Pancreatic neuroendocrine neoplasms (pNENs), formerly known as islet cell tumors, account for approximately 3% of primary pancreatic tumors. Based on the hormone secretion status and clinical manifestations of patients, they are classified into functional and nonfunctional pancreatic neuroendocrine tumors.
Non-functional pNENs account for about 75%-85%; functional pNENs commonly include insulinoma and gastrinoma, while insulinoma is usually located in the pancreas and gastrinoma is mostly seen in the duodenum or pancreas; the rest of functional pNENs are rare and are collectively called rare functional pancreatic neuroendocrine tumors, including growth inhibitory tumors, pancreatic hyperglycemia, growth hormone tumors, etc.; functional pNENs Functional pNENs account for approximately 20% of pNENs.
Most pNENs are disseminated and non-functional, mostly found due to local pressure symptoms or physical examination of the tumor, and some due to metastases in the liver and other sites, and further examination reveals the primary pNENs lesions. Functional pNENs often present with hormone-related symptoms, such as hypoglycemia, multiple peptic ulcers, diarrhea, etc., and are usually detected earlier clinically.
A small number of pNENs are one of the manifestations of hereditary neuroendocrine tumor syndromes, such as multiple neuroendocrine tumors type I and VonHippel-Lindau syndrome. These patients are usually younger and have a history of other neuroendocrine tumors in their family or in themselves.
The clinical manifestations of pNENs are diverse, and the treatment measures are complicated and long-period. It is recommended to be performed in a multidisciplinary collaborative model with the participation of professionals from pancreatic surgery, endocrinology, diagnostic imaging, endoscopy, medical oncology, interventional medicine, pathology and nursing, and through the whole process of patient diagnosis and treatment. According to the patient’s basic health status, hormone secretion-related clinical symptoms, tumor staging and grading and other information, evidence-based medicine is used to individualize the application of multidisciplinary and multiple therapeutic means in order to achieve the best treatment effect for patients.
I. Staging and grading of pNENs
(A) Grading of pNENs
Grading is done according to the degree of tissue differentiation and cell proliferation activity. The proliferative activity grading is recommended by the number of nuclear schizophrenic images per high magnification and/or Ki-67 positive index, and the grading criteria are shown in Table 1.
(B) Staging of pNENs
The seventh edition of the TNM staging of pNENs published by AJCC in 2010 is recommended (Table 2).
II. Preoperative diagnosis of pNENs
The preoperative diagnosis of pNENs includes qualitative diagnosis and localization diagnosis. Qualitative diagnosis is to clarify the nature of the lesion, and puncture biopsy is a common tool, but for resectable pancreatic tumors, preoperative pathological evidence is not required. pNENs commonly used serological indicators include chromogranin A (CgA) and neuronspecific enolase (NSE), and abnormalities in CgA indicate the presence of neuroendocrine tumors. The elevated levels suggest the possibility of neuroendocrine tumors. Based on the symptoms related to hormone secretion and serum hormone levels, the functional status of functional pNENs can be determined, and the symptomatic treatment of hormone-related symptoms can be guided.
Imaging examinations such as enhanced CT and MRI have important diagnostic value for pNENs, which mostly show early enhancing blood-rich lesions in the arterial phase. For the surgical treatment of pNENs, localization is a key step, which not only can clarify the site of the primary tumor, but also assess the status of the lymph nodes surrounding the tumor and the presence of distant metastases.
The common means of localization examination are: (1) pancreatic enhanced CT and/or MRI; (2) endoscopic ultrasonography; (3) growth inhibitor receptor imaging and 68G-PET-CT; (4) percutaneous transhepatic puncture splenic vein segmental blood sampling; (5) arteriography; (6) intraoperative ultrasound.
III. Surgical treatment of pNENs
Surgery is the main treatment for pNENs, and is the only possible cure for pNENs. The aim of surgery is to strive for RO resection.
(A) Surgical treatment of locally resectable pNENs
1, insulinoma and <2cm non-functional pNENs, can be considered for tumor removal or local resection. For pNENs >2 cm, or with malignant tendency, surgical resection is recommended regardless of whether they are functional or not, including adjacent organs if necessary, and clearing regional lymph nodes. For pNENs in the head of the pancreas, pancreaticoduodenectomy is recommended, and various kinds of pancreatic head resection with preservation of organs can be performed according to the size of the lesion and the extent of local infiltration; for pNENs in the tail of the pancreatic body, distal pancreatectomy with preservation or combined with splenectomy should be performed; for tumors located in the body of the pancreas, segmental pancreatectomy is feasible.
2. For resectable local recurrent lesions, isolated distant metastases or initially unresectable pNENs, when they are transformed into resectable lesions after comprehensive treatment, surgical resection should be considered if the patient’s physical condition allows.
3. It is controversial whether all incidentally discovered non-functional pNENs ≤2 cm need surgical resection, and the choice should be made by weighing the pros and cons according to the location of the tumor, the degree of surgical trauma, the patient’s age, physical condition and the patient’s benefit from surgery.
(ii) Surgical treatment of locally progressive and metastatic pNENs
The imaging evaluation and criteria for locally unresectable pNENs refer to the Pancreatic Surgery Group’s Guidelines for the Diagnosis and Management of Pancreatic Cancer (2014). At present, it is considered that reduction or palliative primary resection does not prolong patient survival, but may be considered in the following cases.
(1) Patients with locally advanced or metastatic G1/G2 grade nonfunctional pNENs, where palliative primary resection is feasible to prevent or treat serious life- and quality-of-life threatening complications such as bleeding, acute pancreatitis, jaundice, and gastrointestinal obstruction.
(2) Reduction surgery for functional pNENs: In patients with functional pNENs, reduction surgery (resection of >90% of the lesions, including metastases) can help control hormone secretion and relieve symptoms associated with hormone overproduction. Normal tissues and organs should be preserved as much as possible during reduction surgery.
(3) Reduction surgery for non-functional pNENs: For non-functional metastatic pNENs, if only unresectable liver metastases are present, resection of the primary foci may be beneficial for the management of liver metastases, and resection of the primary foci may be considered.
(iii) Management of pancreatic lesions in patients with familial neuroendocrine tumor syndrome
For patients with combined MEN-I and VonHippel-Lindau’s syndrome, the timing of surgery and the surgical approach need to be carefully judged preoperatively because multiple lesions are often present in the pancreas. Intraoperative ultrasonography is required to detect all lesions as much as possible. It is recommended to perform distal pancreatectomy + enucleation of the head of the pancreas to preserve part of the pancreatic function as much as possible.
(iv) Cholecystectomy
In patients with progressive pNENs who require long-term treatment with long-acting growth inhibitors after surgery, it is recommended that the gallbladder be removed at the same time as surgery to reduce the risk of cholestasis and cholecystitis, especially in patients with pre-existing combined gallbladder stones.
Preoperative evaluation and preparation of pNENs resection
(A) Preoperative evaluation
Genetic syndromes such as MEN-I and VonHippel-Lindau syndrome need to be excluded, and these genetic disorders require special preoperative preparation, treatment and follow-up strategies. The primary site should be carefully evaluated preoperatively, such as the extent of local tumor invasion, relationship to surrounding organs, lymph node metastases, presence of distant metastases and hormonal secretion status. It is important to assess the risk-benefit ratio of patients undergoing surgery and to develop an individualized surgical plan.
Based on the natural course of neuroendocrine tumors and the relatively slow-growing biological behavior, surgical resection should be abandoned if the risks of surgery outweigh the benefits. Preoperatively, serum CgA and NSE should be checked. Changes in serum CgA level can reflect the metastasis and recurrence of tumor; it also has important predictive value for prognosis; NSE has important value for the follow-up of G3 grade tumor.
(II) Preoperative preparation
Patients with pancreatic hyperglycemia are prone to thrombosis and can be anticoagulated with small molecule heparin. Patients with combined carcinoid syndrome need intravenous infusion of short-acting growth inhibitors before anesthesia to prevent carcinoid crisis.
V. Comprehensive treatment of advanced pNENs
(A) Treatment of pNENs liver metastases
1. The liver is the site where pNENs is most likely to have distant metastases. If the majority of metastases can be removed by surgery (>90% of lesions), the primary and liver metastases can be considered for simultaneous or staged resection. If the tumor is located in the head of the pancreas, it is recommended that the liver metastases be resected first, and then the pancreatic duodenum be resected in a second operation. The following conditions should be met when the liver metastases are to be resected.
(1) Well-differentiated G1/G2 tumor.
(2) No distant lymph node metastasis and extrahepatic metastasis, no diffuse peritoneal metastasis.
(3) No right heart insufficiency. The 5-year survival rate of patients with resected liver metastases is 47%-76%, which is higher than that of unresected patients (30%-40%), but the recurrence rate after resection can reach 76%, and most of them recur within 2 years.
2. Local treatments such as radiofrequency ablation, arterial embolization chemotherapy, and selective internal radiation therapy can be used to control liver metastases, effectively reduce tumor load, and decrease hormone secretion, thus improving the quality of life of patients. There are no prospective clinical studies to prove that local treatments targeting the liver can improve patients’ prognosis, but in clinical practice, these local treatments are usually used in combination with systemic treatments.
3. Liver transplantation: Liver transplantation is one of the means of treating liver metastases from pNENs, but the indications need to be strictly controlled. The indications for liver transplantation are pNENs with unresectable multiple metastases in the liver without extrahepatic metastases and regional lymph node metastases; complete resection of the primary site and biopsy of Ki67<
(B) Drug treatment of metastatic pNENs
1. Growth inhibitors: The objective efficiency of growth inhibitors in the treatment of pNENs is less than 10%, but the disease control rate can reach 50%-60%. A large number of retrospective studies and prospective randomized studies have shown that growth inhibitors can be used for the treatment of slowly progressing pNENs (G1 and G2) and growth inhibitor receptor-positive pNEC (G3), with less adverse effects.
2. Molecularly targeted drugs: Prospective clinical studies have shown that sunitinib and everolimus have better efficacy and tolerability in advanced and metastatic pNENs. Sunitinib is a multi-targeted tyrosine kinase inhibitor; everolimus is an oral mTOR inhibitor, both of which can significantly prolong the tumor progression-free survival of pNENs.
3. Chemotherapy: streptozotocin combined with 5-FU and/or epi-amycin has the strongest evidence for treatment of Gl and G2 pNENs, with objective efficiency rates of 35%-40%. Recent small, retrospective studies suggest that temozolomide alone or in combination with capecitabine is also efficacious in metastatic pNENs. regimens such as 5-Fu or capecitabine in combination with oxaliplatin or irinotecan may also be an option for second-line treatment of pNENs.
Postoperative follow-up and adjuvant therapy
(i) Postoperative follow-up
All pNENs have malignant potential, so long-term follow-up should be performed. For pNENs after radical resection, follow-up every 6-12 months for 10 years is recommended, with review at any time if symptoms appear. For low-risk patients without surgical resection, follow-up should be every 3 months in the first year, then every 6 months for at least 3 years, and annually thereafter.
Patients with pNENs with distant metastases should be followed up every 3-6 months, and those receiving treatment should be followed up for a shorter period accordingly. pNEC patients should follow the follow-up requirements for ductal adenocarcinoma. The follow-up should include at least serum CgA and NSE; imaging examinations such as CT or MRI, and for pNENs expressing growth inhibitor receptor 2a, the follow-up can also be combined with growth inhibitor imaging.
(ii) Adjuvant therapy
There is no high-quality evidence from evidence-based medicine to support that adjuvant therapy such as long-acting growth inhibitors, chemotherapy or molecularly targeted drugs after R0 or Rl resection can benefit patients with pNENs; therefore, adjuvant drug therapy is not recommended to be routinely given to G1 and G2 patients after radical surgery; for patients with high-risk factors for tumor recurrence, such as lymph node metastasis, intravascular cancer thrombus, and positive cut margins, adjuvant therapy can be considered for clinical study. For patients with G3 grade pathology after radical surgery, systemic adjuvant therapy and/or local treatment can be given according to the treatment principles of ductal adenocarcinoma.
(iii) Others
For pNENs with initial combined metastases, if RO resection is obtained for both metastases and primary foci, adjuvant therapy is recommended to prevent recurrence due to the high recurrence rate. However, there is no established protocol for the treatment or drugs to be used, and prospective controlled clinical studies are recommended.