High Mast Cell Density Predicts a Favorable Prognosis in Patients with Pancreatic Neuroendocrine Neoplasms

Introduction: Mast cells are involved in allergic diseases, immune regulation, and tumor microenvironment modulation, with both pro- and anti-tumorigenic functions, and could serve as a prognostic factor in various cancers. However, their potential role in pancreatic neuroendocrine neoplasms (PanNENs) is largely unknown. Here, our aim was to investigate the presence of mast cells in PanNENs and evaluate their association with clinicopathological parameters and other common tumor-infiltrating immune cells. Methods: Tissue microarrays containing PanNEN samples from 187 patients were constructed and stained immunohistochemically for CD117, CD15, CD68, CD3, CD4, and CD8. Immune cells were counted from four high-power fields (HPFs; 400×) at maximal concentrations, and the mean counts were calculated per HPF. The cut-off values were set by X-tile. Results: The median (interquartile range) counts of CD117+ mast cells, CD15+ neutrophils, CD68+ macrophages, CD3+ T cells, and CD4+ T cells were 3.5 (2.0–6.0), 3.0 (1.3–6), 3.8 (2.5–5.8), 13 (8.0–24.0), 2.0 (1.0–4.0)/HPF, respectively. CD8+ T cells were not detected. The cut-off values for these immune cells were 1.5/HPF, 6/HPF, 4.8/HPF, 32.5/HPF, and 2/HPF, respectively. Low mast cell density was correlated with higher grades, non-insulinoma, and advanced stages. Moreover, high mast cell infiltration was associated with elevated CD4+ T cell and CD15+ neutrophil counts. Multivariate analysis revealed that high mast cell density was an independent predictor of prolonged progression-free survival in the entire cohort, in pancreatic neuroendocrine tumors, and in intermediate-grade, non-insulinoma, and advanced stage subgroups. Conclusions: These findings suggest a protective role of mast cells in PanNENs.

Is there a role for biomarkers in surveillance of pancreatic neuroendocrine neoplasms in Von Hippel-Lindau’s disease?

Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized by the development of multi-organ neoplasms. Among the manifestations of VHL are pancreatic neuroendocrine neoplasms (panNENs). In order to detect these lesions in a timely manner, patients are enrolled in a surveillance program, in accordance with the several existing VHL guidelines. However, these guidelines remain unclear about the role of biomarkers in diagnosing panNENs, despite the benefits a biomarker may offer regarding early detection of new lesions, thereby possibly limiting radiation exposure, and improving quality of life. The aim is to determine which biomarkers might be available in VHL patients and to assess what their clinical relevance in diagnosing panNENs in VHL patients is. We searched the databases of Pubmed/Medline, Embase and Web of Science to identify relevant articles. Seven studies assessing the diagnostic or prognostic value of biomarkers were included. The results from these studies were conflicting. Since no evident association between VHL-related panNENs and biomarkers was established in studies with larger study populations, currently biomarkers do not play a significant role in early detection or follow-up for panNENs in VHL patients. The absence of evidence underscores the need for specific research to address this unmet need.

C-reactive protein independently predicts survival in pancreatic neuroendocrine neoplasms

Pancreatic neuroendocrine neoplasms (pNEN) are highly variable in their postresection survival. Determination of preoperative risk factors is essential for treatment strategies. C-reactive protein (CRP) has been implicated in the pathogenesis of pNEN and shown to be associated with survival in different tumour entities. Patients undergoing surgery for pNEN were retrospectively analysed. Patients were divided into three subgroups according to preoperative CRP serum levels. Clinicopathological features, overall and disease-free survival were assessed. Uni- and multivariable survival analyses were performed. 517 surgically resected pNEN patients were analysed. CRP levels were significantly associated with relevant clinicopathological parameters and prognosis and were able to stratify subgroups with significant and clinically relevant differences in overall and disease-free survival. In univariable sensitivity analyses CRP was confirmed as a prognostic factor for overall survival in subgroups with G2 differentiation, T1/T2 and T3/T4 tumour stages, patients with node positive disease and with and without distant metastases. By multivariable analysis, preoperative CRP was confirmed as an independent predictor of postresection survival together with patient age and the established postoperative pathological predictors grading, T-stage and metastases. Preoperative serum CRP is a strong predictive biomarker for both overall and disease free survival of surgically resected pNEN. CRP is associated with prognosis independently of grading and tumour stage and may be of additional use for treatment decisions.

What Are the Place and Modalities of Surgical Management for Pancreatic Neuroendocrine Neoplasms? A Narrative Review

Pancreatic neuroendocrine neoplasms (panNENs) are a heterogeneous group of tumors derived from cells with neuroendocrine differentiation. They are considered malignant by default. However, their outcomes are variable depending on their presentation in the onset of hereditary syndromes, hormonal secretion, grading, and extension. Therefore, although surgical treatment has long been suggested as the only treatment of pancreatic neuroendocrine neoplasms, its modalities are an evolving landscape. For selected patients (small, localized, non-functional panNENs), a “wait and see” strategy is suggested, as it is in the setting of multiple neuroendocrine neoplasia type 1, but the accurate size cut-off remains to be established. Parenchyma-sparring pancreatectomy, aiming to limit pancreatic insufficiency, are also emerging procedures, which place beyond the treatment of insulinomas and small non-functional panNENs (in association with lymph node picking) remains to be clarified. Furthermore, giving the fact that the liver is generally the only metastatic site, surgery keeps a place of choice alongside medical therapies in the treatment of metastatic disease, but its modalities and extensions are still a matter of debate. This narrative review aims to describe the current recommended surgical management for pancreatic NENs and controversies in light of the actual recommendations and recent literature.

Second Primary Malignancies in Patients with Pancreatic Neuroendocrine Neoplasms: A Population-Based Study on Occurrence, Risk Factors, and Prognosis

Background. This study aimed to evaluate the risk factors of developing second primary malignancies (SPMs) among patients with pancreatic neuroendocrine neoplasms (pNENs) and the prognosis of pNENs patients with SPMs (pSPMs) using data from the Surveillance, Epidemiology, and End Results (SEER) database. Methods. Data from patients diagnosed with pNENs between 1988 and 2016 were extracted. A case-control study was conducted to investigate the risk factors of developing SPMs among patients with pNENs. Meanwhile, cox regression analysis was also conducted to obtain the independent prognostic factors in pSPMs. Results. Of 7,630 patients with pNENs, 326 developed SPMs. Patients with pNENs who had not undergone surgery and had been diagnosed in recent periods had a higher risk of developing SPMs. The following independent prognostic predictors for pSPMs were identified: age, latency period, SEER stage, radiotherapy, and surgery. Conclusions. These findings may improve the surveillance of risk factors for developing SPMs in patients with pNENs and the prognostic risk factors in pSPMs.