Abstract
Introduction
Surgical resection is the only curative treatment for pancreatic neuroendocrine tumors (PNETs), but pancreatic operations carry a significant morbidity. We investigated whether the resection of small, asymptomatic nonfunctioning PNETs is beneficial. Clinicopathologic factors were retrospectively reviewed for all PNET cases from 1998 to 2014.
Methods
Kaplan-Meier survival and multivariable regression analyses were performed. A total of 249 patients had nonfunctioning PNETs with adequate follow-up, of whom 193 were resected and 56 were observed. Median age was 56 years, and 48 % of the patients were female.
Results
Overall, the resected patients had a significantly longer survival (OS) (p = 0.001). However, for the patients with PNETs ≤2.5 cm in size and without metastasis at presentation, tumor size significantly modified the effect of resection on overall survival (p < 0.05). The protective effect of resection increased as tumor size increased. An operation became a significant predictor of overall survival for tumors >1.5 cm (p = 0.050 or less for larger tumors) but was not significant for tumors <1.5 cm (p = 0.317 or more for smaller tumors), controlling for age-adjusted Charlson comorbidity index.
Conclusion
Resection of nonfunctioning PNETs over 1.5 cm is independently and significantly associated with a longer survival. However, the benefit of resection for tumors under 1.5 cm is unclear.
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Acknowledgments
The authors would like to thank AJ Samaras for his kind help and the Loeffler Family Foundation for their generous support of this work.
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The data collection had approval from the institutional human research review committee.
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Generous support from the Loeffler Family and the Warshaw Foundation is acknowledged.
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Primary Discussant
Steven J. Hughes, MD (Gainesville, FL)
I want to congratulate the authors on a clearly presented study and the forthcoming well-written manuscript. Thank you for providing a copy of it to me in advance.
So what should we do about the incidental finding on computerized tomography of a small, enhancing lesion in the pancreas? A small percentage of these lesions will ultimately threaten the patient’s life, but most will not. With the very rare exception of the small-cell variant of PNET, most small PNETs appear to lack metastatic potential, and even those lesions that ultimately metastasize progress slowly over a significant time frame. We lack sufficient tools to predict this more threatening natural history, and while pancreatic surgery has become increasingly safer, it is far from perfect.
Last year, at this meeting, the University of Chicago group led by Marshall Baker presented an analysis of the NCDB, concluding that resection conferred a survival benefit over observation for PNETs ≤2 cm. This is a wonderful study to follow, with clinical data from a single center. It improves our understanding of the management of PNETs, but the debate will continue. One can conclude from the data presented today that observation of PNETs ≤1.5 cm is as safe as operation.
To me, the greatest confounding variable impacting the ability to draw conclusions from this data is surgical judgment, and the group behind this study has this concept in abundance. Consistent with this, none of the deaths in the observation cohort can be attributed to the PNET. Yet, the Charlson age comorbidity index does not differ between the groups. There must be bias in this study introduced by the surgeon’s judgment to operate versus observe that the CACI cannot capture. Further, there are many clinical details not accounted for in the presented data and not driven by comorbidities or age that may have factored into this decision that do not lend themselves to a table or a sample size amenable to a subgroup analysis, for example a lesion deep in the head of the pancreas versus a lesion “hanging” off the body of the pancreas.
So, I applaud the authors on a provocative study of great importance to pancreatic surgeons, but caution the audience about over interpretation of the data.
I have two questions for the group:
1. Please speculate on why you did not observe an association between survival and proliferation rates or lymph node metastases.
2. What is the current algorithm for management of PNET at your institution, and what is your current recommendation regarding imaging modality and timing of follow-up for those patients placed into observation?
Closing Discussant
Dr. Zhang
1. Please speculate on why you did not observe an association between survival and proliferation rates or lymph node metastases.
Within the surgically resected group, we were also surprised to find a lack of significant association between overall survival and Ki-67 proliferative index and between overall survival and lymph node involvement at the time of the operation. One potential reason that Ki-67 was not a significant prognostic factor in this analysis may be that this study spanned a large number of years in order to include an adequate number of patients for this rare condition, and that particularly for patients from the earlier years, the surgical pathology either did not include Ki-67 or was performed by pathologists who did not specialize in pancreatic conditions. Of note, as part of another study currently being done by our group, surgical pathology specimens are being re-evaluated by pancreas-specialist pathologists and we are finding that many Ki-67 values have changed with the re-evaluation. With regard to lymph node involvement, previous reports have varied as to whether or not lymph node metastases are significant prognostic factors for long-term survival. In a validation study of different PNET staging systems, Ellison et al. 18 found that including lymph node status did not significantly improve survival prognostication.
2. What is the current algorithm for management of PNET at your institution, and what is your current recommendation regarding imaging modality and timing of follow-up for those patients placed into observation?
At our institution, we generally follow patients with asymptomatic nonfunctioning PNETs with serial CT imaging, starting with one at 6 months and then every year thereafter for 5 years. If there is no tumor growth seen over this period, then the imaging is spaced out to every 2 years. Additionally, depending on the patient’s age and comorbidities, which may suggest that they cannot tolerate a pancreatic operation, then we may not continue to scan them or space out the scans to every 2 years. Further studies, ideally prospective in nature, will be needed to determine the optimal protocol for following PNET patients.
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Zhang, I.Y., Zhao, J., Fernandez-del Castillo, C. et al. Operative Versus Nonoperative Management of Nonfunctioning Pancreatic Neuroendocrine Tumors. J Gastrointest Surg 20, 277–283 (2016). https://doi.org/10.1007/s11605-015-3043-5
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DOI: https://doi.org/10.1007/s11605-015-3043-5