Pancreatic neuroendocrine tumors (P-NETs), or islet cell tumors, arise from pluripotent pancreatic exocrine cells and are relatively uncommon. Their incidence is estimated at fewer than 1 per 100,000 persons per year in Europe and Asia and has increased in recent decades, probably due to modern imaging and endoscopic technologies.
There is no universally accepted definition for their classification. Prognosis differs among different types of P-NETs and their curative treatment is radical resection. Compared to pancreatic adenocarcinoma, P-NETs have a much better prognosis, and therefore long-term postoperative outcomes may be more significant.
P-NETs comprise less than 2% of all pancreatic tumors. They are a very heterogeneous disease due to their origin in different cells. They have been traditionally defined, according to their hormone production into functional (insulinomas, gastrinomas, glucagonomas, VIPomas and somatostatinomas, with their characteristic associated symptoms) or nonfunctional, according to their clinical manifestation into symptomatic or asymptomatic, and according to their histopathologic behavior into indolent and aggressive.
Most patients have a solitary primary tumor but up to 11.7% of cases can present with two or more synchronic lesions.
In up to 60% of cases there is metastatic disease on diagnosis.
Several staging or grading systems are used, with no widely accepted staging system. The ones most frequently used are the following:
- The European Neuroendocrine Tumor Society (ENETS, 2006) classification, based on the TNM stage.
- The American Joint Committee on Cancer classification (AJCC, 2010).
Nevertheless, all these classifications have limitations in predicting patient prognosis. Some studies have attempted to identify prognostic factors. Age, stage and histologic grade are associated with worse survival rates, as are Ki-67 expression and mitotic rate.
Due to their asymptomatic course, nonfunctional tumors tend to be diagnosed later and thus be larger or be at a more advanced stage. This may result in a bias leading to the conclusion that nonfunctional tumors have a worse prognosis.
Lymph node ratio (LNR), calculated using the number of positive regional lymph nodes divided by the number of examined regional lymph nodes, has been shown to be a powerful prognostic factor.
Somatostatin analogues (SSAs) have been increasingly used and have shown to improve symptoms of hormone overproduction. Although they might not alter the natural history of P-NETs, stable disease can be reached even for nonfunctional tumors.
Surgical procedures to treat patients with P-NETs depend on tumor location and size. Tumors are usually divided into small (≤2 cm) and large (>2 cm), and microscopic margins must be at least 1 mm. Both standard pancreatic resection and enucleation can be performed, open or laparoscopically.
- Enucleation: small and superficial tumors with no infiltration of the pancreatic duct can be treated by enucleation, which does not systematically include lymphadenectomy and can be performed laparoscopically.
- Pancreatoduodenectomy: pylorus-preserving or classical Whipple pancreatoduodenectomy can be performed for tumors located in the head of the pancreas.
- Distal pancreatectomy can be performed, with or without splenectomy, for tumors located in the body or the tail of the pancreas.
- Central pancreatectomy is reserved for deep tumors that carry a high risk of pancreatic duct damage if treated by enucleation.
Postoperative complications are described according to the International Study group of Pancreatic Surgery (ISGPS) and Clavien-Dindo grading system.
Pancreatic fistula is classified into grades A, B and C, according to clinical and radiologic characteristics. Grade C pancreatic fistulas persist over 3 weeks, require surgical treatment, and have a considerable morbidity and mortality rate.
The range of surgical procedures and the lack of a uniform definition for “standard resection” make it difficult to analyze postoperative outcomes.
Pancreatic fistula, postoperative bleeding and delayed gastric emptying have been described as early complications. Long-term follow-up can show both exocrine and endocrine insufficiency, when steatorrhea and diabetes mellitus are detected.
A non-dilated pancreatic duct and a soft pancreas are often found in P-NETs, which can lead to an increased pancreatic fistula rate. Tumor location in the head of the pancreas and a BMI > 25 kg/m2 have also been described as risk factors for overall complications after tumor enucleation. A distance of 2-3 mm from the pancreatic duct is a risk factor for pancreatic fistula if an enucleation is performed.
The highest rate of grade B/C pancreatic fistula is found after tumor enucleation, especially in the pancreatic head, with a rate as high as 40%, whereas pancreatic endocrine and exocrine insufficiency are higher after pancreatoduodenectomy and can affect 19% and 55% of patients, respectively.
Even though tumor enucleation is described as a minimally invasive operation, it can carry a higher risk of pancreatic fistula. Therefore, in some cases, laparoscopic tail resection may be safer and faster. The surgical procedure is generally chosen by the surgeon, thus inducing a selection bias. The lack of standardization in treatment and whether small tumors need lymphadenectomy or not, as well as the lack of randomized controlled trials, makes it impossible to reach evidence-based conclusions.
A large database of patients with P-NETs showed that high-risk patients (over 60 years old, male, with tumor location at the head of the pancreas, high histologic grade, advanced AJCC stage, size over 34.5 mm and a LNR over 0.33) had a 5-year recurrence rate of 80.8%, whereas low-risk patients had a recurrence rate of 23.4%.
In summary, P-NETs are relatively uncommon tumors of the pancreas and constitute a heterogeneous disease. Hormone production can help in diagnosis. They have a better prognosis than adenocarcinomas and the only curative treatment is surgery. There is not a widely accepted staging system. Radical resection or enucleation can be performed. Pancreatic postoperative fistula can be seen, especially after enucleation of tumors in the head of the pancreas and close to the pancreatic duct. Tumor size and location, as well as histopathologic behavior, determine both the surgical treatment and prognosis.