Francesca Muffatti

A New Scoring System to Predict Recurrent Disease in Grade 1 and 2 Nonfunctional Pancreatic Neuroendocrine Tumors

Objective:The aim of this study was to predict recurrence in patients with grade 1 or 2 nonfunctioning pancreatic neuroendocrine tumors (NF-pNET) after curative resection. Background:Surgical resection is the preferred treatment for NF-pNET; however, recurrence occurs frequently after curative surgery, worsening prognosis of patients. Methods:Retrospectively, patients with NF-pNET of 3 institutions were included. Patients with distant metastases, hereditary syndromes, or grade 3 tumors were excluded. Local or distant tumor recurrence was scored. Independent predictors for survival and recurrence were identified using Cox-regression analysis. The recurrence score was developed to predict recurrence within 5 years after curative resection of grade 1 to 2 NF-pNET. Results:With a median follow-up of 51 months, 211 patients with grade 1 to 2 NF-pNET were included. Thirty-five patients (17%) developed recurrence. The 5- and 10-year disease-specific/overall survival was 98%/91% and 84%/68%, respectively. Predictors for recurrence were tumor grade 2, lymph node metastasis, and perineural invasion. On the basis of these predictors, the recurrence score was made. Discrimination [c-statistic 0.81, 95% confidence interval (95% CI) 0.75–0.87] and calibration (Hosmer Lemeshow Chi-square 11.25, P = 0.258) indicated that the ability of the recurrence score to identify patients at risk for recurrence is good. Conclusions:This new scoring system could predict recurrence after curative resection of grade 1 and 2 NF-pNET. With the use of the recurrence score, less extensive follow-up could be proposed for patients with low recurrence risk. For high-risk patients, clinical trials should be initiated to investigate whether adjuvant therapy might be beneficial. External validation is ongoing due to limited availability of adequate cohorts.

Systematic review and meta-analysis on laparoscopic pancreatic resections for neuroendocrine neoplasms (PNENs).

ABSTRACT Introduction: The safety of laparoscopic resections (LPS) of pancreatic neuroendocrine neoplasms (PNENs) has been well established in the literature. Areas covered: Studies conducted between January 2003 and December 2015 that reported on LPS and open surgery (OPS) were reviewed. The primary outcomes were the rate of post-operative complications and the length of hospital stay (LoS) after laparoscopic and open surgical resection. The rate of recurrence was the secondary outcome. Eleven studies were included with a total of 907 pancreatic resections for PNENs, of whom, 298 (32.8%) underwent LPS and 609 (67.2%) underwent open surgery. LPS resulted in a significantly shorter LoS (p < 0.0001) and lower blood loss (p < 0.0001). The meta-analysis did not show any significant difference in the pancreatic fistula rate, recurrence rate or post-operative mortality between the two groups. Expert commentary: LPS is a safe approach even for PNENs and it is associated with a shorter LoS.

Management of neuroendocrine carcinomas of the pancreas (WHO G3): A tailored approach between proliferation and morphology

Neuroendocrine carcinomas (NEC) of the pancreas are defined by a mitotic count > 20 mitoses/10 high power fields and/or Ki67 index > 20%, and included all the tumors previously classified as poorly differentiated endocrine carcinomas. These latter are aggressive malignancies with a high propensity for distant metastases and poor prognosis, and they can be further divided into small- and large-cell subtypes. However in the NEC category are included also neuroendocrine tumors with a well differentiated morphology but ki67 index > 20%. This category is associated with better prognosis and does not significantly respond to cisplatin-based chemotherapy, which represents the gold standard therapeutic approach for poorly differentiated NEC. In this review, the differences between well differentiated and poorly differentiated NEC are discussed considering both pathology, imaging features, treatment and prognostic implications. Diagnostic and therapeutic flowcharts are proposed. The need for a revision of current classification system is stressed being well differentiated NEC a more indolent disease compared to poorly differentiated tumors.

Surgical management of neuroendocrine tumors.

During the last decades an increase in the incidence of neuroendocrine tumors (NETs) was observed. Gastroenteropancreatic NETs represent the majority of NETs. Compared with their epithelial counterpart they usually have a more indolent behaviour and surgical resection improves survival. Tumor diameter is one of the main parameter in the decision making process for nonfunctioning forms. Generally, small lesions can be treated conservatively whereas larger tumors should be treated with standard surgical resection and lymphadenectomy. Functioning tumors should be resected regardless the dimension of the lesion. Locally advanced and metastatic disease should be also treated with extended resections, keeping in consideration the grading, size, Ki67, and presence of extra-abdominal disease. In the case of metastases the panel of operative treatment includes resection, ablation, up to liver transplantation.

Peptide receptor radionuclide therapy as neoadjuvant therapy for resectable or potentially resectable pancreatic neuroendocrine neoplasms

Background. Peptide receptor radionuclide therapy is a valid therapeutic option for pancreatic neuroendocrine neoplasms. The aim of this study was to describe an initial experience with the use of peptide receptor radionuclide therapy as a neoadjuvant agent for resectable or potentially resectable pancreatic neuroendocrine neoplasms. Methods. The postoperative outcomes of 23 patients with resectable or potentially resectable pancreatic neuroendocrine neoplasms at high risk of recurrence who underwent neoadjuvant peptide receptor radionuclide therapy (peptide receptor radionuclide therapy group) were compared with 23 patients who underwent upfront surgical operation (upfront surgery group). Patients were matched for tumor size, grade, and stage. Median follow‐up was 61 months. Results. The size (median greatest width) of the primary pancreatic neuroendocrine neoplasms decreased after neoadjuvant peptide receptor radionuclide therapy (59 to 50 mm; P = .047). There were no differences in intraoperative and postoperative outcomes and there were no operative deaths, but the risk of developing a pancreatic fistula tended to be less in the peptide receptor radionuclide therapy group when compared to the upfront surgery group (0/23 vs 4/23; P < .02). The incidence of nodal metastases at the time of resection was also less in the peptide receptor radionuclide therapy group (n = 9/23 vs 17/23; P < .02). Neither median disease‐specific survival (not reached in either group; P = .411) nor progression‐free survival (52 vs 37 months; P > .2) differed between groups, but progression‐free survival in the 31 patients who had an R0 resection seemed to be greater in the 15 patients in the peptide receptor radionuclide therapy group versus 16 patients the upfront group (median progression‐free survival not reached vs 36 months; P < .05). Conclusion. Neoadjuvant peptide receptor radionuclide therapy for resectable or potentially resectable pancreatic neuroendocrine neoplasms in patients with high‐risk features of recurrence seems to be beneficial, but well‐designed and much larger prospective trials are needed to confirm the safety and the oncologic value of this approach.

Clinical Usefulness of 18F‐Fluorodeoxyglucose Positron Emission Tomography in the Diagnostic Algorithm of Advanced Entero‐Pancreatic Neuroendocrine Neoplasms

BACKGROUND The role of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in the diagnostic algorithm of entero-pancreatic neuroendocrine neoplasms (EP NENs) is unclear because most available data derive from heterogeneous populations in terms of tumor biology and disease status at time of examination. The aim of this study was to determine the ability of 18F-FDG PET to identify patients with more aggressive disease among those with advanced EP NENs. Subjects, Materials, and Methods . Patients with advanced EP NENs and known disease status (progressive disease [PD] or stable disease [SD]) according to imaging procedures, who received 18F-FDG PET and computed tomography scans during a time frame of 1 month, were included. RESULTS A total of 93 patients, including 69 patients with pancreatic NENs and 24 patients with small-intestine NENs, were included. At the time of study entry, 64 patients (68.8%) had PD, and the remaining 29 patients (31.2%) had SD. A total of 62 patients (66.7%) had positive 18F-FDG PET, whereas 18F-FDG PET was negative in the remaining 31 patients (33.3%). Overall, 18F-FDG PET sensitivity and specificity to detect PD were 90.6% and 86.2%, respectively, resulting in a diagnostic accuracy of 89.2%. A positive 18F-FDG PET was significantly associated with PD at the time of study entry (p < .0001 at multivariate analysis). Although a higher proportion of 18F-FDG PET-positive examinations were observed in patients with higher tumor grade (p = .01), 53.8% of patients with grade 1 neuroendocrine tumors (NETs) had positive 18F-FDG PET, and 37.5% of patients with grade 2 NETs had negative 18F-FDG PET. Overall survival was significantly shorter in 18F-FDG PET-positive patients (median: 60 months) in comparison with 18F-FDG PET-negative patients (median not reached; p = .008). CONCLUSION 18F-FDG PET has a high diagnostic accuracy to identify progression of disease with unfavorable clinical outcome in patients with advanced EP NENs. Knowledge of disease status and G grading are key factors for physicians to better select patients for whom 18F-FDG PET is clinically useful. IMPLICATIONS FOR PRACTICE The findings of the present study may help physicians dealing with advanced neuroendocrine neoplasms to select patients for whom 18F-fluorodeoxyglucose positron emission tomography is useful to predict poor clinical outcome.

Tumor size correlates with grading in nonfunctioning pancreatic neuroendocrine tumors and is not age-dependent

1Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, “Vita-Salute” University, Milan, Italy; 2Center for Statistic, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, “Vita-Salute” University, Milan, Italy; 3Department of Pathology, Ospedale Sacro Cuore-Don Calabria, Negrar, Italy; 4Department of Pathology, Università Politecnica delle Marche, Ancona, Italy; 5Pathology Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, “Vita-Salute” University, Milan, Italy

Therapy for Locoregional Disease: Pancreas

Surgery is the mainstay for the treatment of localized pancreatic neuroendocrine neoplasm tumors (PanNENs). Either formal or limited pancreatic resections are commonly used for large (> 2 cm), sporadic PanNENs and for functioning neoplasms. However, given the high rate of perioperative morbidity and mortality after pancreatic surgery and the indolent behavior of PanNETs, a conservative approach consisting of active surveillance has been proposed for small, nonfunctioning, low-to-intermediate-grade tumors. Treatment of locally advanced PanNENs appears particularly challenging. Although surgery can be proposed in the presence of tumor invasion of nearby organs, it is currently unclear whether an aggressive surgical approach is associated with improved survival outcomes. On the other hand, it has been suggested that chemotherapy or peptide receptor radionuclide therapy (PRRT) is effective in the neoadjuvant setting and may lead to increased rates of curative resections in patients with locally advanced disease. Studies investigating the molecular underpinnings of PanNENs in relation to their clinical behavior are needed for optimal treatment tailoring.

Guideline for the Management of Pancreatic Neuroendocrine Tumor

Pancreatic neuroendocrine neoplasms (PNENs) have been steadily increasing in terms of incidence and prevalence over the last two decades. As a broad variety of tumors in regard to presentation, histology, and prognosis, they represent a growing challenge for the clinicians of many specialties. Lately, surgeons are called to decide whether to offer surgery for neoplasms that may be indolent and very limited and have potentially small benefit from major operations, while in others cases can manifest at advanced stages when symptom control is the only rationale for surgical treatment.

Surgical Therapy of Pancreatic Neuroendocrine Neoplasms

Pancreatic neuroendocrine tumors are relatively rare entities, which consist of single or multiple benign or malignant neoplasms. It will be shown that in 10–20 % of patients, they can be associated with inherited syndromes, such as multiple endocrine neoplasia type 1. Those tumors are clinically heterogeneous and classified into functioning (10–30 %) and nonfunctioning (70–90 %) types, depending on their ability to produce symptoms due to hormone production. Because of their rarity, as well as their relatively indolent natural history, treatment approaches are not standardized, yet. A formal pancreatic resection is usually mandatory for large and localized sporadic pancreatic tumors or in the presence of symptoms. Nevertheless, in the case of small and asymptomatic lesions, a conservative approach consisting of a wait-and-see policy is going to look as more appropriate, in particular when, in order to remove the lesion, an aggressive surgical procedure is required, such as pancreaticoduodenectomy or distal splenopancreatectomy, depending on the localization of the tumor. Also, surgery plays a significant role in locally advanced and metastatic forms.