PanNEN have a more indolent biological behaviour and they are usually associated to a longer survival when compared to their exocrine counterpart. Therefore, it is of paramount importance to evaluate the long-term functional sequelae following pancreatic resection for PanNEN and to find a balance between the oncological risk and the impact of endocrine and exocrine impairment on general health status. Various studies have explored the functional outcomes after pancreatic resection in large populations, including patients affected by different pancreatic diseases, ranging from benign conditions to cancer [19
]. In contrast, data on the long-term endocrine and exocrine pancreatic insufficiency after pancreatic surgery specifically performed for PanNEN are currently limited [32
]. The risk of developing a postoperative DM and/or PEI can be influenced by specific characteristics that are related to the underlying primary pancreatic disease.
The incidence of post-pancreatectomy DM ranges from 5% to 78% [20
], probably due to the heterogeneity of the selecting criteria of study populations and to the different duration of follow-up. In the present series, the onset of postoperative DM was observed in nearly one-third of patients after six years from surgery. A similar incidence of DM (23%) was reported in a series including 229 patients submitted to surgery for benign tumors [20
]. In contrast, the incidence reported by Falconi et al. [19
] in a previous study including only benign diseases was lower, with postoperative DM being reported only in the 14% of cases after DP and in the 18% of cases after PD, respectively [19
]. Similarly, another series, including only benign or low-grade malignant neoplasms, reported a low incidence of postoperative DM (<10%) after a median follow-up of less than two years [35
]. The higher incidence of DM found in the present series is probably related to the longer duration of follow-up, which also represents one of the main strengths of the present study. Various factors have been described as being able to influence the risk of developing endocrine insufficiency: these include the extent of resection, the nature of disease, some patient’s characteristics, and the functionality of the remaining parenchyma [19
In the present series, BMI was found to be the only independent predictor of postoperative DM: specifically, a BMI greater than 25 Kg/m2
increased the risk of developing postoperative DM up to five times. Of note, four out of nine patients submitted to islet autotransplantation developed postoperative DM: all of them had a BMI greater than 25 Kg/m2
. This result corroborates previous findings reporting that increasing BMI is associated to a higher risk of postoperative endocrine insufficiency [20
]. This result confirms the importance of a personalised prehabilitation before surgery in those patients who are overweight or obese. At this regard, the relatively indolent nature of PanNEN allows for safely postponing the day of operation from initial diagnosis. The result here presented is consistent with data from the National Health and Nutrition Examination Surgery (NAHNES) reporting that the prevalence of DM in general population increases with the increasing of BMI class [37
]. According to this survey, the prevalence of DM among normal-weight patients is around 8%, whereas it is reported to almost double (15%) in the overweight patients. The prevalence of DM increases even more in obese patients, attesting itself around 28% [37
]. In the present series, overweight patients developed postoperative DM in 32% of cases (vs. 15% in general population), whereas the rate of DM among obese patients was 38% (vs. 28% in general population). In contrast, normal-weight patients developed postoperative DM in 8% of cases, consistently with data that were reported in general population. Moreover, patients who developed a postoperative DM were more frequently males and had an older age compared to those who did not. Although these findings were not confirmed at multivariate analysis, they represent well-known risk factors for DM and they were also reported by other series as factors that are associated to the development of postoperative DM [19
]. In particular, according to data from the Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes (SHIELD), male patients with a high BMI (≥ 28 Kg/m2
) display a DM prevalence of around 40%, whereas in the present series half of patients with the same characteristics developed DM, which suggested that the pancreatic resection has a role in determining the onset of the disease. Interestingly, no statistically significant differences were found in terms of risk of developing DM between patients submitted to different surgical procedures, even if a trend towards a higher incidence of DM after DP (26%) than after PD (20%) was observed, as previously reported by other series [20
]. Probably, in the present series, the difference between DP and PD failed to reach a statistically significant difference because patients that were submitted to DP had smaller tumors when compared to patients who underwent PD. Consequently, the extent of DP was often limited for sparing parenchyma and preserving its functionality. Various studies have previously reported a lower incidence of postoperative pancreatic impairment after parenchyma-sparing surgery [15
]. In the present series, patients that were submitted to enucleation were excluded in order to focus on partial pancreatic resections; therefore, as only eight patients submitted to atypical resections (middle pancreatectomy or middle-preserving pancreatectomy) were considered, a statistically significant difference in terms of DM development between these subjects and those that were submitted to a formal resection could not be demonstrated. However, when patients also submitted to enucleation were considered for this specific analysis, the rate of postoperative DM was significantly lower (p
= 0.001) in those that were submitted to a parenchyma-sparing surgery (10%) when compared to those who underwent a formal resection (25%).
The occurrence of PEI is another important outcome following pancreatic resection [7
]. PEI is frequently misdiagnosed, as it usually presents with mild or moderate symptoms that may be underestimated, leading to a poor quality of life [8
], micronutrients deficiencies [38
] and decreased survival [10
]. In the present study, the overall incidence of PEI was 43% that is consistent with the rate reported by Lim et al. [39
]. The rate of PEI development that was reported in literature varies between 56% and 98% after PD [7
] and between 19% and 80% after DP [7
]. This wide range is probably due to the different methods that were used to assess pancreatic exocrine function and to the low accuracy of available tests in determining PEI [41
]. Of note, in the present series, exocrine impairment was observed in nearly nine out of 10 patients after PD and this operation was found to be independently associated with an increased risk of PEI. PD has been widely demonstrated to be strongly correlated to PEI [29
]. The higher frequency of PEI after PD is essentially explained by the surgical reconstruction, as it can predispose to a progressive damage of the remaining pancreatic stump [43
], to bile salt malabsorption [44
] and to bacterial overgrowth [7
]. In the present series, a lower rate of PEI among patients submitted to atypical resection could not be demonstrated, as only eight patients undergoing this kind of surgery were included. However, when also patients submitted to enucleation were considered for this specific analysis, the rate of PEI after parenchyma-sparing surgery was significantly lower (2%) than after formal resection (43%). Moreover, a lower preoperative BMI was found to be associated with a higher rate of PEI, as previously reported by Kusakabe et al. [29
]. At this regard, it is possible that patients with a lower preoperative BMI have an undiagnosed preoperative PEI and, consequently, they are more likely to develop an evident PEI after pancreatic resection. Finally, patients who developed high-grade postoperative complications displayed a significantly higher rate of PEI when compared to other patients. However, this association was not confirmed at multivariate analysis, probably because patients with high-grade postoperative complications were the same who underwent PD, which is an independent predictor of PEI development.
Our findings are in partial agreement with the few previous reports that were obtained in smaller series. Neophytou et al. [32
] investigated the postoperative rate of DM and PEI in 92 patients operated for benign tumours, including PanNEN. Factors that were associated with the occurrence of DM were male sex, a BMI > 28 Kg/m2
and metabolic syndrome, whereas factors that were associated with the risk of PEI were preoperative chronic pancreatitis, a BMI < 18.5 Kg/m2
and tumors located in the pancreatic head. Of note, although the role of chronic pancreatitis in the remnant pancreas was not investigated, this is unlikely to be relevant in PanNEN, as patients who undergo pancreatic resection for these neoplasms usually have a normal, non-fibrotic, pancreatic remnant that was not affected by the presence of the tumor. Indeed, PanNEN typically exhibit an expansive evolution rather than an infiltrative growth.
In the present series, DM occurred as a gradual phenomenon, as the majority of patients did not develop it immediately after surgery, but during follow up, over the course of several months or even years, consistently with data that were previously reported by Falconi et al. [19
]. This finding corroborates the fact that the development of DM is not only dependent from the surgical procedure, but even after a pancreatic resection, other factors, such as a BMI > 25 Kg/m2
, strongly contribute to its appearance. In contrast, most of patients developed PEI in the early postoperative period, probably because its occurrence is strictly related to the surgical procedure. As previously pointed out, PD is more frequently associated with PEI and its early occurrence might be related not only to the reduced pancreatic volume, but also to a sudden impairment of pancreatic stimulation, which is physiologically induced by endocrine cells of the resected duodenum [43
]. However, one could speculate that patients that were submitted to PD could experience a worsening of PEI during follow up as the surgical reconstruction associated to PD can predispose to progressive damage and atrophy of the pancreatic stump.
The secondary outcome of the present study was to investigate whether endocrine or exocrine pancreatic insufficiency were associated with disease outcome. We focused on the association with PFS, as the rate of disease-related deaths was low, as expected for surgically treated PanNEN. While DM was not associated with PFS, there was a lower five-year PFS rate in patients who developed PEI. However, when corrected for other prognostic factors at multivariate regression, PEI was not a significant factor.
The overall rate of postoperative DM and PEI observed in the present series is relatively high (24% and 43% for DM and PEI, respectively), and it has been reported that pancreatic impairment might be associated with a significant impact on general health status and on quality of life [7
]. This is one of the reasons in support of an active surveillance management instead of a pancreatic resection for patients that were affected by non-functioning PanNEN ≤ 2 cm without features of aggressiveness [6
The present study has several limitations. The major limit is represented by the retrospective design. Secondly, the diagnosis of PEI was not based on specific tests objectively evaluating the pancreatic function, but on the presence of related signs and symptoms that were cured with pancreatic enzymes replacement treatment. However, the accuracy and feasibility of the available tests are currently debated [41
]. Indirect tests, such as fecal elastase-1, fecal chymotrypsin, and 13C breath test, evaluate the quantitative changes of pancreatic secretion and are less expensive, easier to be performed, but less accurate, compared to direct ones. Direct tests, on the contrary, evaluate directly the secretive production, but, despite their good sensitivity, are invasive, time-consuming, and expensive [41
]. However, the use of both these test after pancreatic surgery is unreliable. Indeed, it has been reported that fecal elastase 1 is not accurate in diagnosing PEI after pancreatic surgery [47
]. 13C breath test has been previously performed to evaluate pancreatic exocrine function in patients that were submitted to pancreatic resection [48
] and it seems to be more accurate than fecal elastase-1 [48
]. However, the validity of 13C breath test is still questionable as a comparison between this test and a gold standard (72 h fecal fats or bicarbonate dosage in pancreatic juice) in patients that were submitted to pancreatic surgery has not been made. Of note, when PD is performed, besides the reduced enzyme output following the removal of pancreatic parenchyma, other factors, such as small bowel bacterial overgrowth, deranged antral grinding, abnormal mixing of food with digestive secretions, abnormal hormonal stimulation, and acidic intraluminal pH, can affect the results [47
]. Moreover, various steps, including gastric emptying time of the tracer, absorption, hepatic circulation, and metabolism, are involved in breath test and some of them might be altered after pancreatic resection [48
]. Regarding direct tests, such as endoscopic aspiration of pancreatic juice, it has to be said that they are invasive and cannot be performed when anatomy is modified by surgical procedures [40
]. Another possible limitation of the present study is represented by the lack of data on the possible role of medical treatments initiated during follow-up for a recurrence of the PanNET, which might have contributed to occurrence of PEI [50
]. However, the rate of PEI occurring after tumor recurrence was 54% in patients that were treated with somatostatin analogues and 69% in patients who did not us them, which suggests that this is not a relevant issue. Finally, a more complete analysis of pancreatic endocrine function with the execution of oral glucose tolerance test (OGTT), dosage of insulin and C-peptide, and calculation of Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) could have been performed, thus adding interesting information regarding glucose metabolism in patients that were submitted to pancreatic resection. However, according to the current American Diabetes Association (ADA) guidelines, either fasting plasma glucose (FPG), 2-h plasma glucose during 75 g OGTT and HbA1c are equally appropriate for diagnosing DM [23
]. In particular, HbA1c seems to have some advantages when compared to both FPG and OGTT, as it is reported to have a greater convenience (as fasting is not required), a greater pre-analytical stability, and fewer perturbations during stress and illness [23
]. This is an important point given the fact that patients who undergo a pancreatic resection are subjected to a severe physical stress, which could easily alter plasma glucose levels.
In conclusion, the present study demonstrated that the risk of postoperative pancreatic endocrine and exocrine insufficiency after surgery for PanNEN is significantly high and patients should be aware of these complications. A personalized prehabilitation should be recommended in those patients with a BMI > 25 kg/m2 for reducing the risk of DM development in the postoperative period. Endocrine and exocrine insufficiency do not seem to influence PFS. Further studies are needed to better elucidate the time of onset and the severity of DM and/or PEI and to assess their impact on quality of life of patients that were surgically treated for PanNEN.