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 non-functional pancreatic neuroendocrine neoplasms.
Non-functional pNENs account for about 75%-85%; functional pNENs commonly include insulinoma and gastrinoma, with insulinoma usually located in the pancreas and gastrinoma mostly found in the duodenum or pancreas; the rest of functional pNENs are rare and are collectively called rare functional pancreaticneuroendocrine tumors (RFTs), including growth inhibitory tumors, pancreatic hyperglycemia, growth hormone tumors, etc.; functional pNENs account for about 20% of pNENs.
The majority of pNENs are disseminated and non-functional, mostly found due to local tumor pressure symptoms or physical examination, and some are found as primary pNENs lesions due to metastases in the liver and other sites on further examination. Functional pNENs often present with hormone-related symptoms, such as hypoglycemia, multiple peptic ulcers, diarrhea, etc., and are usually detected early in clinical practice.
A small number of pNENs are manifestations of hereditary neuroendocrine tumor syndromes, such as multiple neuroendocrine neolasia I (MEN-I) and Von Hippel-Lindau syndrome, and these patients are usually younger and have a family or personal history of other neuroendocrine tumors.
The clinical manifestations of pNENs are diverse, and the treatment measures are complex and long-period, so 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 throughout the whole process of patient diagnosis and treatment. Based on the patient’s basic health status, clinical symptoms related to hormone secretion, tumor stage and grading and other information, we apply multidisciplinary and multiple treatments individually based on evidence-based medicine in order to achieve the best treatment effect for patients.
I. Staging and grading of pNENs
(I) Grading of pNENs
Grading is based on the degree of tissue differentiation and cell proliferative activity. The proliferative activity grading is recommended by the number of nuclear schizograms per high magnification and/or Ki-67 positivity index, and the grading criteria are shown in Table 1.
(II) Staging of pNENs
The seventh edition of the TNM staging of pNENs published by AJCC in 2010 is recommended (Table 2).
Preoperative diagnosis of pNENs
The preoperative diagnosis of pNENs includes qualitative diagnosis and localization diagnosis. The 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 neuron specific enolase (NSE), and abnormal elevation indicates 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 are of great diagnostic value for pNENs, which mostly show blood-rich lesions with early enhancement in the arterial phase. For the surgical treatment of pNENs, localization is a key step to identify the primary tumor site and to assess the status of the lymph nodes surrounding the tumor and the presence of distant metastases.
Common means of localization examination are.
(1) Enhanced CT and/or MRI of the pancreas;
(2) Endoscopic ultrasonography;
(3) growth inhibitor receptor imaging and 68G-PET-CT;
(4) Percutaneous transhepatic puncture of the splenic vein for 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.
(a) Surgical treatment of locally resectable pNENs
1. For insulinoma and non-functional pNENs <2 cm, tumor removal or local excision can be considered. For pNENs >2 cm or with malignant tendency, surgical resection is recommended regardless of whether they are functional or not, including adjacent organs and clearing regional lymph nodes if necessary. For pNENs in the head of the pancreas, pancreaticoduodenectomy is recommended, and various types of pancreatic head resection with preservation of organs can be performed according to the size of the lesion and the extent of local infiltration; pNENs in the tail of the pancreatic body should undergo distal pancreatic resection, which can be preserved or combined with splenectomy; tumors located in the body of the pancreas can undergo segmental pancreatectomy.
2. For resectable local recurrent lesions, isolated distant metastases or initially unresectable pNENs, if 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 require surgical resection, and the choice should be made based on the location of the tumor, the degree of surgical trauma, the patient’s age, physical condition and the patient’s benefit from surgery, weighing the pros and cons.
(II) Surgical treatment of locally progressive and metastatic pNENs
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). It is currently believed that reduction or palliative primary resection does not prolong patient survival, but may be considered in the following circumstances.
(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 of non-functional pNENs: In 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.
(C) Management of pancreatic lesions in patients with familial neuroendocrine tumor syndrome
In patients with combined MEN-I and Von Hippel-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 ultrasound is required to detect all lesions as much as possible. Distal pancreatectomy + enucleation of the head of the pancreas is recommended in order to preserve as much of the pancreatic function as possible.
(iv) Cholecystectomy
In patients with progressive pNENs who require long-term treatment with long-acting growth inhibitors, it is recommended to remove the gallbladder at the same time of surgery to reduce the risk of cholestasis and cholecystitis, especially in patients with pre-existing gallbladder stones.
Preoperative evaluation and preparation for resection of pNENs
(A) Preoperative evaluation
Genetic syndromes such as MEN-I and Von Hippel-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 their relatively slow-growing biological behavior, surgical resection should be abandoned if the risks of surgery outweigh the benefits. The change of serum CgA level can reflect the metastasis and recurrence of tumor; it also has an important predictive value for prognosis; NSE has an important value for the follow-up of G3 tumor.
(B) Preoperative preparation
In addition to the conventional preoperative preparation, pNENs surgery is different from other pancreatic surgeries: for patients with functional pNENs, serum hormone levels should be tested and symptoms caused by hormone overproduction should be controlled before surgery; for example, glucose drip should be used to control hypoglycemia in insulinoma; proton pump inhibitors should be used to control diarrhea and ulcer bleeding in gastrinoma; growth inhibitors should be used to control diarrhea and water-electrolyte imbalance in vasoactive intestinal peptide tumor; patients with pancreatic hyperglycemic tumor are prone to thrombosis, so small blood clots can be used. 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
If most of the metastases can be removed by surgery (>90% of the lesions), the primary foci 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 removed first, followed by a second operation to remove the pancreatic duodenum. 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, extrahepatic metastasis, or 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 therapies such as radiofrequency ablation, arterial embolization chemotherapy and selective internal radiation therapy can be used to control liver metastases, effectively reduce tumor load and hormone secretion, thus improving the quality of life of patients. There are no prospective clinical studies to prove that local treatment targeting the liver can improve the prognosis of patients, but in clinical practice, these local treatments are usually applied in combination with systemic treatments.
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<< span="">10% (Ki67<5% has a better prognosis); presence of symptoms that cannot be controlled by drugs and affect the patient's quality of life; and no contraindications to liver transplantation.
(B) drug treatment of metastatic pNENs
1, growth inhibitors: growth inhibitors for the treatment of pNENs objective efficiency of 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 levels) and growth inhibitor receptor-positive pNEC (G3 level), 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.
Chemotherapy: streptozotocin in combination with 5-FU and/or epi-amycin has the best evidence for the treatment of Gl and G2 pNENs, with an objective efficiency of 35%-40%. Recent small, retrospective studies suggest that temozolomide alone or in combination with capecitabine may also be effective in metastatic pNENs. 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 develop. For low-risk patients without surgical resection, follow-up should be every 3 months for 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, or less frequently if they are treated. pNEC patients should be followed up according to the follow-up requirements for ductal adenocarcinoma. Follow-up should include at least serum CgA and NSE, imaging such as CT or MRI, and for pNENs expressing growth inhibitor receptor 2a, combined with growth inhibitor imaging.
(ii) Adjuvant therapy
There is no high-quality evidence to support that adjuvant therapy such as long-acting growth inhibitors, chemotherapy or molecular targeted drugs after R0 or Rl resection can benefit patients with pNENs, so adjuvant drug therapy is not recommended routinely for G1 and G2 patients after radical surgery; clinical studies of adjuvant therapy can be considered for patients with high risk factors for tumor recurrence, such as lymph node metastasis, intravascular cancer thrombus, and positive cut margins. For patients with G3 grade pathology report after radical surgery, systemic adjuvant therapy and/or local treatment can be given according to the treatment principles of ductal adenocarcinoma.