In this series, we analyzed 122 patients with small (≤3 cm) pancreatic, ampullary, and duodenal NETs based upon the type of surgical treatment (enucleation vs. resection) received over an 18-year period at four institutions. Patients undergoing enucleation were more likely to have functional tumors in the head of the pancreas and less likely to have a splenectomy. The estimated blood loss, operative time, length of stay, overall morbidity, and all-cause mortality were similar between the enucleations and resections. While the pancreatic fistula rate was higher after enucleation, the fistulas tended to be less severe compared to those that occurred following resection. For patients with NETs in the head of the pancreas, enucleation was associated with decreased blood loss, operative time, and length of stay compared to pancreaticoduodenectomy.
The type of procedure performed for NETs of the pancreas, ampulla, and duodenum is important because surgical resection is considered to be the only curative modality.16
Even for small tumors, the risk of malignant transformation is present. This risk is highlighted by the 4% overall recurrence rate in this study of patients with 3 cm or less tumors who were node negative and metastasis free. The operative strategy regarding these NETs has focused on the relative advantages and disadvantages of local, less invasive procedures versus a formal pancreatic resection. As the morbidity and mortality of pancreatic resection at high-volume centers has decreased, distal pancreatectomy of small pancreatic tail lesions has become the norm.13
Similarly, pancreaticoduodenectomy, although more invasive than distal pancreatectomy, has grown to be an acceptable treatment option for small tumors of the pancreatic head, especially when in close proximity to the pancreatic duct.13,17,18
Central or middle segment pancreatectomy is also being employed in patients with pancreatic neck lesions.19,20
Reports of safe and effective laparoscopic resections have added to the types of surgical resections performed.21–23
However, risks associated with formal pancreatic resection include loss of healthy pancreatic tissue (with possible endocrine or exocrine insufficiency), the potential for splenectomy with distal resections, and a variety of complications related to bowel anastomoses or dysfunction of the stomach. Our study confirms that the rate of splenectomy is higher in patients undergoing resection. In addition, small bowel obstruction, ileus, and delayed gastric emptying occurred more frequently after resection, though this difference was not statistically significant.
As an alternative to resection, enucleation has remained an important part of the surgical armamentarium for pancreatic, ampullary, and duodenal NETs. The guiding principles for enucleation are the size of the tumor, absence of evidence of malignancy, and proximity to the pancreatic duct.18,24–26
Previous reported benefits of enucleation include reduced blood loss and operative time compared to resection, but not decreased length of stay.22,25–28
Like resection, enucleations can be performed laparoscopically with reduced blood loss and operative time when compared to resection.22,29,30
In this investigation, operative blood loss and time were statistically similar when all patients undergoing enucleation or resection were compared (P
=0.11). However, when enucleation was evaluated against pancreaticoduodenectomy, the blood loss and operative time were greater after pancreaticoduodenectomy. Comparison of these same two procedures performed laparoscopically also supports this conclusion.22
The length of hospital stay for our enucleated and resected patients was similar which confirms prior findings.27
But our analysis indicated that hospital stay is significantly longer following pancreaticoduodenectomy than enucleation. In addition, enucleation has been shown to preserve pancreatic tissue.18
This investigation focused on small pancreatic and peripancreatic NETs with a relatively equal overall distribution of functional (45%) and non-functional (55%) lesions. A retrospective review of 125 patients with pancreatic NETs by Phan et al. revealed a similar proportion of functional hormone expression (52%).31
The distribution of functional tumor types in their study showed that insulinomas were the most common followed by gastrinomas, VIPomas, and glucagonomas.31
In the current series, the majority of functional tumors also were insulinomas, and the dispersion was similar, though no VIPomas were seen (). Thus, the functional classification of NETs in our study is comparable to previously published data.9,31–33
We also found that enucleated tumors were more likely to be functioning and in the head of the pancreas. These findings may be the result of surgical preference. Non-functioning tumors were resected more often, likely because non-functional status is a known adverse prognostic factor for survival.6–8
In addition, distal pancreatectomy is often the procedure of choice for pancreatic tail lesions.
In this study, we also examined the morbidity, mortality, and survival of enucleations compared to resections. The overall complication rate of 45% is comparable to rates observed in other studies that range from 14% to 50%.18,27,28,30,31,34–37
Our data reveal that overall morbidity does not differ significantly between patients undergoing enucleation (49%) versus resection (44%). Enucleation has previously been shown to have similar morbidity to resection while preserving pancreatic tissue.18
The 30-day mortality rate in this series (0.8%) also was comparable between the patients studied and was not different from previously reported rates for these operations.11,12,36
While the overall morbidity and mortality were similar, pancreatic fistula development occurred more commonly following enucleation. After enucleation, 38% of patients developed a pancreatic fistula which is within the previously reported range for enucleated patients—16% to 38%.22,27,30,31
In patients who were treated with resections, 15% formed fistulas which also is similar to other studies (range 9–26%).22,27,30,31
Retrospective chart review in each case showed that the leaks following enucleation were ISGPF grade A or B pancreatic fistulas which, by definition, are not associated with other complications or prolonged hospitalizations. Comparison of grade A versus grade B and C pancreatic fistulas in the two groups revealed that those fistulas diagnosed in the resected patients tended to be worse suggesting that the overall leak rate should be examined in the context of fistula grade. In terms of survival, when compared to tumors of other cell types, the prognosis of patients with pancreatic and peri-pancreatic NETs is very good and is excellent when only patients with “benign” or localized disease are evaluated.7,8,33
With a mean follow-up of 50 months, the survival in our study was no different between the surgical groups. In addition, the overall mortality for the resection group is in line with other reports of formal pancreatic resections.7,8,11,12
The present study is limited by the non-randomized retrospective design and inherent selection bias. Thus, resection may have been performed more often in patients with more aggressive disease. The resection group did have more systemic recurrences and a larger proportion of non-functioning tumors. Because enucleation is not indicated for patients with large tumors, lesions in close proximity to the pancreatic duct, or in the known presence of nodal or metastatic disease, a size limitation was essential to creating comparable groups. In recent years, laparoscopic approaches to NETs have been reported with increasing frequency.22,29,30
Therefore, in the future, open enucleation will need to be compared to laparoscopic enucleation. An analysis of the associated costs of these procedures also might enhance forthcoming studies. Due to the rarity of pancreatic and peri-pancreatic NETs, multi-institutional studies and larger population-based data sets also will be important to analyze in order to advance future practices.
In conclusion, this multi-institutional retrospective review of 122 patients compared enucleation to resection for small pancreatic, ampullary, and duodenal NETs. The overall effectiveness of enucleation and resection for these NETs is comparable, with similar morbidity, mortality, and survival.9,31
The surgical procedures also were similar with respect to estimated blood loss, operative time, and length of hospital stay. However, enucleation resulted in decreased blood loss, operative time, and duration of stay compared to pancreaticoduodenectomy when just patients with NETs in the head of the pancreas were considered. Furthermore, enucleation was associated with a significantly lower rate of splenectomy compared to all distal pancreatectomies. While enucleated patients had a higher incidence of pancreatic fistula formation compared to the resection group, the fistulas that formed after resection were mostly grade B and C, clinically significant fistulas. Therefore, enucleation of small pancreatic and peri-pancreatic NETs is safe and does not compromise long-term survival. This analysis further confirms that enucleation of small NETs with low malignant potential remains a viable operative approach. The procedure of choice in these patients with smaller NETs may be enucleation for lesions in the pancreatic head and distal pancreatectomy with splenic preservation for lesions in the pancreatic tail.