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The Chinese guidelines for the diagnosis and treatment of pancreatic neuroendocrine neoplasms (2020)

Wu, Wenminga; Chen, Jieb; Bai, Chunmeic; Chi, Yihebalid; Du, Yiqie; Feng, Shitingf; Huo, Lig; Jiang, Yuxinh; Li, Jingnani; Lou, Wenhuij; Luo, Jiek; Shao, Chenghaol; Shen, Linm; Wang, Fengn; Wang, Liweio; Wang, Oup; Wang, Yuq; Wu, Huanwenr; Xing, Xiaopingp; Xu, Jianmings; Xue, Huadant; Xue, Lingu; Yang, Yangv; Yu, Xianjunw; Yuan, Chunhuix; Zhao, Hongy; Zhu, Xiongzengz; Zhao, Yupeia,∗; on behalf of the Chinese Pancreatic Surgery Association

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doi: 10.1097/JP9.0000000000000064
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Abstract

Introduction

Neuroendocrine neoplasms (NENs) are relatively rare, with the pancreas being one of the most affected sites. In recent years, the incidence of pancreatic neuroendocrine neoplasms (pNENs) has increased significantly along with its detection rate due to the liberal use of imaging modalities, the advancements in diagnostic technologies, and the popularization of physical examinations. Moreover, with the progressively enhanced understanding of this disease, the diagnosis and treatment of pNENs have also been largely improved.

pNENs have insidious onsets with highly heterogeneous biological behaviors. pNENs can manifest via inert growth, invasive growth, or even early metastasis, and their biological characteristics may also change with disease progression. Clinically, pNENs can be sporadic or hereditary depending on their genetic features, and can be functional or nonfunctional according to the corresponding endocrine-related symptoms, or syndromes induced by the hormone-secreting tumors. Additionally, the prognoses of pNENs vary considerably amongst different grades or stages of the disease. Therefore, the diagnosis and treatment strategies for pNENs should be comprehensive and holistic.

Based on the concept of evidence-based medicine and multiple disciplinary treatment (MDT), the Group of Pancreatic Surgery of the Chinese Society of Surgery of the Chinese Medical Association, together with experts in the related fields, compiled this guideline jointly. We hope to provide the most reasonable diagnosis and treatment approaches to Chinese pNENs patients while taking China's national conditions into consideration.

Grading and staging

Definitions

Generally, pNENs are considered as a group of tumors with neuroendocrine differentiation and express neuroendocrine markers. pNENs are relatively rare, accounting for approximately 2% to 5% of all pancreatic tumors.[1] Histopathologically, pNENs can be divided into well differentiated neuroendocrine tumor (NET), poorly differentiated neuroendocrine carcinoma (NEC), and mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN).[1] From a clinical perspective, pNENs can be classified as functional or nonfunctional based on whether the patient has hormone-related symptoms corresponding to tumor secretion, and can also be divided into sporadic and hereditary pNENs based on the patient's family history and the genetic characteristics of the tumor.

The incidence of pNENs increases evidently[2–4] with approximately 0.8/100,000 people/year in the United States[3] and 1.27/100,000 people/year in Japan.[5] Studies in China have shown that pNENs account for the highest proportion of digestive NENs and that the age group with the highest prevalence of pNENs is 40–70 years old. Most patients are asymptomatic at the initial diagnosis (approximately 69.6%).[4,6] Furthermore, most pNENs in Chinese patients are sporadic (approximately 90.3%) and nonfunctional (approximately 65.6%), while about 34.4% of all cases are functional pNENs, of which around 94.8% are insulinomas. And the incidence of G1, G2, and G3 pancreatic neuroendocrine tumors (pNETs) are approximately 49.2%, 45.7%, and 5.1%, respectively.[6]

Pathological classification

The 2019 World Health Organization (WHO) Classification of Digestive System Tumors (5th edition) is the recommended system for the identification of differentiation and proliferation activity of pNENs, and proliferation activity should be measured by both mitotic count and Ki-67 proliferation index (Table 1).[1] If the diagnosis is ambiguous, immunohistochemical markers such as TP53, RB1, DAXX, and ATRX can help to identify whether a tumor is a well-differentiated NET (expected phenotype: TP53− RB1+ DAXX+/− ATRX+/−) or poorly differentiated NEC (expected phenotype: TP53+ RB1− DAXX+ ATRX+).[1]

Table 1 - 2019 WHO classification and grading criteria for pancreatic neuroendocrine neoplasms
Terminology Differentiation Grade Mitotic count (/2 mm2) Ki-67 index
NET, G1 Well differentiated Low <2 <3%
NET, G2 Intermediate 2–20 3–20%
NET, G3 High >20 >20%
NEC, small-cell type (SCNEC) Poorly differentiated High >20 >20%
NEC, large-cell type (LCNEC) >20 >20%
MiNEN Well or poorly differentiated Variable§ Variable§ Variable§
LCNEC = large-cell NEC, MiNEN = mixed neuroendocrine-non-neuroendocrine neoplasm, NEC = neuroendocrine carcinoma, NET = neuroendocrine tumor, SCNEC = small-cell NEC.
Mitotic count is denoted as the number of mitoses/2 mm2 (equalling 10 high-power fields at 40 × magnification and a diameter of 0.5 mm in each ocular field) by counting 50 fields of 0.2 mm2; the Ki-67 proliferation index was obtained by counting at least 500 cells in highly labeled regions (hot-spots); the final grade is that from whichever of the 2 indexes placed the neoplasm in a higher grade category.
Mitotic count and Ki-67 index of NET G3 have no upper limit because the Ki-67 index for NET G3 (especially pNET G3) can occasionally be as high as 70%–80%. Therefore, NETs cannot be graded based on the Ki-67 index solely, but also depend on the morphological features such as well-differentiated. For indistinguishable NET G3 and NEC, immunohistochemical staining of TP53, RB1, ATRX, and DAXX should be performed to facilitate identification.
NECs are defined as high-grade level and further grading is unnecessary.
§In most MiNEN, both neuroendocrine and non-neuroendocrine components are poorly differentiated, and the proliferation index for the neuroendocrine components is consistent with that for other NECs. However, both of these 2 components can also be well differentiated, and they should be graded separately in this case. There are 4 subtypes of pancreatic MiNENs: mixed ductal carcinoma-NEC (SCNEC or LCNEC), mixed ductal adenocarcinoma-NET, mixed acinar cell carcinoma-NEC (distinct components), and mixed acinar cell carcinoma-ductal carcinoma-NEC (distinct components).

Staging

The 2017 American Joint Committee on Cancer (AJCC) Staging Manual (8th edition) is recommended (Tables 2 and 3) for pNETs staging, indicating that pNECs should be staged according to the corresponding standards for pancreatic cancer.[7] In addition, a modified staging criteria proposed by Chinese scholars has been shown to be more suitable for prognostic stratification of pNET patients and can be used as a reference in clinical practice.[8]

Table 2 - 2017 AJCC TNM staging system for pancreatic neuroendocrine tumors
T Primary tumor
 TX Primary tumor cannot be assessed
 T1 Tumor limited to the pancreas, <2 cm
 T2 Tumor limited to the pancreas, 2–4 cm
 T3 Tumor limited to the pancreas, >4 cm or invading the duodenum or common bile duct
 T4 Tumor invading adjacent organs (stomach, spleen, colon, and adrenal gland) or the wall of large vessels (celiac axis or superior mesenteric artery)
N Regional lymph nodes
 NX Regional lymph nodes cannot be assessed
 N0 No regional lymph node metastasis
 N1 Regional lymph node metastasis
M Distant metastasis
 M0 No distant metastasis
 M1 Distant metastases
  M1a Metastasis confined to the liver
  M1b Metastasis in at least one extrahepatic site (lung, ovary, nonregional lymph node, peritoneum, bone, etc)
  M1c Both hepatic and extrahepatic metastases
For patients with multiple primary tumors, the largest tumor should be used to assign T staging. Use T(#) if the number of primary tumors is known, e.g., pT3(4) N0 M0; Use T(m) if the number of primary tumors is unavailable or numerous, e.g., pT3(m) N0 M0.
Limited to the pancreas is defined as the absence of tumor invasion of adjacent organs (stomach, spleen, colon, adrenal gland, etc) or the wall of large blood vessels (celiac axis or superior mesenteric artery). Tumor invasion of peripancreatic adipose tissue is not a basis for staging.

Table 3 - 2017 AJCC prognostic stage groups
T N M
Stage I T1 N0 M0
Stage II T2 N0 M0
T3 N0 M0
Stage III T4 N0 M0
Any T N1 M0
Stage IV Any T Any N M1

Clinical manifestations and classification

pNENs are highly heterogeneous (Table 4) tumors that can be classified as functional or nonfunctional depending on whether it induces endocrine-related symptoms. Functional and nonfunctional pNENs account for approximately 34% and 66% of all pNENs, respectively. Also, pNENs can be classified as sporadic or hereditary based on the onset behaviors of multifocal tumors or disorders and the genetic characteristics of tumors. Sporadic and hereditary pNENs account for approximately 90% and 10% of all pNENs, respectively.[6]

Table 4 - Clinical classifications and characteristics of pNENs
Type Incidence (×106/yr) Hormone secretion Tumor site Malignancy (%) Main symptoms
Functional pNENs
 Insulinoma 1–32 Insulin Pancreas 5–10 Hypoglycemia
 Gastrinoma 0.5–21.5 Gastrin Duodenum, pancreas 50–60 Diarrhea, abdominal pain, acid reflux
 Glucagonoma 0.01–0.1 Glycan Pancreas 50–80 Necrolytic migratory erythema, anemia, glucose intolerance, weight loss
 Somatostatinoma Rare Somatostatin Pancreas, duodenum, and jejunum 50–60 Diabetes, cholelithiasis, and diarrhea
 ACTH-producing NET Rare ACTH Pancreas >90 Cushing syndrome
 VIPoma 0.05–0.2 VIP Pancreas 40–80 Watery diarrhea, hypokalemia
Nonfunctional pNENs May have excessive hormones but do not cause clinical symptoms Pancreas 60–90 Nonspecific symptoms caused by tumor occlusion, invasion, or metastasis, such as gastrointestinal obstruction, bleeding, abdominal pain, jaundice, etc
Data are sourced from the references[5,10,11,15,20,21].ACTH: adrenocorticotropic hormone; NET: neuroendocrine tumor; pNET: pancreatic NET; VIP: vasoactive intestinal peptide.

Functional pNENs

Insulinoma is the most common functional pNEN, followed by gastrinoma.[5,6] Other functional pNENs are often referred to as rare functional pancreatic neuroendocrine tumors (RFTs), which mainly include somatostatinoma, glucagonoma, vasoactive intestinal peptide tumor (VIPoma), serotonin-producing neuroendocrine tumor, adrenocorticotropic hormone (ACTH)-producing neuroendocrine tumor, and corticotropin-releasing hormone (CRH)-producing neuroendocrine tumor. Normally, functional pNENs are easy to diagnose, since patients with functional pNENs exhibit symptoms caused by excessive hormone secretion, such as hypoglycemia, hyperglycemia, necrolytic migratory erythema, multiple peptic ulcers, diarrhea, and hypokalemia. Some functional pNENs can secrete different hormones simultaneously or sequentially, resulting in more complicated clinical manifestations.[9]

Insulinoma

Insulinoma, also known as pancreatic islet beta-cell tumor, is the most common functional pNEN.[6] The vast majority of insulinomas are unifocal and sporadic, and approximately 4% of insulinomas are multifocal and associated with multiple endocrine neoplasia type 1 (MEN1). In addition, most insulinomas are small (<2 cm, 82%) and located in the pancreas (>90%), with similar incidences in the pancreatic head, body, and tail.[10,11] The malignancy of insulinoma is low, and the occurrences of local invasion and distant metastasis range from 5% to 10%. However, malignancy increases drastically for metastatic insulinomas, with patient prognosis no more favorable than that of nonfunctional pNENs and other functional pNENs.[12]

Insulinoma is characterized by the abnormal secretion of a large amount of insulin leading to paroxysmal neuroglycopenic symptoms, which include a series of autonomic and central nervous system symptoms. Autonomic symptoms include adrenergic symptoms (such as palpitation and tremor) and cholinergic symptoms (such as sweating, hunger, and paresthesia). Central nervous system symptoms mainly include confusion, anxiety, cognitive dysfunction, blurred vision, seizures, transient loss of consciousness, and hypoglycemic coma. The typical clinical manifestation of insulinomas is the Whipple triad.[13] If a patient presents with paroxysmal neuroglycopenia (such as coma and neurological symptoms), blood glucose lower than 2.8 mM at each episode, and immediate relief of symptoms after oral or intravenous glucose supplementation, the diagnosis of insulinoma should be strongly suspected, and further examinations should be performed to confirm the diagnosis.

Gastrinoma

Gastrinoma is the second most common functional pNEN.[6] Most gastrinomas are sporadic, and MEN1-associated gastrinomas are usually multifocal.[14] Although gastrinomas can be located in any part of the pancreas, the vast majority of them occur in the gastrinoma triangle, that is, the triangular area enclosed by the junction of the cystic duct and the common bile duct, the junction of the pancreatic head and pancreatic neck, and the junction of the descending and horizontal part of the duodenum.[15]

Gastrinoma is characterized by the secretion of a large amount of gastrin, which sequentially stimulates the excessive secretion of gastric acid, resulting in Zollinger-Ellison syndrome (ZES). The common manifestations of gastrinoma (ZES) include acid reflux, heartburn, nausea, vomiting, weight loss, refractory peptic ulcers, ulcer-related recurrent abdominal pain, and gastric-acid-stimulated diarrhea.[11,15] Diarrhea, specifically watery diarrhea, is one of the characteristic manifestations of gastrinoma, which can be found in approximately 70% of patients. Diarrhea can be accompanied by peptic ulcers or be the only clinical manifestation of gastrinomas.[16] Most symptoms of gastrinoma can be significantly improved by taking proton pump inhibitors (PPIs) or other antacids but can be recurrent after the withdrawal of the medication.

Nonfunctional pNENs

The onset of nonfunctional pNENs is more insidious. Some nonfunctional pNENs can also secrete small amounts of hormones while insufficient to cause endocrine-related symptoms. Patients may present with nonspecific symptoms upon first visit, such as abdominal distension, abdominal pain, gastrointestinal obstruction, and gastrointestinal bleeding, which are caused by tumor compression of the pancreaticobiliary duct and even by the invasion of peripancreatic organs. pNENs in the pancreatic head can cause biliary obstruction and subsequently lead to jaundice, and pNENs in the pancreatic tail can cause regional portal hypertension. Metastasis-induced symptoms can even be the primary manifestation in a small number of patients. Usually, whether patients with nonfunctional pNENs have concomitant symptoms at initial diagnosis can indicate the biological behavior of tumors.[17] In recent years, an increasing number of nonfunctional pNENs have been screened out and diagnosed at their early stages, owing to the advancements in examination techniques and the popularization of physical examinations.

Hereditary pNENs

pNEN can be an important manifestation of hereditary tumor syndrome, and such pNENs are often referred to as hereditary pNENs. Characteristically, patients with hereditary pNENs are often younger (20–40 years old) and with multifocal nonfunctional tumors; in contrast, functional pNENs are usually gastrinomas and insulinomas.[14]

pNENs-concomitant hereditary tumor syndromes commonly include MEN1 (approximately 80% are associated with pNENs), Von Hippel-Lindau syndrome (VHL syndrome, approximately 10% to 17% are associated with pNENs), neurofibromatosis type 1 (NF1, <10% are associated with pNENs), and tuberous sclerosis complex (TSC, rarely associated with pNENs).[18] MEN1 is the most common hereditary tumor syndrome with a prevalence of approximately 1 to 10/100,000. These patients are characterized by parathyroid hyperplasia (approximately 98%), pNENs (approximately 50%), and pituitary adenomas (approximately 35%); some may also have neoplasms in the adrenal gland and thymus.[18,19]

Diagnosis

Clinical characteristics

Patients with functional pNENs often have clinical symptoms or signs caused by excessive hormone secretion. For example, insulinoma can cause the Whipple triad, and glucagonoma can cause necrolytic migratory erythema. ACTH-producing NET can cause Cushing syndrome, which typically manifests as moon face, buffalo hump, purple stretch marks on the skin, etc. Most patients with nonfunctional pNENs lack specific symptoms, and the first manifestations are often nonspecific symptoms caused by tumors compression, invasion to adjacent organs, and distant metastases. Patients with hereditary pNENs are often younger, with a family history of certain tumors, and concomitant with other tumors or disorders.

Peripheral blood biomarker examinations

Serum/plasma chromogranin A (CgA) is the most important tumor marker that has been commonly used for NENs. It can not only be used to assist the diagnosis, but also to evaluate treatment efficacy and patient prognosis.[22,23] The sensitivity and specificity of CgA for NENs diagnosis have been reported as 73% and 95%, respectively.[22] The combined detection of CgA and pancreatic polypeptide (PP) can further improve diagnostic sensitivity.[24] However, the diagnostic efficacy of CgA can be affected by characteristics of the tumor, such as the classification, location, differentiation, tumor burden, and functionality. Other variables such as patient clinical condition and laboratory test method may also influence the result.[25,26] For example, the diagnostic accuracy of CgA for NECs is low,[27] the elevation of CgA levels in insulinoma is indistinctive,[28] and patients with PPIs administration history or combined with hypertension, renal insufficiency, or liver cirrhosis will have falsely elevated CgA.[26] Therefore, the application and interpretation of CgA in clinical practice should be cautious and comprehensive.

Neuron-specific enolase (NSE) is significantly elevated in some high-grade NETs or NECs patients. Meanwhile, the baseline and posttreatment change of NSE are correlated with patient prognosis, which may contribute to the diagnosis and follow-up of patients with NECs and advanced high-grade NETs.[29,30] Serum procalcitonin (PCT) levels are usually elevated in patients with G3 NETs and NECs and are closely related to treatment efficacy and patient prognosis, thus it can be used for disease monitoring.[31] AFP, CEA, CA125, CA19-9, and some other tumor markers are also elevated in high-grade pNENs patients, which may indicate tumor metastasis, recurrence, and poorer prognosis.[32] In addition, the NETest, a newfashioned biomarker using peripheral blood mRNA-sequencing and analysis technique, which not only has excellent diagnostic accuracy for NENs (95% to 96%) but also has outstanding performance in efficacy monitoring, may replace the traditional biomarkers in the future.[33]

Laboratory examinations for functional pNENs

When diagnosing a functional pNEN, examinations of biochemical indicators, hormones, and even stimulation tests should be used properly, according to the suspected tumor type.

For patients suspected to have insulinoma, at the time when blood glucose is ≤3.0 mM (or ≤55 mg/dL), if insulin level is >3 mcIU/mL, C-peptide concentration is ≥0.6 ng/mL, and proinsulin is ≥5 pM, the diagnosis of endogenous hyperinsulinemic hypoglycemia (EHH) can be confirmed. If necessary, a 72-hour fasting test can be performed to further confirm the diagnosis of insulinoma. Importantly, differential diagnosis of other hypoglycemia-causing diseases is indispensable, such as insulin autoimmune syndrome (IAS), nesidioblastosis, and other non-insulin-induced hypoglycemia (e.g., adrenal insufficiency, malnutrition).[34]

For patients suspected of gastrinoma, if fasting serum gastrin (FSG) is >10-fold elevated and gastric pH is ≤ 2, the diagnosis of gastrinoma can be made. If the patient also suffers from refractory peptic ulcers and other typical symptoms such as diarrhea, ZES can be diagnosed.[35] However, for patients with gastric pH ≤ 2 while FSG < 10-fold elevated (approximately 60% of gastrinoma patients), other examinations should be performed. The basal acid output[36] or secretion stimulation tests (such as secretin testing and the calcium infusion provocative test) should be measured or conducted to assist the diagnosis (2A, II; see Appendix 1).[37] Since PPIs can increase the FSG level, the medication should be stopped at least 1 week before the examination. However, the timing of drug withdrawal should be carefully evaluated to avoid the aggravation of peptic ulcers, which may further lead to gastrointestinal bleeding or perforation.[38] In addition, parathyroid hormone, serum calcium, and prolactin should also be measured for all gastrinoma patients at their initial diagnosis and during the follow-up to exclude MEN1.

For other RFTs, the corresponding hormones or tests should be assessed according to the clinical symptoms of patients. For example, the glucagon level should be measured when glucagonoma is suspected; the plasma ACTH, 24-hour urinary free cortisol, circadian rhythm of adrenal glucocorticoid, and dexamethasone suppression test should be assessed when ACTH-producing NET is suspected.

Imaging examinations

Imaging examinations are crucial for the diagnosis, localization, staging, and response evaluation and can assist the qualitative and differential diagnosis of pNENs. Each type of imaging examination has its advantages. By using different examinations complementarily, the diagnostic accuracy of pNENs can be greatly improved and the therapeutic and follow-up plans can be developed more appropriately. Commonly used imaging examination methods include computed tomography (CT), magnetic resonance imaging (MRI), conventional ultrasound (US), contrast-enhanced ultrasonography (CEUS), endoscopic ultrasound (EUS), intraoperative ultrasound (IOUS), somatostatin receptor imaging (SRI), positron emission tomography-computed tomography (PET-CT), and selective angiography (SAG).

Multiphasic enhanced CT is important for the diagnosis and staging of pNENs and can be used preferentially for most patients. The average diagnostic sensitivity and specificity of multiphasic enhanced CT for primary sites are 82% and 96% (84% and 92% for hepatic metastases), respectively.[39] In addition, CT also plays an important role in predicting the pathological grade and in assessing the response efficacy of pNENs.[40–43] Radiomic analysis based on enhanced CT imaging and clinical information has robust performance in predicting the pathological grade of pNENs.[42,44] The imaging signatures and peri-treatment variations of pNENs on CT are also important for response assessment and prognosis evaluation.[40,43] Insulinomas are usually small and with variable enhancement patterns,[45] and approximately 24.9% of insulinomas are isoattenuating in contrast-enhanced CT.[46] In contrast, the whole-pancreas perfusion CT can help capture the transiently enhanced tumors and also locate the isoattenuating tumors. The combination of contrast-enhanced CT and perfusion has a sensitivity and specificity of 94.6% and 94.7% in diagnosing insulinomas, respectively. The performance is superior to those of contrast-enhanced CT only, but has the drawback of increased dosage of radiation, contrast agent, and scan time.[47] However, the mean temporal images constructed from perfusion CT have higher diagnostic efficacy and comparable or superior image quality for insulinomas than that from traditional bi-phasic CT, and hopefully can be used alone in diagnosis.[48] Moreover, perfusion CT can also reflect the angiogenesis of pNENs, which is correlated to patient prognosis.[49] For patients allergic to contrast agent and those with low creatinine clearance rate (< 30 mL/min), other imaging examinations can be used; for multifocal pNENs (such as MEN1) and NENs that usually accompanied extrapancreatic lesions (such as gastrinoma), other auxiliary examination methods should be used for full evaluation.

MRI and diffusion-weighted imaging (DWI) are also effective methods to identify, diagnose, and evaluate pNENs. Since MRI has a relatively high detection rate for small pNENs and hepatic metastases, it can be used as a supplementary method to CT. MRI (including DWI) has a comparable detection rate for insulinoma to that of perfusion CT, but demonstrates higher tumor conspicuity and depicts a better correlation between tumor and pancreatic duct.[50] Compared to the full field-of-view DWI, the reduced field-of-view has further improved the detection rate for insulinoma, especially for smaller ones (<1.5 cm).[51] Meanwhile, MRI also has high sensitivity in diagnosing gastrinoma.[52] In terms of disease assessment, MRI has practical value in predicting lymph node metastasis of pNENs preoperatively.[53] And the application of hepatocellular-specific contrast agents can further improve the detection rate of MRI for liver metastases.[54] Moreover, MRI can also be used preferentially for patients with suspected brain or bone metastases.

The efficacy of conventional ultrasound can be easily affected by many factors, so its diagnostic value for pNEN primary site is limited. However, it still has preferable sensitivity and specificity for liver metastases.[55] CEUS is sensitive to perfusion, thus it can assist the diagnosis and differential diagnosis of pNENs[56] and can also improve the diagnostic accuracy of biopsy.[57] EUS is one of the most sensitive examinations for pNENs with the mean detection rate of 86%,[39] and also has differential diagnostic value,[58] thus is preferentially recommended in pNENs evaluation. For some insulinomas and gastrinomas that are difficult to localize, a careful scan by EUS of the pancreatic and duodenal region of the patient is recommended. Additionally, EUS-guided fine-needle aspiration (EUS-FNA) biopsy is crucially important for diagnosing pNENs,[59] and EUS-guided interventional therapy and submucosal resection is an effective treatment for small pNENs or pNENs that are located at certain sites (such as the duodenum) (2A, II).[60,61] Besides, EUS can help assess the relationship between the tumor and the pancreatic duct and adjacent vessels, and subsequently to evaluate the surgical feasibility and guide the surgical approach. IOUS also has an excellent detection rate for pNENs, but it is mainly used in rescreening and excluding multifocal pNENs during surgery, as well as for locating the tumor accurately during enucleation to avoid pancreatic duct damage.[62]

SRI, including the somatostatin receptor scintigraphy (SRS) and the positron emission tomography/computed tomography (PET/CT) using 68Ga-labeled somatostatin analog (SSA), is very important in diagnosing G1/G2 pNETs (2A, I), and can also be used in diagnosing some G3 pNETs (2A, II). SRI may detect lesions that are less conspicuous on CT and MRI, thus plays a special role in the systemic assessment of tumors, excluding extrapancreatic lesions, and formulating therapeutic regimens.[63] PET/CT using 68Ga-SSA (including DOTA-TATE, DOTA-NOC, DOTA-TOC, etc) can significantly improve the diagnostic sensitivity for NETs. Conventional SRI has relatively low sensitivity for insulinomas, while the glucagon-like peptide 1 receptor (GLP-1R) can be used as a target to improve the detection rate (2A, II).[64]18F-FDG PET-CT is less sensitive in diagnosing proliferation-inactive pNETs (usually G1/G2) but has satisfactory diagnostic and staging value for proliferation-active pNETs (usually G3), pNECs, and metastatic pNENs.[65]18F-FDG PET-CT can also predict the biological behavior of tumors. Generally, the higher the standardized uptake value (SUV) the tumor has, the more proliferative and aggressive the tumor is. Thus, 18F-FDG PET-CT may help determine a more appropriate regimen and also to evaluate patient prognosis.[66]

Methods such as SAG and arterial stimulation and venous sampling are invasive and are now rarely used in diagnosing gastrinoma or insulinoma. They may only be used for pNENs that cannot be localized by other imaging examinations (2A, II).

Pathological examinations

Pathological examination is the golden standard for diagnosing pNENs. H&E, Ki-67/MIB1, and some other immunohistochemical staining are recommended for all pNENs specimens. Classification and grading should also be conducted according to tumor differentiation and proliferation activity. NENs are highly heterogeneous spatially and temporally, so it is necessary to carry out biopsies both for primary tumors and metastases. For tumors that have significant progression or inconsistent pathological results with clinical suspicions, re-biopsy is recommended. Moreover, a multipoint biopsy can be performed for highly heterogeneous pNENs based on functional imaging examinations such as PET-CT.[67,68]

Both mitotic count and Ki-67 index are necessary and recommended for determining cell proliferation activity. If these 2 indicators are inconsistent, the result of higher value is recommended for grading (Table 1).[69] Mini-biopsy can usually obtain more samples and have a higher diagnostic value compared to EUS-FNA, while the diagnostic accuracy of EUS-FNA can be improved by increasing the number and quantity of sampling. When specimens are still limited (e.g., fewer than 10 high power fields), Ki-67 can be used preferentially and mitotic count should also be noted (e.g., X/Y high-power fields). Among other immunohistochemical markers, CgA and synaptophysin (Syn) are usually compulsory, and others such as SSTR2, CD56, MGMT, certain hormones (e.g., insulin, somatostatin, glucagon, and gastrin) are optional. TP53, RB1, DAXX, and ATRX can be used for the differential diagnosis of NETs and NECs. For metastatic NENs with unknown primary sites, positive result of Isl1 and PAX8 may indicate pancreatic origin.[70,71] Notably, functional pNENs must be diagnosed based on the patients’ clinical symptoms and diagnostic biochemical indicators. The immunohistochemical results for specific hormones are neither necessary nor sufficient for clinical diagnosis.

Hereditary pNENs

Hereditary tumor syndromes are often manifested as autosomal dominant inheritance diseases. Therefore, the patient's family history of cancer is important for diagnosis. For patient with a negative family history of cancer, if the primary disorder is accompanied by other tumors or disorders in the parathyroid gland, pituitary, neural system, retina, kidney, adrenal gland, and/or skin, the hereditary tumor syndrome should also be highly suspected. In general, the pathogenic genes of hereditary tumor syndromes include MEN1, VHL, NF1, and TSC1/2, and genetic testing can also assist in the diagnosis (2A, II).[14,18]

Minimal consensus statement

A comprehensive diagnosis of pNENs mainly includes (1) the functionality and heredity of tumors, (2) the staging of tumors, and (3) the pathological classification and grading of tumors. For functional pNENs, appropriate biochemical indicators and hormones can be selected based on the patient's signs or symptoms to assist the diagnosis. For hereditary pNENs, factors such as a family history of cancers, the concomitant tumors or disorders, and the genetic testing results can be considered integrally. Biomarkers such as CgA and NSE are often used to assist the diagnosis, as well as for monitoring treatment efficacy and evaluating prognosis. The focus of imaging examinations is to assess the location, size, number, and metastasis of the tumor. Specific examinations and techniques should be selected based on tumor characteristics. Generally, CT and MRI are recommended in preference, and perfusion CT can be used in conjunction to improve the detection rate for insulinoma. For multifocal tumors or tumors that are difficult to locate, EUS should be used to scan the pancreatic and duodenal region carefully. The efficacies of nuclear medicine examinations are often affected by the expression levels of tumor-related receptors, as well as the proliferation activity of tumor cells. SRI and 68Ga-SSA PET-CT are often used for low- and intermediate-grade pNETs, and can evaluate the rationality of certain treatments, such as peptide receptor radionuclide therapy (PRRT), while 18F-FDG PET-CT is usually suitable for high-grade pNETs and pNECs. Pathological examinations should indicate the differentiation, grading, and proliferation activity (mitotic count and/or Ki-67 index) of tumors, the immunohistochemistry assays of CgA and Syn should be conducted at the minimum.

Surgical treatment

A comprehensive treatment based on surgery is the best approach for obtaining a satisfactory long-term prognosis for pNENs patients. Formulation of the surgical strategy should take the general condition of the patient, the function and biological characteristics of the tumor, and the risks and benefits of surgery into consideration.

Preoperative evaluation

The preoperative assessment of pNENs should include the following: (1) the general condition of patients, such as age, performance status, comorbidities, etc; for patients with carcinoid syndromes, cardiac and valvular function should be evaluated before the surgery; (2) determine whether the symptoms of patients conform with hereditary tumor syndromes, such as MEN1; (3) the functionality of tumor; for patients with functional pNENs, hormone induced symptoms should be actively controlled, and the necessity of perioperative SSAs treatment should be evaluated; (4) the biological behavior of tumor; different imaging exminations can be used to assess tumor staging, and biopsies of primary site and/or metastases can be performed to determine pathological grading; (5) the assessment of primary site; the location, size, number, and relationship with the surrounding organs and tissues should be evaluated, and any extrapancreatic lesion should also be specified; for pNENs with aggressive biological behaviors, the involvement of surrounding blood vessels should be identified to determine the resectability of tumor; for pNENs with low malignancy and can be treated by tumor enucleation, the relationship between tumor and pancreatic duct should be evaluated; (6) the assessment of metastasis; regional lymph nodes metastasis and distant metastasis (such as the liver) should be evaluated, as well as the sites, number, and resectability of the metastatic foci; and (7) the baselines of CgA, NSE, and other biomarkers before surgery, in order to facilitate the follow-up evaluations and disease monitoring.

The resectability of pNENs can be evaluated by CT regarding the relevant standards for pancreatic cancer, and MRI can be performed supplementarily.[72] (1) Resectable pNENs: the invasion of major arteries (coeliac axis, CA; superior mesenteric artery, SMA; common hepatic artery, CHA) and veins (superior mesenteric vein, SMV; portal vein, PV) should be absent. If the tumor does invade the SMV or PV, the abutment should be ≤180° without vein contour irregularity. (2) Borderline resectable pNENs: tumor may invade the CA (for pancreatic body/tail tumor), CHA, or SMA ≤180°, or the abutment >180° (usually CA and CHA) while combined arterial resection and reconstruction is feasible (e.g., pancreatic head tumor segmentally involves the CHA, pancreatic tail tumor segmentally involves the CA); tumor may invade the SMV/PV with the abutment >180° or cause vein contour irregularity/segmental thrombosis, while combined venous resection and reconstruction is feasible. (3) Locally advanced pNENs: tumor may encase the CA, SMA, or CHA >180°, or invade the aorta, in which combined arterial resection is unfulfillable; or the SMV/PV reconstruction is less achievable due to the encasement or occlusion. The resectability evaluation aims at achieving R0 resection safely. It is mainly determined by the relationship between the tumor and surrounding blood vessels, but also depends on the surgical techniques of surgeons, as well as the circumstances of individual medical centers. Surgeons should evaluate the resectability of tumors comprehensively, based on the imaging results, the biological characteristics of tumors, and their own surgical experiences and conditions.

Preoperative preparation of functional pNENs

For patients with functional pNENs, the levels of CgA, NSE, and corresponding hormones should be measured before surgery. Symptoms caused by excessive hormone secretion should also be managed actively. For insulinoma, perioperative glucose monitoring is recommended; intravenous glucose infusion can be used to avoid hypoglycemia (2A, I), and diazoxide can be used to suppress insulin secretion (2A, II).[73] For gastrinoma, PPIs or SSAs are recommended to control diarrhea, peptic ulcers, etc.[74] For VIPoma, SSAs are recommended to control diarrhea and to correct fluid and electrolyte disorders.[75] For glucagonoma, low molecular weight heparin (LMWH) can be used to prevent thrombosis, and SSAs can be used to control necrolytic migratory erythema.[75,76] For patients with carcinoid syndrome, SSAs should be used perioperatively to prevent the carcinoid crisis.[77]

Surgical treatment of locoregional pNENs

Surgery should be the preferred treatment for most patients with locoregional pNENs. Tumor grade, stage, surgical margin, and lymph node metastasis are risk factors for poor prognosis. For high-risk surgical patients, such as patients of advanced age or with severe systemic disease, more conservative treatment strategies can be adopted.

Patients with functional pNENs should receive surgical treatment more actively to relieve hormone-related symptoms and to reduce the dosage of medication. The malignancy of insulinoma is generally low. To better retain the endocrine and exocrine functions of the pancreas, parenchyma-sparing resections (especially enucleation) may be prioritized. Meanwhile, a negative surgical margin should be guaranteed and the active prevention of postoperative pancreatic fistula should also be taken.[78] Compared with laparotomy, robot-assisted tumor enucleation of small pNETs (≤2 cm) reduces operation time and blood loss without increasing the postoperative complication rates.[79] Other functional pNENs usually have higher malignant potentials; therefore, local resection or enucleation is not commonly recommended. The surgical strategy should consult that for nonfunctional pNENs (see details below), and regional lymph node dissection should be routinely performed.

In general, the surgical strategy for locoregional nonfunctional pNENs depends on the size and pathological grade of the tumor. For G1/G2 pNETs that are <2 cm, asymptomatic, with no evidence or signs of regional lymph node metastasis or local invasion, the necessity of surgery is still controversial. Although some studies recommended a watchful strategy for these patients, the safety of a long-term follow-up has not been well demonstrated.[80,81] In addition, other studies have suggested the notable malignant potential of small nonfunctional pNETs[82] and that surgery can significantly improve the prognosis of these patients.[83] Overall, for small G1/G2 pNETs (<2 cm), imaging-based surveillance is acceptable under the premise of full communication with patients and should be performed every 6 to 12 months (2B, I). However, surgical treatment may be considered more actively for small G2 pNETs. And for those who have tumors that progressed significantly (volume increase >20%), evidence of regional lymph node metastasis or local invasion, pancreatic duct dilation, or obstructive jaundice, surgical treatment is highly recommended. The surgical approach usually relies on the general condition of the patient, as well as the location and number of the tumor(s). For small nonfunctional G1/G2 pNETs, enucleation is commonly the preferred recommendation, for it has advantages of reducing the surgical duration and blood loss, and preserving pancreatic functions; meanwhile, the long-term prognosis is similar to that of regular pancreatectomy.[84] For pNENs in the pancreatic head/uncinate process or adjacent to the main duct, and for multifocal tumors in the pancreatic body, surgical procedures should be chosen accordingly and regular pancreatectomy is commonly recommended. The significance of lymph node dissection in nonfunctional pNETs is controversial.[85] Some studies have suggested that the incidence of lymph node metastasis in small nonfunctioning pNETs is approximately 16.7% to 27.3%,[86,87] and lymph node metastasis is usually related to the prognosis of pNETs patients.[88,89] Therefore, regional lymph node dissection or at least lymph node sampling is recommended.

For nonfunctional pNETs with diameters ≥2 cm, regular pancreatectomy (including combined resection) and routine regional lymph node dissection are recommended.[90,91] While there is no consensus on the minimal number of dissected lymph nodes, the guidelines for pancreatic cancer can be used as a reference. Generally, more evaluated lymph nodes are associated with more precise staging, which may better predict the patient prognosis and guide the administration of adjuvant therapy.[92,93] Pancreaticoduodenectomy is recommended for pNENs in the pancreatic head/uncinate process (pylorus-preserving pancreaticoduodenectomy is preferred). Depending on tumor size and the extent of tumor invasion, organ-preserving resection of the pancreatic head is also recommended under certain circumstances. For tumors in the pancreatic body, segmental pancreatectomy can be performed. For tumors in the pancreatic tail, distal pancreatectomy (including combined splenectomy) is recommended. In comparison to open surgery, laparoscopic distal pancreatectomy can significantly reduce blood loss and the incidence of serious complications; furthermore, it may result in a shorter hospital stay and a lower incidence of recurrence with a long-term OS equivalent to open surgery.[94] Therefore, laparoscopic distal pancreatectomy can be performed preferably.

For pNECs, surgical procedures should be chosen in accordance with that for pancreatic cancer.

Surgical treatment of locally advanced/metastatic pNENs

Generally, neoadjuvant therapy and conversion therapy can achieve tumor regression and increase the resection rate and R0 rate, thereby improving patient prognosis. Although prospective studies are lacking, the present evidence still indicates favorable clinical outcomes for advanced pNENs; nevertheless, further explorations are needed.[95]

pNECs and some pNETs can be highly aggressive. For pNENs that invade the surrounding vessels and organs severely or even accompanied by distant metastasis, the values of surgical treatment should be comprehensively evaluated based on the age and general condition of the patient, the functionality and grade of the tumor, the number and distribution of the metastases, etc. Although the surgical values for patients who are less likely to achieve R0/R1 resection remain controversial, effective cytoreductive surgery (usually >90% of tumor burden, including primary and metastases) can alleviate patient symptoms and tend to improve their prognosis. Resection of the primary site alone may even improve the outcomes for metastatic pNENs patients (2B, I).[21,96–99]

For patients with locally advanced/metastatic functional pNENs, cytoreductive surgery is recommended in general to alleviate hormone-related symptoms and to reduce the dose of medication. For locally advanced well-differentiated (G1/G2) nonfunctional pNENs, extended resection of the primary site and combined resection of involved organs or tissues may be considered.[100] For patients with metastatic (as in refers to hepatic metastases) G1/G2 nonfunctional pNENs, surgical plans should be made according to the characteristics of liver metastases, and curative surgery is still the goal. For patients with resectable primary tumor and type I liver metastases, primary and metastatic lesions should all be resected as much as possible.[101,102] For patients who may require pancreaticoduodenectomy, treatments towards liver metastases should be performed in priority.[103] For patients with type II liver metastases, simultaneous resection or staged resection should be performed if the estimated tumor reduction rate is >70% (>90% is highly preferred, including the primary and metastatic lesions), as well as subsequent local treatments for hepatic metastases.[102] For patients with type III liver metastases, resection of metastatic lesions may not be appropriate, while resection of the primary tumor may improve the patient's prognosis.[104] Notably, when an inoperable primary lesion is accompanied by operable hepatic metastases, resection of metastases alone is not commonly recommended.[102] For locally advanced/metastatic G3 pNETs and pNECs, the value of surgery is more controversial. However, for patients with serious tumor-related complications (such as bleeding, gastrointestinal obstruction, biliary obstruction, etc) and failed conservative treatments, palliative operations are always recommended. For patients who may receive long-term SSAs treatment after surgery, prophylactic cholecystectomy should be performed simultaneously to reduce the risk of biliary symptoms and gallstones caused by SSAs.[105]

Surgical treatment of hereditary pNENs

Hereditary pNENs are often characterized by early-onset and multifocal lesions, and the risk of neoplasia in the remnant pancreas remains unchanged after surgery; therefore, the optimal subjects, timing, and approaches of surgical treatment for hereditary pNENs are still controversial. Surgical plans should be formulated based on multidisciplinary discussions and patient's will.[106]

For most patients with functional hereditary pNENs (such as hereditary insulinoma, glucagonoma, and VIPoma), surgery is still recommended to control hormone-related symptoms, with surgical approaches similar to that for sporadic functional pNENs.[18] For hereditary gastrinoma, however, PPIs can be used with priority. Hereditary gastrinomas are often multifocal with extrapancreatic lesions, the hormone-related symptoms can be well controlled by medication, and most patients (with tumor <2 cm) may have favorable outcomes. But surgery remains the first option for patients with large gastrinomas (usually ≥2–3 cm) and confirmed tumor positions.[18,107] For patients with nonfunctional hereditary pNENs, although surgery has not been proven to help reduce liver metastasis or improve prognosis, it is still recommended for tumors ≥2–3 cm.[106,108] For patients with small hereditary pNENs (<2 cm), watchful surveillance is usually recommended and surgical treatment is appropriate for patients whose tumors progressed.[109]

Minimal consensus statement

Surgery is the most important approach in the comprehensive treatments of pNENs. Surgical plans should be considered comprehensively based on the characteristics of tumors, such as functionality, size, location, resectability, staging, pathological classification, and grading, as well as the risks and benefits of surgery. Before surgery, symptoms of functional pNENs should be well managed, the involved organs should be fully assessed, and perioperative carcinoid crisis should be avoided. For functional pNENs with unmanageable symptoms, surgical treatment is actively recommended. For small nonfunctional G1/G2 pNETs (usually <2 cm), watchful surveillance is generally acceptable; otherwise, surgery is still recommended. For pNECs patients, surgical procedures should be in accordance with that for pancreatic cancer. As for surgical approaches, enucleation may only be appropriate for insulinomas; regular pancreatectomy and regional lymph node dissection are commonly recommended for most of the other pNENs. As for surgical methods, experienced physicians should opt for minimally invasive techniques such as laparoscopic surgery. For locally advanced G1/G2 pNETs, extended resection may be considered. For metastatic G1/G2 pNETs (usually hepatic metastases), resection of the primary and metastatic lesions, or effective cytoreductive surgery (reduction ratio >70%) can be performed according to the type of liver metastasis; nevertheless, resection of metastases alone is not suggested. For locally advanced/metastatic G3 pNETs and pNECs, surgery is not always preferred unless palliative surgery is needed to prevent or treat tumor-related complications. For patients who may receive long-term SSAs after surgery, simultaneous prophylactic cholecystectomy may be an option. There is currently no consensus regarding the best surgical subjects, approaches, and timing for hereditary pNENs. To formulate an appropriate surgical plan, the age of patients, risk of tumor recurrence, and the efficacy of medication on hormone-related symptoms should be considered comprehensively, in order to balance the therapeutic effect of surgery and the postoperative quality of life.

Adjuvant therapy

Most pNETs are indolent. However, studies have also shown that the postoperative recurrence and metastasis rate for pNETs can reach 13.7% to 36.2%.[110–113] Currently, it is believed that higher tumor burden, higher tumor stage or grade (especially higher Ki-67 index), lymph node metastasis, and vascular invasion are risk factors for tumor recurrence and poor prognosis.[112,114–117] Therefore, it is necessary to make full assessments on the presence of these risk factors when we intend to conduct adjuvant therapy and to estimate its necessity comprehensively.[95]

At present, there is no consensus on the target population nor standard regimen for adjuvant therapy. Since radical resection alone cannot always achieve satisfactory results in patients with high-grade pNETs or pNECs, postoperative adjuvant therapy is still recommended in principle for these patients. For pNECs patients, the EP/EC (etoposide+cisplatin/etoposide+carboplatin) regimen is usually recommended.[118] Although there is no widely accepted chemotherapy regimen for G3 pNETs, the CAPTEM (capecitabine+temozolomide) can be used primarily (2B, Level I recommendation).[119] Radical resection usually has favorable performance for patients with G1/G2 pNETs, hence the adjuvant therapy is not routinely recommended while further validations are warranted.[120,121] For patients who underwent palliative or cytoreductive surgery, systemic and local treatment should be performed conforming to the treatment strategies for patients with locally advanced tumors and/or distant metastases.

Minimal consensus statement

There is no consensus about the criteria or strategy on adjuvant treatment for pNENs. However, for patients with poorer tumor differentiation, more advanced staging, and higher tumor burden, adjuvant therapy is still recommended in principle. For well-differentiated pNENs, the necessity of adjuvant therapy is controversial and further studies are warranted.

Systemic therapy of locally advanced/metastatic pNENs

The systemic therapy for patients with locally advanced/metastatic pNENs includes controlling the hormone hypersecretion of functional tumors and inhibiting the proliferation of tumor cells. A comprehensive multidisciplinary approach should be considered when formulating the specific treatment plan for each patient, taking into account the general condition and organ function of the patient, the presence of hormone-related symptoms, the disease progression rate, the tumor burden, the grade and stage of the disease, baseline levels of biomarkers, imaging examination results (such as SRI), therapeutic feasibilities for metastases, and so on.

Biotherapy

The biotherapy of pNENs mainly includes somatostatin analogs (SSAs) and interferon-α (IFN-α).

SSAs are recommended as the first-line therapy to control hormone-related symptoms resulting from functional pNENs,[122,123] but it may aggravate the hypoglycemia in some patients with insulinoma due to inhibited secretion of glucagon.[124] SSAs also have antiproliferative activity and can prolong the disease-free survival time of some pNETs patients; in particular, the long-acting release therapy of SSAs have higher evidence level of the efficacy in gastroenteropancreatic NETs.[125] SSAs are usually well-tolerated in pNENs patients. For G1 pNETs and G2 pNETs with indolent proliferative activities (usually Ki-67 < 10%), if the patient is asymptomatic, with lower tumor burden, slowly disease progression, and positive results in SRI, SSAs can be used as the first-line approach for antiproliferation treatment (1A, I).[125,126] For G3 pNETs and pNECs, SSAs are not recommended as an antiproliferation therapy (3, experts do not recommend).

IFN-α is mainly used as a second-line regimen in combination therapy to control hormone-related symptoms of functional pNENs, especially in patients with unsatisfactory response to SSAs treatment or are SRI negative. The antiproliferation effect of IFN-α is so far undetermined.[127,128]

Systemic chemotherapy

Systemic chemotherapy is a preferred treatment for locally advanced/metastatic pNENs patients, with higher pathological grade, higher tumor burden, and more aggressive disease progression.

For patients with G1/G2 pNETs, monotherapy or combination therapy involving temozolomide is recommended, with the CAPTEM regimen being preferred (2A, I).[129,130] Combination therapy based on streptozocin can also be used (2A, II).[131] For patients with G3 pNETs, combination therapy based on temozolomide can also be used.[129,130,132] Also, the CAPTEM may achieve a better therapeutic effect in patients with Ki-67 index ranging from 10% to 40%; thus, it is preferentially recommended for this population.[133] For patients with pNECs, a platinum-based combination therapy, such as the EP/EC regimen, can be used,[134,135] and this regimen may be more effective in patients with Ki-67 ≥ 55%.[118] In addition, platinum combined with irinotecan also showed a modest effect in patients with advanced pNECs.[136,137]

Currently, there is no well-recognized second-line chemotherapy regimen. For patients who failed to respond to or are intolerant of the first-line treatment, combination chemotherapies based on oxaliplatin (such as XELOX[138] and FOLFOX[139]), irinotecan (such as FOLFIRI[140]) or temozolomide,[141] can be attempted.

Targeted therapy

The targeted therapy for pNETs mainly includes everolimus (mTOR inhibitor), sunitinib (tyrosine kinase inhibitor), and surufatinib (tyrosine kinase inhibitor). Everolimus can be used for patients with low-grade or intermediate-grade advanced pNETs, and it has been proven to inhibit tumor growth as well as prolong the median progression-free survival (PFS) of patients (1A, I).[142] However, the combination therapy with everolimus and SSAs may not further improve the long-term prognosis of patients,[143] and a higher incidence of severe adverse events was observed in patients who failed chemotherapy or PRRT.[144] Sunitinib can be used for patients with well-differentiated advanced pNETs, since it can inhibit tumor growth and significantly prolong the PFS (1A, I).[145] Notably, the standard dose (37.5 mg/d) of sunitinib may cause severe adverse events in Asian patients, while an appropriate reduction (to 25 mg/d) does not significantly impair the clinical efficacy of treatment.[146] Surufatinib can also be used for patients with well-differentiated advanced pNETs and prolong the patients’ PFS. It may serve as a novel treatment option for patients with advanced pNETs (1A, I).[147]

Other targeted therapies, such as lenvatinib,[148] have also shown promising efficacy in patients with low- and intermediate-grade advanced pNETs.

PRRT

PRRT may be applied for low- and intermediate-grade advanced pNETs with positive SRI results. Although the prospective randomized controlled studies of PRRT on pNETs are lacking, most retrospective studies have suggested that PRRT may have satisfactory efficacy in pNETs. Meanwhile, the prospective studies have suggested that PRRT can significantly prolong the PFS of midgut NETs patients.[95,149]

90Y and 177Lu are commonly used in PRRT, and combination therapy with 90Y and 177Lu may further improve patients’ outcomes.[150] Additionally, selective hepatic intra-arterial injection of the agent may increase the therapeutic effect of PRRT on liver metastases.[151] Moreover, the peptide receptor chemoradionuclide therapy is also one of the promising treatment options,[152] and patients with higher 18F-FDG uptake may have better responses to this therapy.[153]

In general, PRRT is an effective treatment method that can improve the prognosis of some advanced NETs patients, and is also the frontier of current research.

Symptoms control

For insulinoma patients, blood glucose can be stabilized by eating smaller and more frequent meals and by intravenous infusions of glucose; diazoxide can also be used to inhibit the secretion of insulin (2A, II). SSAs can alleviate hypoglycemic symptoms in some insulinoma patients, but their effects may be influenced by the abundance of tumor-related receptors (such as SSTR2 and SSTR5) and the presence of liver metastasis.[154] For other patients, however, the inhibitory effect of SSAs on hyperglycemic hormones (such as glucagon) may surpass that for insulin, thereby aggravating hypoglycemia. Therefore, use of short-acting SSAs for symptom management should be initiated under close clinical observation.[155] Furthermore, everolimus can increase blood glucose, therefore, it can be used as a method in controlling hypoglycemia symptoms in metastatic insulinomas.[156] For gastrinomas, PPIs are recommended as the first-line approach for inhibiting the oversecretion of gastric acid.[157] However, the long-term administration of PPIs may lead to malabsorption of vitamin B12, magnesium, and iron, and may increase the risk of bone fractures.[158] The secretion of gastric acid in some gastrinoma patients may not reduce immediately after surgery; therefore, the sudden withdrawal of PPIs should be avoided.

For other RFTs, SSAs can achieve satisfactory effects in controlling hormone-related symptoms in general.[159] For functional pNETs with poor responses to SSAs, the INF-α ± SSA regimen can be used.[160] For RFTs patients with Cushing's syndrome, steroidogenesis enzyme inhibitors[161] or glucocorticoid receptor antagonists[162] are recommended. Adrenalectomy should be considered if the response to medication is unsatisfactory.

Local treatment for liver metastases

Liver is the most common site for distant metastasis of pNENs.[163] Local treatment for liver metastases is an important supplementary approach to surgery and medication. For metastatic patients who are no longer suitable for surgery, local treatment should be actively performed if the tumor burden and grade of the liver is low, or present as a functional metastasis.[164] For high-grade pNETs or pNECs patients with a higher tumor burden of hepatic metastases, the timing and efficacy of local treatment are still controversial, but active treatment may still improve the prognosis of these patients to a certain extent.[165,166]

The local treatment approaches for liver metastases mainly include arterial-directed therapy and ablation therapy. The arterial-directed therapy mainly includes transarterial embolization (TAE), transarterial chemoembolization (TACE), and transarterial radioembolization. Current studies have suggested that there may be no significant difference in efficacy amongst these three treatment options.[167] For patients with functional pNENs, the short-acting somatostatin is recommended peri-TAE/TACE to control the hormone-related symptoms. For patients with high tumor burden (≥75%), staged treatment is recommended and physicians should be alert about the occurrence of tumor lysis syndrome.[166] The morphological response of TACE (similar to TAE) is around 33% to 80%, the symptomatic response is around 60% to 95%, the PFS is between 18 and 24 months, and the five-year survival rate is around 50% to 65%.[168] Ablation therapy mainly includes radiofrequency ablation and microwave ablation. pNETs patients with liver metastasis <5 cm (better if <3 cm[169]) and the number of metastatic loci ≤5 should receive ablation therapy while receiving other systemic therapies.[164] The symptomatic response after ablation is also high, the median duration of symptom improvement is 14 to 27 months, and the 5-year survival rate is around 57% to 80%.[170]

The 5-year survival rate for pNETs patients who received liver transplantation is 33% to 60%, but most will still experience tumor recurrence; therefore, liver transplantation is not recommended as a routine treatment.[171] In special cases, based on the Milan and ENETS standards, liver transplantation may be considered for younger patients (usually ≤55 years old), with low/intermediate-grade pNETs (usually Ki67 ≤10%), have received radical resection of the primary lesion, metastatic diffusion <50% of the liver (<75% for those with hormone-related symptoms), have no extrahepatic metastasis, and good response or stable disease for at least 6 months before transplantation.[172]

Minimal consensus statement

The systemic treatments for patients with advanced pNENs are diverse. The performance status of patients and the characteristics of tumors should be comprehensively evaluated when formulating the therapeutic plans. The hypersecretion of hormones in most functional pNENs patients can be well controlled by SSAs; thus, SSAs are often used as the first-line regimens in symptoms control. As for antiproliferation treatment, SSAs can be used for well-differentiated pNENs patients with slow tumor progression, low tumor burden, and positive SRI; and are usually used in preference because of the high tolerance. Chemotherapy is often used for pNENs patients with rapid tumor progression. Temozolomide-based and platinum-based combination chemotherapy regimens are usually administered; the former is mainly used for G2/G3 patients, while the latter is mainly used for pNECs. Targeted therapy is often used for well-differentiated advanced pNETs, which can inhibit tumor growth and prolong PFS of patients. However, dose adjustments may be considered to avoid the occurrence of severe adverse events. PRRT is also an option for low-/intermediate-grade advanced NETs with positive SRI. Although the efficacy of PRRT in pNETs has not been prospectively studied yet, most retrospective studies have advocated its effectiveness. Local treatment for liver metastases is an important supplementary to surgery and medication. This approach can be actively performed for metastatic patients with low-/intermediate-grade or functional pNENs, but liver transplantation is not routinely recommended. In general, no recommendation has been made for the order of priority of different treatments, and the advantages and disadvantages of each treatment also have not been compared. In clinical practice, the general condition, treatment tolerance, tumor stage, and pathological characteristics should be considered comprehensively to determine an appropriate treatment strategy.

Prognosis and follow-up

The prognosis of a pNEN patient is closely related to tumor classification, grading, and staging. The 5-year overall survival (OS) rate for pNET patients is approximately 54%, and the 5-year relative survival rate for localized, regional, and distant pNET is approximately 93%, 77%, and 27%, respectively[173]; however, the survival time for pNEC patients is usually less than 1 year.[1,3] Meanwhile, the median survival time for localized pNENs is approximately 19 years, that for metastatic pNENs is approximately 20 months,[3] and only 8 to 12 months for metastatic pNECs.[173] Curative surgery can significantly improve patient prognosis. The 5-year survival rate for nonfunctional pNETs patients after surgery is approximately 65% to 86%.[1] For functional pNETs, the cure rate for insulinoma can reach up to 93% after surgery,[174] and the 10-year survival rate for localized gastrinomas can also exceed 90%.[175] Besides, the prognosis of hereditary pNENs (such as MEN1) is generally better than that of sporadic pNENs.[176]

All pNENs have malignant potential; therefore, regular follow-up or even lifetime follow-up should be conducted. The follow-up plans should be made according to factors such as tumor characteristics and previous treatment regimens (such as with or without radical surgical treatment) comprehensively. Patients who are undergoing systemic treatments should have shorter follow-up intervals and should be re-examined promptly if symptoms relapse. Re-examination should include biomarkers such as CgA and NSE, routine imaging examinations such as ultrasound, CT, and/or MRI, and advanced imaging examinations such as SRI/68Ga-SSA and/or 18F-FDG PET-CT. For patients with functional pNENs, the corresponding biochemical indicators (such as blood glucose) and hormone levels (such as insulin and gastrin) should also be monitored. For patients suspected with MEN1, regular hormonal and imageological assessments of the pituitary, parathyroid glands, and adrenal glands are necessary.

For pNETs patients who received curative surgery, follow-up should be conducted every 6 to 12 months with serological and routine imaging examinations. For insulinoma and other tumors with low malignancy, the follow-up interval can be extended to 12 to 24 months as appropriate. For low-risk pNETs patients who did not receive surgical treatment, follow-up should be conducted every 3 months in the first year, with serological and routine imaging examinations. If the disease is stable, the patient should be followed up every 6 months for the next 3 years and annually thereafter. For patients with locally advanced/metastatic pNETs who underwent palliative/cytoreductive surgery or cannot be treated with surgery, follow-ups should be conducted every 3 to 6 months. In addition to routine serological and imaging examinations, advanced imaging examinations, such as SRI, should be performed as appropriate. The follow-up intervals and plans for pNECs patients should be in accordance with that for pancreatic cancer. Special imaging examinations, such as 18F-FDG PET-CT, should be performed if necessary.

Minimal consensus statement

Regular long-term follow-up is recommended for all pNENs patients. For low-risk patients who did not receive surgery, the purpose of follow-up is to monitor the progression or metastasis of the tumor. For patients who underwent radical surgery, the purpose of follow-up is to exclude tumor recurrence in situ, as well as heterochronic metastasis. For patients with advanced or metastatic pNENs, the purpose of follow-up is to assess the efficacy of systemic treatment, so as to modify the treatment regimen promptly. Clinicians should formulate an appropriate follow-up schedule and examination program according to tumor characteristics, previous treatment regimen, and the follow-up purpose. Generally, blood tests and conventional ultrasound are recommended to be performed routinely. Imaging examinations, such as CT, can be performed every 6–12 months. SRI and other advanced imaging examinations can be performed every 12–24 months, depending on the examination results at initial diagnosis and the necessity in clinical practice.

Chinese Pancreatic Surgery Association members

All Chinese Pancreatic Surgery Association members, listed alphabetically by family names.

Shouwang Cai, MD (Department of Hepatobiliary Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, China), Rufu Chen, MD (Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province, China), Deliang Fu, MD (Department of Pancreatic Surgery, Pancreatic Disease Institute, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China), Chunlin Ge, MD (Department of General Surgery, First Affiliated Hospital, China Medical University, Shenyang, Liaoning Province, China), Chunyi Hao, MD (Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital Anad Institute, Beijing, China), Jihui Hao, MD (Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China), Heguang Huang, MD (Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China), Zhixiang Jian, MD (Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province, China), Gang Jin, MD (Department of Hepato-Biliary-Pancreatic Surgery, Changhai Hospital Affiliated to Navy Medical University, Shanghai, China), Fei Li, MD (Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China), Haimin Li, MD (Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, China), Shengping Li, MD (Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, China), Yixiong Li, MD (Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, China), Tingbo Liang, MD (Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou), Xubao Liu, MD (Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu), Wenhui Lou, MD (Department of General Surgery, Zhongshan Hospital of Fudan University, Shanghai, China), Yi Miao, MD (Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China), Yiping Mou, MD (Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang Province, China), Chenghong Peng, MD (Departement of General Surgery, Pancreatic Disease Center, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China), Renyi Qin, MD (Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China), Chenghao Shao, MD (Department of Pancreatic-biliary Surgery, Changzheng Hospital, Navy Medical University, Shanghai, China), Bei Sun, MD (Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China), Guang Tan, MD (Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian), Huaizhi Wang, MD (Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, China), Lei Wang, MD (Department of Pancreatic Surgery, General Surgery, Qilu Hospital, Shandong University, Ji’nan, Shandong Province, China), Wei Wang, MD (Department of Biliopancreatic Surgery, Huadong Hospital, Fudan University, Shanghai, China), Weilin Wang, MD (Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China), Junmin Wei, MD (Department of General Surgery, Beijing Hospital, Beijing, China), Heshui Wu, MD (Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China), Wenming Wu, MD (Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China), Zheng Wu, MD (Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, China), Changqing Yan, MD (Department of Hepatobiiary Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China), Yinmo Yang, MD (Department of General Surgery, Peking University First Hospital, Beijing, China), Xiaoyu Yin, MD (Department of Pancreato-Biliary Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China), Xianjun Yu, MD (Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai), Chunhui Yuan, MD (Department of General Surgery, Peking University Third Hospital, Beijing, China), Yupei Zhao, MD (Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China).

Acknowledgments

A great effort was made by Chinese Pancreatic Surgery Association and by all participants, equally and generously devoting their time and experience to update the guideline. We thank The Editorial Board of Guideline organizational staff for this long-term endeavor and all participants for their substantial efforts and good will. All three consensus conferences which were held in Peking Union Medical College Hospital (Beijing, China) for attendees both on site and online due to the pandemic were all supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) 2017-I2M-1-001. We also wish to thank Dr. Xianze Wang (Department of Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.) for collecting, updating and analyzing all the references of the aforementioned guidelines, for efficiently mediating consensus conferences and participants.

Author contributions

YZ who led the whole guideline update project organized The Editorial Board of the Guideline (EBG), and appointed WW and JC in charge of EBG while taken fully responsibility on drafting manuscript. WW and JC equally prepared manuscript and a working booklet served as a basic structure for EBG participants to review during consensus conference, in which the basic questions were asked and the suggestions to each of the possible procedures were given. CB, YC, YD, SF, LH, YJ, JNL, WL, JL, CS, LS, FW, LW, OW, YW, HW, XX, JX, HX, LX, YY, XY, CY, HZ and XZ are Members of EGB who all participated three consensus conferences led by WW and JC both on site and online. During each consensus conference, all participants jointly defined and approved a protocol establishing the design of Guideline, the definition of tasks for authors, the general authorship policy and the assignment in different sessions. CB, WW, JC, LH, YJ, XX, HX and LX acted as chairperson responsible for different working session in parallel, reviewed the contents of working booklet and conducting the general assembly toward consensus statements and manuscript. WW and JC equally participated into revising and logical consequence of the final manuscript. All authors approved the final manuscript, authorship and copyright transfer agreement.

Financial support

This project was supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) 2017-I2M-1-001.

Conflicts of interest

The authors declare no conflicts of interest.

Ethics approval

Not applicable.

Appendix 1

In this guideline, the levels (Appendix 2) and preferences (Appendix 3) of recommendations are categorized based on the instructions provided by the Chinese Society of Clinical Oncology (CSCO). All recommendations are category “2A, I” unless otherwise indicated. To avoid ambiguity, additional statements are provided for some “2A, I” recommendations.

Appendix 2

Table 5 - Categories of evidence level in the guideline
Category Level Source of evidence Expert consensus
1A High A rigorous meta-analysis, large-scale randomized controlled trials (RCTs) Uniform consensus
1B High A rigorous meta-analysis, large-scale RCTs Basic consensus with less controversy
2A Slightly lower A general-quality meta-analysis, small-scale RCTs, well-designed large-scale retrospective study, and case-control study Uniform Consensus
2B Slightly lower A general-quality meta-analysis, small-scale RCTs, well-designed large-scale retrospective study, and case-control study Basic consensus with less controversy
3 Low An uncontrolled single-arm trials, case report, and expert opinion No consensus, controversy

Appendix 3

Table 6 - Categories of recommendations in the guideline
Recommendations Criteria
Level I Generally, category 1A evidence and some category 2A evidence with high levels of consensus and accessibility in China are classified as level I recommendations. Specifically, level I recommendations are characterized as follows: (1) diagnostic and therapeutic options with general applicability and good accessibility (also with clear indications); (2) relatively stable values in tumor treatment; (3) generally covered by the National Health Insurance. The identification of level I recommendations should not be influenced by commercial insurances, but mainly depends on the benefits they may bring to patients.
Level II Generally, category 1B evidence and some category 2A evidence with less consensus or accessibility in China are classified as level II recommendations. Specifically, level II recommendations are characterized as follows: (1) high-level evidence from randomized controlled multicenter studies conducted in China or other countries, but is less accessible or has a poorer cost-performance ratio that is unaffordable for the public; (2) interventions that are significantly beneficial but costly can also be classified as level II recommendations on occasions, considering the prominent therapeutic values.
Level III Therapeutic regimens that are being studied and have a uniform consensus from experts, although may lack strong evidence, can also be classified as level III recommendations for reference.
Not Recommend
/Objection For drugs or interventions from which patients cannot get benefits or even be harmed by, Experts Do Not Recommend or Objection should be noted if with sufficient evidence and uniform consensus. All levels of evidence should be considered.

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Keywords:

Diagnosis; Guidelines; Pancreatic Neuroendocrine Neoplasm; Treatment

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