Asymptomatic Pancreatic Neuroendocrine Tumors Research Articles

A256 SURVEILLANCE OF SMALL, NON-FUNCTIONING, ASYMPTOMATIC PANCREATIC NEUROENDOCRINE TUMORS: THE BRITISH COLUMBIA EXPERIENCE

Abstract Background Expert consensus surrounding surveillance for small, non-functioning, asymptomatic pancreatic neuroendocrine tumors (PNETs) remains conflicting. Recent observational studies have shown that surveillance is a safe strategy while large database studies show superior overall survival with surgical resection. Aims To describe the growth of small (<2cm), non-functioning, asymptomatic PNETs undergoing surveillance at a tertiary hospital in British Columbia. Methods We conducted a retrospective case series of patients with biopsy-proven, non-functioning, asymptomatic PNETs which were <2cm by RECIST criteria at diagnosis, who were followed through active surveillance at Vancouver General Hospital, British Columbia from February 1, 2011-February 1, 2021. Patients were included if serial imaging, whether by endoscopic ultrasound or cross-sectional imaging, was available for a minimum of 24 months. Results Of the 57 patients with pathology-proven PNETs that were identified, 14 cases were included after excluding those with resection within 1 year (n=17), lost to follow up (n=13), metastatic disease (n=6), size greater than 2cm at diagnosis (n=4), and with concurrent cancer (n=3). Included patients were predominantly female (n=10, 71%), Caucasian (n=8, 57%), and had a mean Charlson comorbidity index of 3.14. Mean PNET size at diagnosis was 12mm with standard deviation of 4.26mm. Tumors were located in the pancreatic head (n=4, 29%), body (n=6, 42%), and tail (n=4, 29%). Of 8 patients who had Ki67 stains, all were <3%, and of 11 patients with mitotic index, all had <2 mitotic figures. As such, of the 8 patients with available WHO grading, all were grade 1. The average follow-up was 49.6 months with an average tumor growth of 0.82mm per year. When grouping these tumors by growth, 9 (62%) tumors exhibited no growth, 2 tumors grew <1mm per year, 2 tumors grew 1-1.5mm per year, and 1 tumor grew 7.7mm per year. Two cases (14%) of PNETs underwent surgical resection due to size surpassing 2 cm. No patients undergoing surveillance developed metastatic disease. Conclusions To our knowledge, we have performed the first Canadian series of small, low-grade PNETS and demonstrated that active surveillance is a safe strategy with most tumors exhibiting no growth of several years. Of the subset of PNETs which demonstrate progression, the preceding surveillance strategy did not disadvantage patients in terms of progression to metastases and allowed for delay of potentially morbid surgery. Further research with prospective studies and larger samples should be conducted. Funding Agencies CAG

Molecular detection of pancreatic neuroendocrine tumors using methylated DNA markers: Discovery and tissue validation.

e16705 Background: The prevalence of pancreatic neuroendocrine tumors (PNETs) has increased in the last decade. Despite being clinically asymptomatic PNETs can be biologically aggressive. There is currently no reliable non-invasive diagnostic biomarker for PNETs. In this study we aimed to identify and validate methylated DNA marker (MDM) candidates that differentiate PNET from normal pancreas. Methods: For discovery, reduced representation bisulfite sequencing (RRBS) was performed on DNA extracted from frozen normal pancreas (n = 13) and PNET (n = 51) tissues. Area under the receiver operator characteristic curve (AUC), fold-change, and p-value criteria selected candidates MDMs for blinded validation in independent FFPE tissues from primary PNET (n = 67; solid = 50, cystic = 17), normal pancreas controls (n = 24), and normal buffy coat (n = 36) using methylation specific PCR. MDM distributions in primary PNETs were compared to primary lung (n = 36) and small bowel (n = 36) NETs and metastatic PNET tissue (n = 25). The discrimination accuracy of candidate markers was summarized as the AUC with corresponding 95% confidence intervals (CI). Results: From the RRBS discovery, 31 candidate MDMs were selected for validation. Four MDMs ( SRRM3, HCN2, SPTBN4 and TMC6) achieved individual AUCs ≥0.95 in the validation set (Table). These MDMs were similarly discriminant in metastatic PNET tissue and in primary lung and small bowel NETs. Three out of these 4 MDMs perfectly differentiated PNET tissue from buffy coat with AUC of 1 and may be ideally suited for further development of a blood-based assay. Conclusions: We identified and validated novel MDMs in tissue that discriminate PNETs from controls with normal pancreas and buffy coat with high accuracy. These MDMs also differentiated metastatic PNETs from normal pancreas tissue. Further exploration of these candidate tissue MDMs in plasma can potentially guide diagnosis and management of PNETs. Funding: P30DK084567. [Table: see text]

A Survival Analysis of Patients with Localized, Asymptomatic Pancreatic Neuroendocrine Tumors: No Surgical Survival Benefit when Examining Appropriately Selected Outcomes

BackgroundSurgical resection for asymptomatic, localized, well-differentiated pancreatic neuroendocrine tumors (PNETs) is common yet controversial. Studies using overall survival as an endpoint have shown a benefit for resection; however, these results may be due to treatment selection bias. We assessed the impact of surgery on both overall (OS) and cancer-specific survival (CSS) for asymptomatic patients with stage I PNETs (AJCC 8th edition). MethodsUsing SEER data, we identified 709 patients from 2007 to 2015 with well- and moderately differentiated stage I PNETs. We performed Kaplan–Meier survival estimates and adjusted Cox regression for OS and CSS. ResultsAmong 709 patients, 628 (88.6%) underwent surgery. There were 37 overall deaths and 11 cancer-specific deaths. All cancer-specific deaths occurred within 3 years of diagnosis. Five-year OS and CSS rates were 89% and 98%, respectively, for the population. Five-year OS rates were 56% in the non-surgical cohort versus 92% in the surgical cohort (log rank, p < 0.001). However, the 5-year CSS rates were similar; 94% in the non-surgical group and 98% in the surgical group (log rank, p = 0.207). On multivariable analysis, surgery predicted improved OS but not CSS. ConclusionAlthough OS is superior in surgically treated stage I PNETs, CSS is not improved, implying treatment selection bias towards surgery being performed in healthier patients. These data suggest that overall survival is a problematic endpoint for the study of asymptomatic, stage I PNETs. Surgery should be individualized for this cohort of patients as the primary cause of death is non-cancer related.

Does attending a Delphi consensus conference impact surgeon attitudes? Survey results from the Americas HepatoPancreatoBiliary Association consensus conference on small asymptomatic pancreatic neuroendocrine tumors

BackgroundManagement of asymptomatic small well-differentiated (panNET) <2 cm remains controversial. A consensus conference was held on this topic. The impact of attending the conference and participating in the audience response survey on surgeon's clinical approach to pancreatic neuroendocrine tumors was assessed. MethodsAudience members were surveyed using a smartphone real-time response system at the beginning and end of the conference. ResultsThe majority of 75 attendees underwent fellowship training, and 30% had >10 years experience as attending surgeons. Previously published consensus statements on the topic were considered insufficient to guide surgical practice by 82% of attendees, and over 96% desired additional data. After review of the data, consensus statements, and decision-making process, a significant number of participants changed their opinions regarding indications for tissue biopsy (p = 0.001), size thresholds for excision (p = 0.002), and regional lymph node dissection (p = 0.002) independent of whether a consensus was reached by the content-expert panel. ConclusionsThis represented the first Delphi process consensus on the topic, and the survey confirmed the topic as well-chosen and timely. Attendees changed opinions on management of panNET regardless of whether formal consensus was reached. Therefore, statements of consensus combined with presentation of literature and live discussion served to impact attendees’ approach to this disease.

The management of small asymptomatic pancreatic neuroendocrine tumors: A matched case-control study.

239 Background: Overdiagnosis and overtreatment has become an evolving challenge for several cancer sub-types. We hypothesized that a substantial portion of incidentally diagnosed small pancreatic neuroendocrine tumors(PanNET) are overtreated as a result of overdiagnosis and that non-operative management may be reasonable for selected patients. Methods: Consecutive patients evaluated for incidentally discovered, sporadic, stage I-II PanNET were analyzed retrospectively. Diagnosis was determined either by pathology or unequivocal imaging characteristics. Patients selected for radiographic surveillance (RS) were matched with patients who underwent resection based on tumor size at initial imaging. Clinicopathological characteristics were compared between the groups. Results: During the study period (2000-2013), RS was recommended for 80 patients, and 79 matched patients underwent resection (resection group). Pathologic diagnosis was obtained in 42 (53%) of the 80 RS patients. Median initial tumor size was similar between the RS vs resection groups (1.2cm (0.8-1.7) vs 1.3 cm (1-1.9), respectively, p=0.4). The resection group was younger and had a longer median follow-up compared to the RS group (58 vs 65 years, p&lt;0.001; 50 vs 29 months, p=0.006; respectively). At the time of last follow-up of the RS group, median tumor size had not changed (1.2cm, p=0.4), no patient had developed metastases, and no patient had experienced radiographic changes in the primary tumor that prompted resection. Within the resection group, low-grade (G1) pathology was recorded in 74 (95%) tumors, one patient had node positive disease, and five developed recurrence (6%). The postoperative complication rate was 36%. No patient in either group died from disease. Death from other causes occurred in 7 out of 159(4%) patients. Conclusions: In this study, no patient who was selected for observation developed metastases or died from disease after a median follow-up of almost 2.5 years.Radiographic surveillance for stable, small, incidentally discovered PanNETs is reasonable in selected patients.

How to Follow Up and When to Operate Asymptomatic Pancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1?

How to Follow Up and When to Operate Asymptomatic Pancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1?

Long-term Follow-up of Asymptomatic Pancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type I Syndrome

Pancreatic neuroendocrine tumors (PNETs) in asymptomatic patients may contribute to mortality. Endoscopic ultrasound (EUS) is the most accurate test to identify and monitor tumor size. The aim of this study was to examine the rate of growth and development of new tumors in multiple endocrine neoplasia type I (MEN 1). A retrospective cohort study in a tertiary academic center. Patients identified in endoscopic databases were included if they had 2 or more EUS examinations with untreated asymptomatic tumors identified. The growth rate and incidence of new lesions was analyzed. A total of 11 patients were studied (7 female, 4 male). Initially, 18 lesions with an average size of 10.3 mm (range, 5 to 24 mm) were found. Mean surveillance was 79 months (range, 18 to 134 mo). The growth rate of index lesions was 1.32 mm/y; 11 lesions exhibited stability or a decrease in size. Twelve new lesions were identified in 7 patients during the surveillance period with an average growth rate of 3.0 mm/y. The earliest new lesion was identified at 12 months and the latest at 70 months after index EUS. New lesions had a faster growth rate than those seen on initial EUS (P=0.01). Multiple endocrine neoplasia type I patients exhibit an overall low rate of growth of pancreatic neuroendocrine tumors. Growth rate of newly diagnosed lesions was significantly faster, suggesting a variation in phenotypic expression of the disease. Therapy should be individualized based upon the tumor size and location, symptoms, overall clinical status, and operative risk.

Evolving Paradigm for Managing Small Nonfunctional Incidentally Discovered Pancreatic Neuroendocrine Tumors

Pancreatic neuroendocrine tumors (PNETs), although rare, have been increasing in incidence over the last two decades (1). Their biological behavior encompasses a spectrum from slow-growing and indolent to aggressive, with the potential to spread to distant sites resulting in death. Studies have documented that the risk of spread and distant disease is often related directly to tumor size (2) and inversely to incidental detection (3). Broadly, PNETs can be classified as functional or nonfunctional. Functional tumors are defined by the production and release into the circulation of hormones, such as insulin, that have biological activity and can result in significant morbidity. Management of these functional PNETs is surgical resection when technically feasible, and this recommendation is generally agreed upon. The best approach for the management of incidentally discovered nonfunctional PNETs is not as straightforward. Nonfunctional tumors are often silent and asymptomatic, discovered only when detected by imaging studies often ordered to work-up unrelated conditions or complaints. Unlike their functional counterparts, the sole reason for managing asymptomatic nonfunctional PNETs is to prevent their spread to distant sites and any subsequent impact on the patient’s survival. With the improvement in cross-sectional imaging techniques, an increasing number of small ( 2.0 cm) asymptomatic PNETs are being discovered. The so-called “incidental” PNET is the subject of a natural history study published in the current issue of the JCEM (4). Gaujoux et al (4) report on an over 10-year experience diagnosing, managing, and following nonfunctioning PNETs less than 2.0 cm in size in 46 patients at two institutions. All patients that were followed had at least 18 months of serial imaging or follow-up after resection. Median overall follow-up for all patients was 34 months, with maximum follow-up of 52 months. As the authors point out in their introduction, there is a paucity of level 1 data available to guide management decisions for the asymptomatic patient found to have a less than 2.0-cm PNET. The authors considered patients for inclusion in their retrospective study based on the following criteria: 1) they must be over 18 years old; 2) they must have been diagnosed with a nonfunctioning PNET, defined according to the European Neuroendocrine Tumor Society guidelines by the absence of clinical symptoms of hormonal hypersecretion (http://www.enets.org); 3) the tumor must be smaller than 2.0 cm in diameter on imaging at initial diagnosis (in multifocal lesions, only the largest lesion was measured); 4) patients must be free of main pancreatic duct or biliary dilatation on imaging; 5) tumors must be of sporadic origin (and with multiple endocrine neoplasia type 1 [MEN1]-negative genetic testing if tumors were multiple); 6) tumors must have been incidentally discovered (ie, defined as lesions detected during abdominal imaging done for nonpancreatic-related reasons); 7) tumors must present without local invasion, node, or distant metastasis on imaging; 8) patients must have a proven diagnosis (ie, positive fine-needle aspiration [FNA], biopsy under endoscopic ultrasound, or positive somatostatin receptor imaging); 9) patients should have a Ki-67 2% when available; 10) patients should not have past or present specific treatment of their PNET (including somatostatin analogs); 11) tumor should be initially nonresected or resected after at least 18 months of radiological follow-up; and 12) tumor should have at least two serial cross-sectional images available.

Pancreatic Cystic Neoplasms: Management and Unanswered Questions

Approximately 10% of persons 70 years old or older are now diagnosed with pancreatic cysts, but it is not clear which ones require additional analysis, interventions, or follow-up. Primary care doctors rely on gastroenterologists for direction because no one wants to miss a diagnosis of pancreatic cancer, but meanwhile there is pressure to limit use of diagnostic tests and limit costs. We review the different cystic neoplasms of the pancreas and diagnostic strategies based on clinical features and imaging data. We discuss surgical and nonsurgical management of the most common cystic neoplasms, based on the recently revised Sendai guidelines. Intraductal papillary mucinous neoplasm (particularly the branch duct variant) is the lesion most frequently identified incidentally. We report what is known about its pathology, its risk of developing into pancreatic ductal adenocarcinoma, the pros and cons of current guidelines for management, and the potential role of endoscopic ultrasound in determining cancer risk. We also review surgical treatment and strategies for surveillance of pancreatic cysts.

Small, nonfunctioning, asymptomatic pancreatic neuroendocrine tumors (PNETs): Role for nonoperative management

Controversy exists regarding the optimal management of incidentally discovered, small pancreatic neuroendocrine tumors (PNETs). Our aim was to review the outcomes of patients who underwent nonoperative and operative management. We retrospectively reviewed patients with nonfunctioning PNETs at our institution from January 1, 2000 to June 30, 2011. Patients were included if the tumor was sporadic and <4 cm without radiographic evidence of local invasion or metastases. Nonoperative patients (n = 77, median age, 67 years; range, 31-94) had a median tumor size of 1.0 cm (range, 0.3-3.2). Mean follow-up (F/U) was 45 months (max. 153 months). Median tumor size did not change throughout F/U; there was no disease progression or disease specific mortality. In the operative group (n = 56, median age, 60 years; range, 27-82), median neoplasm size was 1.8 cm (range, 0.5-3.6). Mean F/U was 52 months (max. 138 months). A total of 46% of the operative patients had some type of complication, more than half due to a clinically significant pancreatic leak. No recurrence or disease specific mortality was seen in the operative group, including 5 patients with positive lymph nodes. Small nonfunctioning PNETs usually exhibit minimal or no growth over many years. Nonoperative management may be advocated when serial imaging demonstrates minimal or no growth without suspicious features.