the understanding of pathology reports of gastroenetropancreactic neuroendocrine neoplasms. In particular, the main problem concerned the difficulty that clinicians experience in extrapolating relevant information from neuroendocrine tumor pathology reports. During the meeting, participants were asked to identify and rate issues which they have encountered, for which the input of an expert pathologist would have been appreciated. This article is a collection of the most rated questions and relative answers, focusing on three main topics: 1) morphology and classification; 2) Ki67 and grading; 3) immunohistochemistry. Patient management should be based on multidisciplinary decisions, taking into account clinical and pathology-related features with clear comprehension between all health care professionals. Indeed, pathologists require clinical details and laboratory findings when relevant, while clinicians require concise and standardized reports. In keeping with this last statement, the minimum requirements in pathology datasets are provided in this paper and should be a baseline for all neuroendocrine tumor professionals.

ENDOCRINE TUMOURS: Calcitonin in thyroid and extra-thyroid neuroendocrine neoplasms: the two-faced Janus.

An increased calcitonin serum level is suggestive of a medullary thyroid cancer (MTC), but is not pathognomonic. The possibility of false positives or other calcitonin-secreting neuroendocrine neoplasms (NENs) should be considered. Serum calcitonin levels are generally assessed by immunoradiometric and chemiluminescent assays with high sensitivity and specificity; however, slightly moderately elevated levels could be attributable to various confounding factors. Calcitonin values >100 pg/mL are strongly suspicious of malignancy, whereas in patients with moderately elevated values (10-100 pg/mL) a stimulation test may be applied to improve diagnostic accuracy. Although the standard protocol and the best gender-specific cut-offs for calcium-stimulated calcitonin are still controversial, the fold of the calcitonin increase after stimulation seems to be more reliable. Patients with MTC show stimulated calcitonin values at least three to four times higher than the basal values, whereas calcitonin-secreting NENs can be distinguished from a C-cell disease by the absence of or

Primary Neuroendocrine Neoplasms of the Breast: Still Open Issues.

Neuroendocrine breast tumors represent a rare subtype of breast cancer, accounting for less than 1% of all neuroendocrine neoplasms. Starting from their pathology definition, and going through their prevalence, prognosis and treatment, our knowledge is still really uncertain. In the present short review of the medical literature on this topic, we have evaluated in details their epidemiology, risk factors, pathogenesis, pathology, clinical presentation, radiographic aspects, prognosis, and therapy. We have thus been able to identify a number of open issues regarding primary neuroendocrine neoplasms of the breast that need to be clarified. Our ultimate aim was actually to try to understand whether neuroendocrine neoplasms of the breast can be considered a definite clinical entity and if neuroendocrine differentiation of breast tumors has a really clinical relevance.

Partitioning of bronchopulmonary carcinoids in two different prognostic categories by ki-67 score.

INTRODUCTION: Histological distinction between typical and atypical bronchopulmonary carcinoids is based on mitotic activity and necrosis. Regardless of these two parameters, outcome after surgery is often unpredictable. In this study the prognostic value of different clinico-pathological factors was retrospectively analyzed in a large series of patients with bronchopulmonary carcinoid. MATERIALS AND METHODS: The long-term post-surgical outcome of 106 radically treated patients affected by bronchopulmonary carcinoid from two Italian centers was correlated with tumor characteristics assessed by combining conventional histology with a panel of immunohistochemical markers of neuroendocrine differentiation (chromogranin-A, NSE) and proliferation activity (Ki-67 score). RESULTS: Carcinoids were assessed as typical (TC = 75; 70.8%) and atypical (AC = 31; 29.2%). Mean follow-up was 8.3 years (range: 0-20; median: 8.0). All cases expressed neuroendocrine markers. At univariate analysis, tumor recurrence [14/75 TC (18.7%), 15/31 AC (48.4%)] correlated with carcinoid histotype (P = 0.003), tumor size (P = 0.012), mitotic index (P = 0.044), Ki-67 score (P < 0.0001), and synchronous node metastasis (P = 0.037). Of these, Cox multivariate analysis confirmed only Ki-67 score as independent predictor of disease recurrence (P = 0.009). The best cut-off for Ki-67 score (calculated by ROC curves) discriminating recurrent vs non-recurrent disease was 4% (sensitivity 79.3%; specificity 83.8%; area under the curve 0.85). By stratifying patients according to this cut-off, a significantly different disease-free survival was found (log-rank test P < 0.0001). CONCLUSION: Ki-67 score accurately separates bronchopulmonary carcinoids in two well-distinct histo-prognostic categories. Ki-67 score predicts the patients outcome better than mitotic count, histotype, and tumor stage and it is therefore helpful in establishing the appropriate follow-up.