Abstract
Purpose
Metastases of pancreatic neuroendocrine tumors (pNETs) can be found at the time of diagnosis in 20–50% of cases. Small asymptomatic tumors may be left for observation; however, they can metastasize. The aim of the study was to evaluate risk factors for distant and lymph node metastases of pNETs.
Patients and methods
One hundred and fourteen patients with postoperatively confirmed pNET were analyzed retrospectively in a single ENETS Center of Excellence. The relationship between location, size, differentiation of the tumor, and occurrence of lymph node and distant metastases was analyzed.
Results
pNETs’ location was pancreatic head – 38 (33.3%), body or tail – 68 (59.7%), and 8 (7.0%) involved the entire organ. Fifty-six (49.1%) tumors were graded G1, 50 (43.9%) G2, and 8 (7.0%) G3. Seventy-two (63.2%) tumors were ≥2 cm in diameter, and 42 (36.8%) <2 cm. Twenty-two (19.3%) patients had distant metastases and 47 (41.2%) had lymph node metastases. In ≥2 cm tumors distant and lymph node metastases were more frequent (p < 0.05). Distant metastases incidence was significantly higher in distally located tumors (p = 0.01) and in G2 and G3 tumors (p < 0.01). In 9.5% of <2cm tumors, distant metastases were present at diagnosis.
Conclusion
Distant metastases are more often found in larger, distally located pNETs grade G2 and G3, while a higher occurrence of lymph node metastases seems to be associated only with larger tumor size. A considerable number of tumors <2 cm in size have distant metastases already at the diagnosis, which might indicate the need for careful qualification of smaller lesions for observation.
Keywords: pancreas, neuroendocrine tumor, lymphatic metastasis, lymph nodes, pancreatic surgery
Introduction
Pancreatic neuroendocrine tumors (pNETs) account for approximately 30% of gastrointestinal neuroendocrine tumors.1 Most of them are non-functional, while some (mostly insulinomas and gastrinomas) are hormonally active.2 They are slow-growing tumors with a poor prognosis, worse in the presence of distant metastases3,4 and in tumor size >2 cm.5,6 Also, nodal metastasis, poorly differentiated cells, and vascular invasion worsen the prognosis.7 According to the literature, distant metastases are found at the time of tumor diagnosis in 20–50% of cases depending on the degree of tumor differentiation.8,9 Lymph node metastases are observed in approximately 35% of resected pNETs.5 The mean survival time for patients with pancreatic NET is approximately 3.5 years from diagnosis.8
Usually, surgery is the first line of treatment. Depending on the location of the tumor, a pancreatoduodenectomy (for pancreatic head location) or a distal pancreatectomy with or without splenectomy (for pancreatic body and tail location) is performed.2,10 These procedures are extremely challenging and have high morbidity and mortality rates, reaching 2.7% and over 30%, respectively, for pancreatoduodenectomy.11
In recent years, a 7-fold increase in diagnosing of small (<2 cm) hormonally inactive tumors has been observed, and they account for 60–90% of pNETs.1,12 These tumors can be asymptomatic for a long time, and prompt surgery is often not recommended.13 Instead, enucleation or even observation may be applied.2 If enucleation is performed, it is recommended since 2016 to obtain a lymph node for pathology exam, but full lymphadenectomy is not required.13 Avoidance of risky surgery in is tempting, especially in small tumors located in the pancreatic head. However, the presence of lymph nodes or distal metastases also in tumors <2 cm in size can worsen the treatment results. Knowledge of features that elevate the risk of distant or nodal metastases is essential for deciding on patient observation or surgery. The aim of this study was to evaluate the risk factors for distant and lymph node metastasis of pNETs.
Materials and Methods
Material
A retrospective analysis of 114 patients operated on between 2015 and 2020 with a postoperative histopathological diagnosis of pNET was performed. This was a retrospective study of medical records, and all data were fully anonymized before our access. All procedures performed were in accordance with the 1964 Helsinki Declaration and its later amendments. Our study is exempted from institutional review board approval, according to national legislation.
The patients were individually qualified for surgery by the multidisciplinary Neuroendocrine Tumor Board of the European Neuroendocrine Tumor Society (ENETS) Center of Excellence, the Department of Endocrinology and Neuroendocrine Tumors. All surgeries were performed at the Department of Gastrointestinal Surgery, also part of the ENETS Center of Excellence. The diagnosis and surgery were executed according to the ENETS Consensus Guidelines on the treatment of pancreatic neuroendocrine tumors.13,14 The main indications for surgical treatment in tumors <2 cm in size were as follows: symptomatic, hormonally active tumors, tumors with malignant features, eg enlarged lymph nodes in CT. For tumors 1–2 cm in size, the patient’s age and preference were also considered.
Methods
Clinical data of patients (gender, age), type of surgery, size (<2 cm or ≥2 cm), location, histological differentiation of tumors, and occurrence of distant and nodal metastases were analyzed. The association of the analyzed parameters with the occurrence of distant metastases and lymph node metastases was investigated. Tumors were classified according to the 2019 WHO classification15 (Table 1).
Table 1.
2019 WHO Classification of Digestive System Neuroendocrine Tumors15
| Differentiation | Grade | Mitotic Index (Number of Mitoses/2 mm2) | Ki-67 Index | |
|---|---|---|---|---|
| NET, G1 | Well differentiated | Low | <2 | <3% |
| NET, G2 | Well differentiated | Intermediate | 2–20 | 3–20% |
| NET, G3 | Well differentiated | High | >20 | >20% |
| NEC | Poorly differentiated | High | >20 | >20% |
Abbreviations: NET, neuroendocrine tumor; NEC, neuroendocrine cancer; Ki-67, cell proliferation index.
Statistical Analysis
Descriptive analysis was performed. A confidence interval of 95% was used. The distribution of quantitative variables was analyzed. In the case of variables with distribution close to normal, their mean was given; in the case of distribution different from normal, their median was given. Correlation analysis was performed between clinical as well as histopathological parameters and the presence of distant and nodal metastases, where p < 0.05 was considered statistically significant. The chi-square test or Fisher's exact test when needed were used during the analysis of nominal variables. Stratification analysis as well as multivariate and binary regression analysis for nodal and distant metastases were made. All calculations, as well as statistical analysis, were performed in IBM SPSS Statistics 26.
Results
Demographic and Clinical Data
There were more females (55.3%) than males (44.7%) in the study group. The median age was 54.9 years (range 23–80).
In 68 (59.7%) cases, tumors were located in the distal part of the pancreas (body and tail) and 38 (33.3%) in the head. Eight (7.0%) patients had multifocal lesions, out of which 2 had MEN1 syndrome diagnosed preoperatively.
Thirty-two (28.1%) pancreatoduodenectomies were performed, 63 (55.3%) distal pancreatectomies, and 8 (7.0%) total pancreatectomies. Eleven (9.6%) enucleations were also performed, of which 5 (4.4%) with staging lymphadenectomy and 6 (5.3%) without lymphadenectomy (according to the ENETS guidelines present at the time of the surgery). In all enucleated tumors, an intraoperative pathology examination confirmed the removal of the whole tumor. Four enucleated tumors were insulinomas, all were G1. There were 42 (36.8%) tumors <2 cm in diameter and 72 (63.2%) ≥2 cm. Lymph node metastases were found in 47 (41.2%) of patients (N1) and distant metastases were in 22 (19.3%) of patients (M1) (Table 2). 63.2% of tumors of the head of the pancreas had G1 grade. In the peripheral part of the pancreas, 51.5% of the tumors were G2; when the entire pancreas was removed, 62.5% were G1 tumors. The full grading of the tumors is presented in Table 3. The distant metastases were located in the liver in 20 cases (91.0%) and in both liver and bones in 2 patients (9.0%).
Table 2.
Occurrence of Lymph Node and Distant Metastases
| Sex | |
| Male | 51 (44.7%) |
| Female | 63 (55.3%) |
| Median age at diagnosis | 54.9 years (range 23–80) |
| Tumor size | |
| <2 cm | 42 (36.8%) |
| ≥2 cm | 72 (63.2%) |
| Tumor location | |
| Pancreatic head | 38 (33.3%) |
| Pancreatic body or tail | 68 (59.7%) |
| Multifocal lesions in pancreas | 8 (7.0%) |
| Type of surgery | |
| Panreatoduodenectomy | 32 (28.1%) |
| Distal pancreatectomy | 63 (55.3%) |
| Total pancreatectomy | 8 (7.0%) |
| Enucleation | 11 (9.6%) |
| With lymphadenectomy | 5 (4.4%) |
| Without lymphadenectomy | 6 (5.3%) |
| Grade | |
| G1 | 56 (49.1%) |
| G2 | 50 (43.9%) |
| G3 | 8 (7.0%) |
| Lymph nodes metastases | |
| Nx | 8 (7.0%) |
| N0 | 59 (51.8%) |
| N1 | 47 (41.2%) |
| Distant metastases | |
| M0 | 92 (80.7%) |
| M1 | 22 (19.3%) |
Notes: Nx- regional lymph node cannot be assessed, N0 – no regional lymph node metastases, N1- regional lymph node metastases.
Table 3.
Tumor Grading in Different Locations
| Grading | N (%) | Pancreatic Head (N=38) | Pancreatic Body and Tail (N=68) | Multifocal Lesions in Pancreas (N=8) |
|---|---|---|---|---|
| G1 | 56 (49.1%) | 24 (63.2%) | 27 (39.7%) | 5 (62.5%) |
| G2 | 50 (43.9%) | 12 (31.5%) | 35 (51.5%) | 3 (37.5%) |
| G3 | 8 (7.0%) | 2 (5.3%) | 6 (8.8%) | 0 |
Distant Metastases
Among tumors ≥2 cm in diameter, significantly more had distant metastases compared to tumors <2 cm in diameter (18 (25.0%) vs 4 (9.5%); p < 0.05). Tumors located distally also had significantly more distant metastases compared to pancreatic head tumors and multifocal lesions (19 (27.9%) vs 3 (7.9%) and 0 (0%), respectively (p = 0.01)). G2 and G3 differentiation compared to G1 was associated with a higher rate of distant metastasis (13 (26.0%) and 5 (62.5%), respectively, vs 4 (7.1%); p < 0.01) (Table 4). Multivariate, binary regression analysis confirmed the relationship between grading, location of the tumors and distant metastases (G3 differentiation compared to G1, OR = 19.313, p = 0.002; pancreatic body and tail compared to pancreatic head tumors, OR = 4.747, p = 0.036). The multivariate analysis showed a non-significant difference in G2 vs G1 tumors concerning distal metastasis (Table 5, Figure 1).
Table 4.
Relationship of Distant Metastasis to Tumor Size, Location, and Grading
| Distant Metastases | P value | ||
|---|---|---|---|
| Tumor size | <2 cm (n=42) | 4 (9.5%) | p<0.05 |
| ≥2 cm (n=72) | 18 (25.0%) | ||
| Tumor location | Pancreatic head (n=38) | 3 (7.9%) | p=0.01 |
| Pancreatic body and tail (n=68) | 19 (27.9%) | ||
| Multifocal lesions in pancreas (n=8) | 0 (0.0%) | ||
| Grading | G1 (n=56) | 4 (7.1%) | p<0.01 |
| G2 (n=50) | 13 (26.0%) | ||
| G3 (n=8) | 5 (62.5%) | ||
Table 5.
Multivariate, Binary Regression Analysis for Nodal and Distant Metastases
| Odds Ratio | 95% CI for OR – Lower Bound | 95% CI for OR – Upper Bound | Significance | |
|---|---|---|---|---|
| Distant metastasis | ||||
| Tumor size | 2.342 | 0.640 | 8.567 | 0.198 |
| G2/G1 | 2.836 | 0.792 | 10.156 | 0.109 |
| G3/G1 | 19.313 | 2.841 | 131.309 | 0.002 |
| Pancreatic body and tail/pancreatic head | 4.747 | 1.107 | 20.348 | 0.036 |
| Nodal metastasis | ||||
| Tumor size | 4.295 | 1.625 | 11.352 | 0.003 |
Abbreviations: OR, Odds Ratio, Exp(B); CI, Confidence Interval.
Figure 1.
Forrest Plot with Odds Ratios and their Confidence Intervals for Multivariate, Regression Analysis
Lymph Node Metastases
Lymph node metastases were significantly more common in tumors ≥2 cm compared to smaller tumors (39 (54.2%) vs 8 (19.0%); p = 0.02). No relationship was found between tumor location or grading and lymph node metastasis (Table 6). These findings were confirmed in multivariate, binary regression analysis for nodal and distant metastases while controlling for the size of the tumors (Table 5, Figure 1).
Table 6.
Relationship of Nodal Metastasis to Tumor Size, Location, and Grading
| Lymph Node Metastases (N1) | P value | ||
|---|---|---|---|
| Tumor size | <2 cm (n=42) | 8 (19.0%) | p=0.02 |
| ≥2 cm (n=72) | 39 (54.2%) | ||
| Tumor location | Pancreatic head (n=38) | 17 (44.7%) | p>0.05 |
| Pancreatic body and tail (n=68) | 27 (39.7%) | ||
| Multifocal lesions in pancreas (n=8) | 3 (37.5%) | ||
| Grading | G1 (n=56) | 19 (33.9%) | p>0.05 |
| G2 (n=50) | 23 (46.0%) | ||
| G3 (n=8) | 5 (62.5%) | ||
Discussion
The size of asymptomatic pNETs, in which surgical treatment should be applied, remains controversial, especially for tumors 1–2 cm large.6,16–18 It must be noted that even in tumors <2 cm, distant and nodal metastases are found in a considerable number of cases (0–27.3% and 0–9.1%, respectively)11,19,20 and a high degree of histological malignancy can be encountered.5,18 Some authors accept watchful waiting for lesions <1 cm in size and advise resection for larger tumors.21 Observation is considered in small tumors in patients with comorbidities, elevating the surgical risk if no features of malignancy are found in the imaging results.20,21 Also, the patient’s age and preference are considered.19,20,22 Even though routine preoperative biopsy is still under debate, it is recommended by some authors to grade the tumor to avoid the risk of observing a malignant lesion.19 In our study, 42 tumors <2 cm in diameter were removed and in 9.5% of them, distant metastases were present already at the diagnosis.
The required surgical procedures have a high incidence of complications: pancreatoduodenectomy for tumors of the pancreatic head and a slightly safer distal pancreatectomy for tumors in the pancreatic body and tail.23 To lower the operative risk and the postoperative endocrine insufficiency, enucleation is accepted but remains controversial. It may be applied to symptomatic tumors <2 cm in size, preferably insulinomas24,25 and/or with confirmed Ki67%<3%, located >3 mm from the main pancreatic duct, and when no signs of malignancy are visible in the preoperative imaging results.21,26,27 Recurrence rates are similar to the patients undergoing more extensive surgeries.24,25,28,29 In our study, in only 11 cases of small tumors (all were G1, 4 insulinomas), enucleation was performed, in 5 cases with staging lymphadenectomy (as the ENETS guidelines changed in 201613).
Hormonally active pancreatic NETs are usually eligible for surgical treatment. Also, NETs ≥2 cm in size, regardless of location in the pancreas and their hormonal function, are recommended to be removed13,16 because the larger size of NETs is known to have a positive correlation with the clinical stage of the disease and the presence of distant and lymph node metastases.12,17,30–32 Our results confirm these data in both univariate and multivariate analysis (19.0% of tumors <2 cm and 54.2% of tumors ≥2 cm with lymph node metastases). Nevertheless, Mintziras et al in a study of a large group of patients did not find any correlation between the tumor size and the occurrence of metastases in the lymph nodes.33
Distant metastases occur in about 20% of cases, most often in the liver and less often in the bones.3,4 They are 4 times more frequent in tumors ≥2 cm in size.3,5,34 Our study confirmed this data in univariate analysis, as distant metastases were found in 22 (19.3%) patients, in 9.5% of tumors <2 cm, and in 25.0% of tumors ≥2 cm. Twenty (91.0%) cases involved liver, and 2 (9.0%) both liver and bones. Usually, distant metastases are found during the diagnosis of the primary tumor lesion,34,35 however, because our analysis had no follow-up data and only involved distant metastases found at the time of primary lesion diagnosis, the total number of distant metastases is possibly underestimated. This may have an impact on the lack of correlation between the presence of distant metastases and the tumor size in the multivariate analysis.
According to the available literature, as the histologic differentiation of the tumor cells decreases, the incidence of distant metastases increases.4,33 In G3 tumors, this concerns more than 60% of cases.9 These data were confirmed in our study, where for tumors with G1 grade only 7.9% had distant metastasis, and in G2 and G3 tumors, they were found in 26% and 62.5% of cases, respectively. The difference between G3 tumors versus G1 and G2 tumors was statistically significant in univariate and in multivariate analyses. Many studies have reported that poor histologic differentiation correlates with a higher incidence of lymph node metastases.5,30,36 In our study, lymph node metastasis occurred in 33.9%, 46.0%, and 62.5% of G1, G2, and G3 tumors, respectively, with no statistically significant difference. This may be due to the different sizes of study groups in other publications.5,30,36
Pancreatic neuroendocrine tumors are more often found in the distal location (pancreatic body and tail).5,37 According to most publications, the location of NETs in the pancreas has no influence on the presence of distant metastases.38 However, there are recent reports by which distal location is a risk factor for distant metastases.36 In our study, 19 (27.9%) tumors in the distal location compared to 3 (7.9%) tumors located in the pancreatic head had distant metastases and this was found to be a statistically significant difference in univariate and multivariate analyses. In our study group, G2 and G3 tumors were found more often in the distal region. This may be due to the fact that the distally located non-functional tumors longer remain asymptomatic.
Regarding the correlation of NET location in the pancreas with the presence of nodal metastases, the available data are conflicting. Some authors believe that tumor location in the body or tail of the pancreas is a risk factor for metastasis of local lymph nodes.4,36 There are also studies showing a higher incidence of nodal metastasis among pancreatic head NETs.30–32 In our study, we found no significant relationship between tumor location and the presence of lymph node metastases.
Undoubtedly, a limitation of our analysis is the retrospective nature of the study and the moderate size of the study group. The lack of follow-up makes it impossible to supplement the study with survival time and the occurrence of distant metastases is most probably underestimated. However, the collected data indicate important features of pancreatic NETs that should be considered in therapeutic decisions.
Conclusions
Larger tumor size of pNETs is associated with a higher incidence of lymph node metastasis and distant metastasis. G2 and G3 grading of the tumor, as well as its distal location, are also associated with the occurrence of distant metastases; however, these tumor features do not affect the occurrence of lymph node metastases. It is important to note that a considerable number of tumors <2 cm in diameter showed distant metastasis at the diagnosis, which might indicate the need for careful qualification of smaller lesions for observation. Decisions during the therapeutic process should be made on an individual basis, keeping in mind the aforementioned risk factors for distant and lymph node metastasis.
Disclosure
The authors report no conflicts of interest in this work.
References
- 1.Kos-Kudła B, Rosiek V, Borowska M, et al. Pancreatic neuroendocrine neoplasms - management guidelines (recommended by the Polish Network of Neuroendocrine Tumours). Endokrynol Pol. 2017;68:169–197. doi: 10.5603/EP.2017.2016 [DOI] [PubMed] [Google Scholar]
- 2.Scott AT, Howe JR. Evaluation and management of neuroendocrine tumors of the pancreas. Surg Clin North Am. 2019;99(4):793–814. doi: 10.1016/j.suc.2019.04.014 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3:1335–1342. doi: 10.1001/jamaoncol.2017.0589 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Kaltenborn A, Matzke S, Kleine M, et al. Prediction of survival and tumor recurrence in patients undergoing surgery for pancreatic neuroendocrine neoplasms. J Surg Oncol. 2016;113:194–202. doi: 10.1002/jso.24116 [DOI] [PubMed] [Google Scholar]
- 5.Mei W, Ding Y, Wang S, Jia Y, Cao F, Li F. Head and body/tail pancreatic neuroendocrine tumors have different biological characteristics and clinical outcomes. J Cancer Res Clin Oncol. 2020;146:3049–3061. doi: 10.1007/s00432-020-03303-w [DOI] [PubMed] [Google Scholar]
- 6.Regenet N, Carrere N, Boulanger G, et al. Is the 2-cm size cutoff relevant for small nonfunctioning pancreatic neuroendocrine tumors: a French multicenter study. Surgery. 2016;159:901–907. doi: 10.1016/j.surg.2015.10.003 [DOI] [PubMed] [Google Scholar]
- 7.Marchegiani G, Landoni L, Andrianello S, et al. Patterns of recurrence after resection for pancreatic neuroendocrine tumors: who, when, and where? Neuroendocrinology. 2019;108(3):161–171. [DOI] [PubMed] [Google Scholar]
- 8.Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063–3072. doi: 10.1200/JCO.2007.15.4377 [DOI] [PubMed] [Google Scholar]
- 9.Riihimäki M, Hemminki A, Sundquist K, Sundquist J, Hemminki K. The epidemiology of metastases in neuroendocrine tumors. Int J Cancer. 2016;139:2679–2686. doi: 10.1002/ijc.30400 [DOI] [PubMed] [Google Scholar]
- 10.Belotto M, Crouzillard BDNS, Araujo KO, Peixoto RD. Pancreatic neuroendocrine tumors surgical resection. Arq Bras Cir Dig. 2019;32(1):e1428. doi: 10.1590/0102-672020180001e1428 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Lim TY, Leitman IM. Risk factors for early morbidity and mortality following pancreatoduodenectomy with concomitant vascular reconstruction. Ann Med Surg. 2021;68:102587. doi: 10.1016/j.amsu.2021.102587 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Kuo EJ, Salem RR. Population-level analysis of pancreatic neuroendocrine tumors 2 cm or less in size. Ann Surg Oncol. 2013;20(9):2815–2821. doi: 10.1245/s10434-013-3005-7 [DOI] [PubMed] [Google Scholar]
- 13.Falconi M, Eriksson B, Kaltsas G, et al. ENETS Consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology. 2016;103:153–171. doi: 10.1159/000443171 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Falconi M, Bartsch DK, Eriksson B, et al. ENETS consensus guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors. Neuroendocrinology. 2012;95:120–134. doi: 10.1159/000335587 [DOI] [PubMed] [Google Scholar]
- 15.Nagtegaal ID, Odze RD, Klimstra D, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020;76:182–188. doi: 10.1111/his.13975 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Shah MH, Goldner WS, Halfdanarson TR, et al. NCCN guidelines insights: neuroendocrine and adrenal tumors. J Natl Compr Canc Netw. 2018;16:693–702. doi: 10.6004/jnccn.2018.0056 [DOI] [PubMed] [Google Scholar]
- 17.Lopez-Aguiar AG, Ethun CG, Zaidi MY, et al. The conundrum of < 2-cm pancreatic neuroendocrine tumors: a preoperative risk score to predict lymph node metastases and guide surgical management. Surgery. 2019;166:15–21. doi: 10.1016/j.surg.2019.03.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Gratian L, Pura J, Dinan M, Roman S, Reed S, Sosa JA. Impact of extent of surgery on survival in patients with small nonfunctional pancreatic neuroendocrine tumors in the United States. Ann Surg Oncol. 2014;21:3515–3521. doi: 10.1245/s10434-014-3769-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Bar-Moshe Y, Mazeh H, Grozinsky-Glasberg S. Non-functioning pancreatic neuroendocrine tumors: surgery or observation? World J Gastrointest Endosc. 2017;16(9):153–161. doi: 10.4253/wjge.v9.i4.153 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Barenboim A, Lahat G, Nachmany I, et al. Resection versus observation of small asymptomatic nonfunctioning pancreatic neuroendocrine tumors. J Gastrointest Surg. 2020;24:1366–1374. doi: 10.1007/s11605-019-04285-y [DOI] [PubMed] [Google Scholar]
- 21.Perri G, Prakash LR, Katz MHG. Pancreatic neuroendocrine tumors. Curr Opin Gastroenterol. 2019;35:468–477. doi: 10.1097/MOG.0000000000000571 [DOI] [PubMed] [Google Scholar]
- 22.Partelli S, Mazza M, Andreasi V, et al. Management of small asymptomatic nonfunctioning pancreatic neuroendocrine tumors: limitations to apply guidelines into real life. Surgery. 2019;166:157–163. doi: 10.1016/j.surg.2019.04.003 [DOI] [PubMed] [Google Scholar]
- 23.McMillan MT, Christein JD, Callery MP, et al. Comparing the burden of pancreatic fistulas after pancreatoduodenectomy and distal pancreatectomy. Surgery. 2016;159:1013–1022. doi: 10.1016/j.surg.2015.10.028 [DOI] [PubMed] [Google Scholar]
- 24.Heidsma C, Tsilimigras D, van Dieren S, et al. Indications and outcomes of enucleation versus formal pancreatectomy for pancreatic neuroendocrine tumors. HPB. 2021;23:413–421. doi: 10.1016/j.hpb.2020.06.015 [DOI] [PubMed] [Google Scholar]
- 25.Mauriello C, Napolitano S, Gambardella C, et al. Conservative management and parenchyma-sparing resections of pancreatic neuroendocrine tumors: literature review. Int. J Surg. 2015;21(Suppl 1):S10–4. [DOI] [PubMed] [Google Scholar]
- 26.Altimari M, Abad J, Chawla A. The role of oncologic resection and enucleation for small pancreatic neuroendocrine tumors. HPB (Oxford). 2021;23:1533–1540. doi: 10.1016/j.hpb.2021.03.005 [DOI] [PubMed] [Google Scholar]
- 27.Howe JR, Merchant NB, Conrad C, et al. The North American neuroendocrine tumor society consensus paper on the surgical management of pancreatic neuroendocrine tumors. Pancreas. 2020;49:1–33. doi: 10.1097/MPA.0000000000001454 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Sadot E, Reidy-Lagunes DL, Tang LH, et al. Observation versus resection for small asymptomatic pancreatic neuroendocrine tumors: a matched case-control study. Ann Surg Oncol. 2016;23:1361–1370. doi: 10.1245/s10434-015-4986-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Doi R. Determinants of surgical resection for pancreatic neuroendocrine tumors. J Hepatobiliary Pancreat Sci. 2015;22:610–617. doi: 10.1002/jhbp.224 [DOI] [PubMed] [Google Scholar]
- 30.Curran T, Pockaj BA, Gray RJ, Halfdanarson TR, Wasif N. Importance of lymph node involvement in pancreatic neuroendocrine tumors: impact on survival and implications for surgical resection. J Gastrointest Surg. 2015;19:152–160. doi: 10.1007/s11605-014-2624-z [DOI] [PubMed] [Google Scholar]
- 31.Postlewait LM, Ethun CG, Baptiste GG, et al. Pancreatic neuroendocrine tumors: preoperative factors that predict lymph node metastases to guide operative strategy. J Surg Oncol. 2016;114:440–445. doi: 10.1002/jso.24338 [DOI] [PubMed] [Google Scholar]
- 32.Hashim YM, Trinkaus KM, Linehan DC, et al. Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs). Ann Surg. 2014;259:197–203. doi: 10.1097/SLA.0000000000000348 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Mintziras I, Keck T, Werner J, et al. Indications for resection and perioperative outcomes of surgery for pancreatic neuroendocrine neoplasms in Germany: an analysis of the prospective DGAV StuDoQ|Pancreas registry. Surg Today. 2019;49(12):1013–1021. doi: 10.1007/s00595-019-01838-1 [DOI] [PubMed] [Google Scholar]
- 34.Wang DS, Zhang DS, Qiu MZ, et al. Prognostic factors and survival in patients with neuroendocrine tumors of the pancreas. Tumour Biol. 2011;32:697–705. doi: 10.1007/s13277-011-0170-9 [DOI] [PubMed] [Google Scholar]
- 35.Zhang Z, Liu M, Ji S, et al. Prognostic value and clinical predictors of lymph node metastases in pancreatic neuroendocrine tumors. Pancreas. 2020;49:381–386. doi: 10.1097/MPA.0000000000001493 [DOI] [PubMed] [Google Scholar]
- 36.Vega EA, Kutlu OC, Alarcon SV, et al. Clinical prognosticators of metastatic potential in patients with small pancreatic neuroendocrine tumors. J Gastrointest Surg. 2021;25(10):2593–2599. doi: 10.1007/s11605-021-04946-x [DOI] [PubMed] [Google Scholar]
- 37.Beane JD, Borrebach JD, Billderback A, et al. Small pancreatic neuroendocrine tumors: resect or enucleate? Am J Surg. 2021;222(1):29–34. doi: 10.1016/j.amjsurg.2020.12.013 [DOI] [PubMed] [Google Scholar]
- 38.Badarna M, Percik R, Aharon-Hananel G, Uri I, Tirosh A. Anatomic site as prognostic marker of pancreatic neuroendocrine tumors: a cohort study. Eur J Endocrinol. 2019;181(3):325–330. [DOI] [PubMed] [Google Scholar]