Gastric Neuroendocrine Tumors (g-NETs): A Systematic Review of the Management and Outcomes of Type 3 g-NETs.

PURPOSE: to collect data from real-life experiences of the management of type 3 g-NETs and identify possible prognostic factors that may impact the decision-making process. METHODS: We performed a systematic review of the literature on type 3 g-NET management using the PubMed, MEDLINE, and Embase databases. We included cohort studies, case series, and case reports written in the English language. RESULTS: We selected 31 out of 556 articles from between 2001 and 2022. In 2 out of the 31 studies, a 10 mm and 20 mm cut-off size were respectively associated with a higher risk of gastric wall infiltration and/or lymph node and distant metastasis at diagnosis. The selected studies reported a higher risk of lymph node or distant metastasis at diagnosis in the case of muscularis propria infiltration or beyond, irrespective of the dimensions or grading. From these findings, size, grading, and gastric wall infiltration seem to be the most relevant factors in management staff making choices and prognoses of type 3 g-NET patients. We produced a hypothetical flowchart for a standardized approach to these rare diseases. CONCLUSION: Further prospective analyses are needed to validate the prognostic impact of the use of size, grading, and gastric wall infiltration as prognostic factors in the management of type 3 g-NETs.

Immunotherapy of Neuroendocrine Neoplasms: Any Role for the Chimeric Antigen Receptor T Cells?

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors with variable clinical presentation and prognosis. Surgery, when feasible, is the most effective and often curative treatment. However, NENs are frequently locally advanced or already metastatic at diagnosis. Consequently, additional local or systemic therapeutic approaches are required. Immunotherapy, based on chimeric antigen receptor T cells (CAR-T), is showing impressive results in several cancer treatments. The aim of this narrative review is to analyze the available data about the use of CAR-T in NENs, including studies in both preclinical and clinical settings. We performed an extensive search for relevant data sources, comprising full-published articles, abstracts from international meetings, and worldwide registered clinical trials. Preclinical studies performed on both cell lines and animal models indicate a significant therapeutic effect of CAR-T cells in NENs. Ongoing and future clinical trials will clarify the possible role of these drugs in patients with highly aggressive NENs.

NETest: A Systematic Review Focusing on the Prognostic and Predictive Role.

The NETest is a standardized and reproducible liquid biopsy for neuroendocrine tumors (NETs). It evaluates the expression of 51 NET genes by real-time polymerase chain reaction, providing an accurate molecular profile of the neoplasm. Diagnostic utility of NETest has been widely demonstrated, while its role in predicting prognosis and treatment response is less studied. This systematic review aims to collect and discuss the available evidence on the prognostic and predictive role of NETest, trying to answer 3 questions, frequently raised in clinical practice. Is NETest able to differentiate stable from progressive disease? Increased NETest levels (at least >40%) correlate with disease progression. Is NETest able to predict tumor progression and tumor response to treatment? Some studies demonstrated that the baseline NETest score >33-40% could predict tumor progression. Moreover, NETest performed after treatment (as peptide receptor radionuclide therapy) could predict treatment response also before radiological findings, since the decrease or stability of NETest score predicts tumor response to treatment. Is NETest able to evaluate tumor recurrence risk after surgery? NETest can predict surgical treatment outcome detecting minimal residual disease after radical surgery, which is characterized by a lower but positive NETest score (20-40%), while a higher score (>33-40%) is associated with nonradical surgery. In conclusion, in addition to its demonstrated diagnostic role, this systematic review highlights the efficacy of NETest to assess disease status at the moment of the NETest execution and to predict tumor recurrence after surgery. The efficacy for other applications should be proven by additional studies.

Sunitinib Treatment for Advanced Paraganglioma: Case Report of a Novel SDHD Gene Mutation Variant and Systematic Review of the Literature.

BACKGROUND: Paragangliomas (PGLs) are neuroendocrine neoplasms arising from chromaffin cells of sympathetic or parasympathetic paraganglia. Systemic therapies have been used only in metastatic PGLs. Antiangiogenic agents, such as sunitinib, could be a viable therapeutic choice in the subgroup of patients with SDH-positive PGLs. We describe the case of a man with Familial Paraganglioma Syndrome type 1 (FPGL) related to a novel mutation in SDHD gene treated with sunitinib. Furthermore, we performed a systematic review of the literature aimed to address the following question: is sunitinib treatment effective in patients with advanced/progressive/metastatic PGL? METHODS: We performed a data search using MEDLINE, Cochrane Library, and Scopus between April 2019 and September 2020. We included studies reporting data on clinical or biological characteristics, or clinical outcomes of patients with PGLs treated with sunitinib. RESULTS: The search leaded to the selection of 25 publications. Data from case reports and case series showed that disease control rate (DCR = stable disease + partial response + complete response) was achieved in 34.7% of cases under sunitinib treatment. In 39% of patients DCR was followed by progressive disease (PD) or tumor relapse, 26.1% patients showed PD. Data from clinical trials showed that DCR was 83%, and the median progression free survival was 13.4 months. DISCUSSION: Data from the present literature review suggested that sunitinib could be a viable therapeutic option in advanced/progressive/metastatic inoperable PGLs. However, further trials on the efficacy of sunitinib in FPGL and sporadic PGL are needed.

Neuroendocrine Carcinomas with Atypical Proliferation Index and Clinical Behavior: A Systematic Review.

BACKGROUND: Highly proliferative (G3) neuroendocrine neoplasms are divided into well differentiated tumors (NETs) and poorly differentiated carcinomas (NECs), based on the morphological appearance. This systematic review aims to evaluate the clinicopathological features and the treatment response of the NEC subgroup with a Ki67 labeling index (LI) < 55%. METHODS: A literature search was performed using MEDLINE, Cochrane Library, and Scopus between December 2019 and April 2020, last update in October 2020. We included studies reporting data on the clinicopathological characteristics, survival, and/or therapy efficacy of patients with NECs, in which the Ki67 LI was specified. RESULTS: 8 papers were included, on a total of 268 NEC affected patients. NECs with a Ki67 LI < 55% have been reported in patients of both sexes, mainly of sixth decade, pancreatic origin, and large-cell morphology. The prevalent treatment choice was chemotherapy, followed by surgery and, in only one study, peptide receptor radionuclide therapy. The subgroup of patients with NEC with a Ki67 LI < 55% showed longer overall survival and progression free survival and higher response rates than the subgroup of patients with a tumor with higher Ki67 LI (≥55%). CONCLUSIONS: NECs are heterogeneous tumors. The subgroup with a Ki67 LI < 55% has a better prognosis and should be treated and monitored differently from NECs with a Ki67 LI ≥ 55%.

Quality of Life in Patients with Neuroendocrine Neoplasms: The Role of Severity, Clinical Heterogeneity, and Resilience.

CONTEXT: Although health-related quality of life (HRQoL) is a fundamental outcome in oncological clinical trials, its evaluation in the neuroendocrine neoplasm (NEN) research field is still limited. OBJECTIVES: This study assessed the role of clinical severity (ie, presence or absence of metastasis and lines of therapies) and heterogeneity (ie, primary site, types of therapy, biology, and surgery) of NEN in relation to HRQoL, as well as resilience as a moderator between clinical severity and HRQoL. DESIGN: Cross-sectional multicentric study. SETTING: Italian university hospitals. PATIENTS: A total of 99 Italian patients (53 men and 46 women) with NEN and ranged in age from 22-79 years old. MAIN OUTCOME MEASURE: Severity and heterogeneity of NENs, HRQoL, and resilience. RESULTS: The presence of metastasis and a greater number of therapies affected the global health and some physical symptoms. Resilience was associated with global health, functional status, and some physical symptoms, and it moderated the impact of metastases on constipation and of the multiple therapies on diarrhea and financial problems. Patients with NEN in districts other than the gastroenteropancreatic system and those in follow-up perceived fewer physical symptoms than their counterparts. Patients with a sporadic NEN perceived their functional status, global health, and disease-related worries as better than those with a hereditary NEN. Patients who underwent surgery were lower in constipation than their counterparts. CONCLUSION: These findings highlight the need to assess the relationships between the clinical severity and heterogeneity of NEN with HRQoL and the role of resilience in improving patients' HRQoL.

Laryngeal Neuroendocrine Tumor With Elevated Serum Calcitonin: A Diagnostic and Therapeutic Challenge. Case Report and Review of Literature.

Introduction: Laryngeal neuroendocrine neoplasms (NENs) are a rare group of NENs of the neck, which commonly show immunostaining for calcitonin. Laryngeal NENs with calcitonin hypersecretion and lymph node metastases represent a diagnostic and therapeutic challenge, which should be included in the differential diagnosis of medullary thyroid carcinoma (MTC). We report a complex case of laryngeal NEN with calcitonin hypersecretion and a review of the literature. Case Presentation: A 59-year-old man presented with dysphagia, dyspnea, and lateral cervical mass; he was a smoker. At first imaging, a laryngeal lesion with lateral cervical lymphadenopathies was found, and it resulted as a moderately differentiated neuroendocrine tumor (G2), Ki67 = 5%, positive for calcitonin. Increased levels of serum calcitonin (50 pg/ml) were found. The patient started somatostatin analogs for lesions positivity to somatostatin receptor-based imaging. After 5 months, the disease progressed at 18F-fluorodeoxyglucose (18F-FDG) PET-CT, and also new painful cutaneous lesions occurred. Considering high serum levels of calcitonin, differential diagnosis with MTC was required. Patient performed a thyroid color Doppler ultrasound, nodule fine needle aspiration, calcitonin dosage in fine needle washout fluid, and a calcium gluconate stimulation test. After multidisciplinary evaluation, we decided to perform a total thyroidectomy associated with lateral cervical lymphadenectomy and resection of skin metastases. No MTC was found. Two of the five resected lymph nodes, left upper parathyroid, and skin lesions were metastases of NEN G2, positive for calcitonin. After 2 months, new painful skin lesions occurred, and a target therapy with everolimus 10 mg/day was started. After 6 months of therapy, partial metabolic response with a reduction of 53.7% of radiotracer uptake at primary tumor was detected together with an improvement of patient's quality of life. Conclusions: The present case is the seventh described in the literature of laryngeal NEN associated with elevated serum calcitonin levels and the first case with parathyroid metastasis, suggesting the importance of a correct differential diagnosis between MTC and calcitonin-secreting laryngeal NEN, using an integrated approach of biochemistry and advanced imaging. This is also the first time that somatostatin analogs and then everolimus were used in this setting, resulting in clinical and partial metabolic response.

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.