Response to Commentary "Are Parenchyma-Sparing Resections Really Appropriate for Small (<3 cm) Non-Functional Pancreatic Neuroendocrine Tumors?"

We thank Peng et al for commenting on our multicenter study evaluating postoperative and long-term outcomes of parenchyma and lymph node sparing procedures (PSRs) in small (<3 cm) nonfunctional pancreatic neuroendocrine tumors (pNETs).1 They have nicely outlined the difficulty of managing patients and assessing cancers for which the biology is poorly understood. The question if parenchyma-sparing procedures are safe for small nonfunctional pNET has long been unclear. Despite an increase in the number of incidentally discovered pNETs on routine imaging, these tumors still make up only 1%–2% of all pancreatic neoplasms.2 Due to the rarity of small (<3 cm) nonfunctional pNETs a randomized trial has not been performed. Rather, decisions are informed by single-center publications or analyses from large National cancer databases plagued by heterogeneity in data collection. Expertise not only in imaging and surgical care influence decisions, but expert evaluation of dedicated experienced pathologists is essential. For all 4 institutions included in this study expert pathologists dedicated to neuroendocrine tumors are evaluating the specimens to provide accurate pathologic assessments. In the light of scarce evidence, complete oncologic resection might appear as the safest option to achieve long-term tumor control. However, PSRs are associated with important benefits such as reducing postoperative morbidity and preserving endocrine and exocrine pancreatic function. Our study demonstrated that PSRs result in equivalent long-term disease-free and overall survival compared with oncologic resections in patients with nonfunctional pNET <3 cm without suspicious lymph nodes on preoperative imaging as determined by expert high-volume radiologists and surgeons. Peng et al raise the question if PSR is in fact safe in all patients with nonfunctional pNET <3 cm and if a subgroup of biologically more aggressive pNETs would receive oncologically inadequate treatment. Arguing that follow-up intervals were too short and aggressive systemic therapy was potentially performed in PSR patients, the authors suspect underreporting of recurrence rates for PSR patients. Median follow-up time for the study cohort was 208 months. PSR is considered a surgical option for pNETs and the centers participating in the multicenter study are some of the pioneering and most experienced institutions of pNET surgery in the United States. The first PSR in our study cohort was performed in 2001. The median follow-up time of over 17 years not only significantly exceeds a classical oncologic follow-up period of 5 years but also is the longest high-volume follow-up period for PSR procedures available to date. Systemic therapy is not recommended as a standard adjuvant option for small nonfunctional pNET by the North American Neuroendocrine Tumor Society guidelines.2 A total of 13 (5.9%) oncologically resected patients and 3 (1.4%) PSR patients were treated with systemic therapy (octreotide, temozolomide, or everolimus), for suspected metastatic spread. We therefore consider the patient selection sound, the follow-up period exceptional and the PSR and oncologic resection group sufficiently balanced to address the oncologic safety of PSR in small nonfunctional pNETs. Peng et al further hypothesize that high-risk features in small nonfunctional pNET <3 cm may potentially be determined by oncologic resection only. The authors emphasize that factors predictive of recurrence such as positive lymph nodes, tumor grade, perineural invasion, vascular invasion, and R status are not available for PSR versus oncologic resection decision making preoperatively. Thus, high-risk patients might not be identified upfront and consequently receive insufficient treatment with PSR. Numerous studies, including those cited by the authors, have identified lymph node metastasis as the major risk factor of recurrence and impaired prognosis in small nonfunctional pNETs, and the risk of lymph node metastasis increases with tumor size.3–6 The surgical approach for patients in our study was carefully discussed by a multidisciplinary board of experienced specialists at the participating high-volume centers. PSR was only considered if there were no suspicious lymph nodes on preoperative imaging and no high-grade features on preoperative biopsies. However, lymph node metastasis may be underestimated based on imaging, and potential lymph node involvement was always reassessed during the operation as an additional step to ensure oncologic safety. PSR allows for lymph node sampling which was performed in 80 (36.2%) patients of the study cohort, with only 6.8% having lymph node metastasis. Our analysis demonstrates that this 2-step procedure, with trained experts, ensures oncologic safety and adequate lymph node dissection for PSR as measured by equivalent long-term disease-free and overall survival to oncologic resection. To date, there are additional options to identify high-risk patients with small nonfunctional pNET preoperatively. Endoscopic ultasound (EUS)-guided fine-needle aspiration can help to determine tumor grade with an accuracy of up to 97.9% with an excellent inter-rater reliability.7 EUS-guided fine-needle aspiration combined with fine-needle biopsy sampling can further guide risk stratification in small nonfunctional pNETs.8 Additionally with the advent of gallium-68 DOTA-DPhe1, Tyr3-octreotate PET scans potential locoregional involvement can be better evaluated.9 Taken together, multiple robust options exist to determine a high-risk profile in small nonfunctional pNETs prior to an operation. We therefore consider it safe to perform a careful preoperative and intraoperative assessment to select patients for PSR procedures. Peng et al suggest performing a splenectomy for all cancer patients since the spleen can harbor tumor cells with metastatic potential in pilot studies of pancreatic ductal adenocarcinoma and hepatocellular carcinoma patients.10,11 Understanding pNET biology and identifying markers predicting a high risk of recurrence remain important aims for nonfunctional pNETs. Such stratification tools are warranted and would be an excellent option to help guide clinical decision-making for oncologic resection versus PSR in the future. However, biological aspects of high-risk nonfunctional pNETs continue to be poorly understood and highly uncertain as to whether tumor cells with metastatic potential or spleen-associated promotion of metastasis and progression identified in small studies for aggressive gastrointestinal malignancies can be confirmed in pNETs. Performing a splenectomy in small nonfunctional pNETs based on preliminary evidence from aggressive cancers does not seem appropriate. In summary, the decision for PSR should be considered carefully in patients with small nonfunctional pNETs <3 cm. Multidisciplinary preoperative assessment, consideration of preoperative imaging, EUS-guided fine-needle biopsy should guide the decision for oncologic resection versus PSR. Lymph node status should be reassessed intraoperatively, and lymph node sampling has to be performed if lymph nodes appear suspicious. If patients are carefully selected for PSR, we consider these procedures safe and beneficial reducing postoperative morbidity with equivalent long-term outcomes.