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Lymphadenectomy for pancreatic neuroendocrine tumors: is that the relevant debate?

P ancreatic neuroendocrine tumors (PNETs) represent approximately 3% of primary pancreatic neoplasms, with approximately 1000 new cases per year in the United States.1 The natural history of these malignancies is poorly defined and understood, which contributes to why there are 3 commonly used staging systems. Most often, these tumors are classified by the 2010 WHO (World Health Organization) staging system, which relies on size, metastases, mitotic rate, perineural invasion, angioinvasion, and Ki67.2 The lesions classified as well-differentiated by the WHO are a heterogeneous group, which are further divided into lowand intermediate-grade lesions on the basis of proliferative rate, as measured by mitoses and the Ki67 labeling index. Many groups have tried to simplify the WHO staging system by focusing on size, metastases, number of mitoses, necrosis, and/or CK19 staining.3,4 Ellison and colleagues5 compared a staging system entirely based on the grade (as measured by Ki67 index) with the 2 existing staging systems: AJCC (2010 American Joint Committee on Cancer) and ENETS (2006 European Neuroendocrine Tumor Society). This novel staging system uses grade to predict overall survival (OS). Tumor size, lymph node involvement, and distant metastases did not improve the model’s prognostic ability. In contrast to the work by Ellison and colleagues, where lymph node status is not a prognostic factor, Hashim and colleagues6 report that a lymphadenectomy is essential when treating PNETs. By retrospectively examining the data of 136 patients who underwent pancreatic resection and lymphadenectomy, both lymph node metastases and Ki67 more than 20% were predictors of recurrence-free survival. Predictors of OS were an R1 resection and Ki67 more than 20%. On the basis of these 2 studies and the results reported by others, the role of lymphadenectomy in the treatment of PNETs remains unclear. Many physicians looking for guidance use the NCCN (National Comprehensive Cancer Network) guidelines, which recommend a lymph node dissection for lesions larger than 2 cm in size. Although no one would debate that knowing the lymph node status improves the staging of the patient, it is not clear whether a lymphadenectomy has any effect on OS.7–9 Would leaving positive lymph nodes behind decrease a patient’s survival? Doubtful, because we have no evidence to support an improved survival with a lymph node dissection in any other gastrointestinal cancer, including gastric cancer.10 Without a lymphadenectomy, a more limited operation can be performed. As expected, a more limited operation has been associated with decreased operative time, blood loss, serious postoperative complications, length of hospital stay, and risk of postoperative diabetes/pancreatic insufficiency.11 For operations in which 44% of patients have 1 or more complications,12 can we justify a lymphadenectomy that may increase the morbidity and mortality further? If the prognostic information is deemed essential, we may want to consider sentinel lymph node biopsies, similar to other cancers, as one method of potentially reducing morbidity. Because the “oncological” resection including the draining lymph node basins seems to be prognostic, rather than therapeutic, can we justify the morbidity? Yes, if surveillance or survival could be improved. Accurate staging has several advantages—it sets expectations for patients and identifies recurrent disease via optimal surveillance strategies. Currently, postresection surveillance has not been standardized. If surveillance schedules were improved and standardized, the expense and morbidity of blood work and imaging could be reduced. The NCCN guidelines recommend surveillance at 3 to 12 months in the first year and then every 6 to 12 months for a maximum of 10 years. These are very broad time frames, with patients potentially being subject to anywhere from 11 to 24 imaging studies over the course of 11 years. More imaging studies may lead to earlier detection of metastases. However, does an earlier intervention for recurrent disease in asymptomatic patients improve survival? Small retrospective series advocate for metastasectomy for PNETs, but there are significant biases when selecting patients, making conclusions difficult. These series have contributed