High-Dose Lanreotide in the Treatment of Poorly Differentiated Pancreatic Neuroendocrine Carcinoma: A Case Report

Pancreatic neuroendocrine tumors (NETs), including poorly differentiated carcinomas (NECs), are rarely encountered. The majority of these tumors do not secrete excess hormones, but functioning NETs produce large amounts of vasoactive peptides and may cause carcinoid syndrome. Synthetic somatostatin analogs (SSAs) have been widely used in NETs for control of hormonal syndromes. Here, we present a case of poorly differentiated, grade 3 pancreatic NEC associated with carcinoid syndrome, for which adequate symptom control was achieved for 2 years and 4 months using the long-acting SSA lanreotide Autogel^®. In February 2009, a 55-year-old woman presented with episodes of flushing, diarrhea and epigastric pain. Imaging techniques revealed the presence of a metabolically active mass expressing somatostatin receptors in the hilar area of the liver. Histopathological examination confirmed the malignant nature of the mass, which was identified as a poorly differentiated grade 3 pancreatic NEC (TNM staging: T4NxM0). Therapeutic options were limited for the patient because of the extent of the primary mass involving the celiac axis, severe gastrointestinal toxicity experienced as a side effect of chemotherapy with cisplatin-etoposide and, later in the course of the disease, extensive liver metastases and carcinoid heart syndrome. Along with a palliative debulking surgery and right portal vein embolization, biotherapy with a high dose of lanreotide Autogel (120 mg/14 days) contributed to alleviation of symptoms caused by hormone overproduction, even after the development of liver metastases. These results suggest that patients with poorly differentiated NECs who exhibit signs of carcinoid syndrome can benefit from treatment with somatostatin analogs.Key words: Neuroendocrine tumor, Pancreas, High-dose lanreotide, Carcinoid     

Gastric neuroendocrine carcinoma: clinicopathologic review and immunohistochemical study of E-cadherin and Ki-67 as prognostic markers

BACKGROUND AND OBJECTIVES: Gastric neuroendocrine carcinoma (NEC) is an uncommon cancer of the stomach. The classification of NEC and its clinical behavior remains controversial, and prognostic markers and their therapeutic guidelines have not been clearly defined. The aim of this study was to evaluate the clinicopathologic characteristics of these tumors and analyze the expression of E-cadherin and Ki-67 as prognostic markers in gastric NECs. METHODS: We retrospectively reviewed 17 cases of gastric NECs. Tumor pathology was reviewed and the tumors were categorized as well-differentiated NEC (n = 5) and poorly differentiated NEC (n = 12) according to the WHO classification. With the aim of evaluating the expression of E-cadherin and Ki-67 and their prognostic role in gastric NEC, immunohistochemical analysis of the tumors was performed. RESULTS: The median survival of patients was 20.0 months (95% confidence interval (CI), 13.2-28.8). There was a statistically significant difference in overall survival between well and poorly differentiated NECs (P = 0.021). However, there was no significant difference in overall survival between patients with poorly differentiated small cell and large cell NEC (P = 0.796). Loss of E-cadherin was correlated with lymph node metastasis (P= 0.044). A high Ki-67 proliferation index (PI) (>60%) was correlated with tumor recurrence (P = 0.013) and histologic differentiation (P= 0.028). CONCLUSIONS: Loss of E-cadherin may predict lymph node metastasis in gastric NECs. A high Ki-67 PI (>60%) could be used as a prognostic marker to predict aggressive gastric NECs in addition to standard pathologic classification.     

Immunohistochemical and mutational analysis of c-kit in gastrointestinal neuroendocrine cell carcinoma

BACKGROUND: Gastrointestinal neuroendocrine cell carcinoma (NEC) is a highly aggressive tumor with poor prognosis, for which an effective therapy is highly desirable. Recently, use of a c-kit inhibitor achieved excellent results against gastrointestinal stromal tumor (GIST) that showed c-kit overexpression and mutation in most cases. According to recent studies, 17-44% of pulmonary NEC also expressed c-kit and the antitumor effect of c-kit inhibitor was demonstrated in vitro against small cell carcinoma of the lung. As gastrointestinal NECs are clinicopathologically similar to pulmonary NECs, we investigated c-kit expression and mutation in gastrointestinal NEC. METHODS: Surgically resected gastrointestinal NEC was examined for c-kit expression by immunohistochemistry and RT-PCR. Mutation of the c-kit gene was also investigated by means of single-strand conformation polymorphisms (SSCP). RESULTS: Twenty-six percent (6 out of 23 patients) of gastrointestinal NEC expressed c-kit protein. c-kit protein expression was demonstrated in 1 out of 4 colorectal, 1 out of 2 duodenal, 4 out of 16 gastric and no esophageal (sample size of 1) NECs. The results of immunohistochemistry for c-kit were consistent with the RT-PCR. No c-kit gene mutation was found in gastrointestinal NEC. CONCLUSION: The frequency of c-kit expression in gastrointestinal NEC was similar to that previously reported for pulmonary NEC. These findings suggest that c-kit inhibitor may be effective against some gastrointestinal NECs.     

Mucin phenotype expression of gastric neuroendocrine neoplasms: analysis of histopathology and carcinogenesis

Background

Gastric neuroendocrine neoplasia has been classified as neuroendocrine tumor (NET), a less-malignant type, and neuroendocrine carcinoma (NEC), a more-malignant type. We investigated phenotypic expression profiles to clarify the differences between NET and NEC in terms of histopathology and carcinogenesis.

Methods

We assayed 86 cases of gastric neuroendocrine neoplasms (NET G1, n = 25; NET G2, n = 9; NEC, n = 52), using six exocrine markers (MUC5AC, human gastric mucin, MUC6, M-GGMC-1, MUC2, and CDX2).

Results

NEC frequently coexisted with adenocarcinomatous components (75 %; 39 of 52) and the majority (71.8 %; 28 of 39) showed intraglandular endocrine cell hyperplasia, although no cases of NET showed adenocarcinomatous components. Mucin phenotype significantly differed between NET and NEC; none of NET cases expressed any exocrine markers other than CDX2, although the majority of NEC (86.5 %; 45 of 52) expressed at least one or more exocrine markers with various positive rates for each marker (range, 8.2–74.0 %). Each NEC component showed only the phenotype expressed in the adenocarcinomatous component in the same tumor. Furthermore, double immunohistochemistry revealed dual expression of CDX2 and chromogranin A in half the NEC cases (23 of 46).

Conclusions

These data suggest that gastric NETs (G1 and G2) and NECs have different processes of carcinogenesis, and gastric NECs may be generated from preceding adenocarcinomas.     

A review of cytologic findings in neuroendocrine carcinomas including carcinoid tumors with histologic correlation

BACKGROUND: The nosology of neuroendocrine neoplasia has evolved substantially in recent years. The aim of this study was to review the authors' institutional experience and diagnostic accuracy for cytologic specimens of neuroendocrine carcinoma (NEC) and to identify features most suggestive of neuroendocrine differentiation. METHODS: The cytologic and histologic findings of 29 archival NEC in which cytology preceded biopsy or resection were compared. The study was comprised of 6 carcinoid tumors, 3 atypical carcinoid tumors, 17 high grade NEC (5 small cell, 9 large cell, and 3 mixed small/large cell), and 3 combined NEC/nonneuroendocrine carcinomas. Cytologic material was derived from 21 fine-needle aspirates (FNA), 6 bronchial brushing/washings, and 2 gastrointestinal tract brushings. RESULTS: Of the 29 cases, the correct cytologic diagnosis was rendered in 11. Two cases were identified as NEC but were graded incorrectly. The remaining 16 cases were interpreted as nonsmall cell carcinoma (8 cases); diagnostic or suspicious of carcinoma, not otherwise specified (7 cases); and atypical, indeterminate for malignancy (1 case). On review, neuroendocrine features were identified in 14 of the latter 16 cases. CONCLUSIONS: The cytologic diagnosis of NEC, both high and low grade, can be difficult. Because of acinus-like formations and columnar cell shapes, low grade NEC may be mistaken for adenocarcinoma. Small cell carcinomas, especially in bronchial brush and wash preparations, may be difficult to classify beyond malignant. Large cell NEC may be confused with nonneuroendocrine carcinomas because of abundant cytoplasm and nucleoli. Attention to the presence of loose cell aggregates in a background of singly dispersed cells; feathery patterns created by tumor cells clinging to capillaries; rosette formations; delicate, granular cytoplasm; inconspicuous nucleoli; molding in high grade tumors; and, most important, speckled or dusty chromatin patterns are useful in identifying neuroendocrine differentiation in cytologic specimens.     

Tumor suppressor role of Notch-1 signaling in neuroendocrine tumors

A growing body of literature is demonstrating that Notch signaling is a more complex process than originally thought. Contradictory findings of notch-1 acting as an oncogene or a tumor suppressor revealed that its role is very specific to the cellular context. In this review we focus on the tumor suppressor role of Notch-1 signaling in neuroendocrine tumors (NETs) such as carcinoid and medullary thyroid cancers. NETs secrete various bioactive hormones that can cause debilitating symptoms. Surgery is the only potential curative treatment for the patients with NETs. Notch-1 signaling is absent in these tumors and activation of Notch-1 significantly reduces tumor growth in vitro. Therefore, identification of compound(s) that activate the Notch-1 pathway in NETs could be a potential strategy to treat patients with NETs.     

Expression of 4F2hc (CD98) in pulmonary neuroendocrine tumors

4F2hc (CD98) has been associated with tumor growth, and is highly expressed in various tumors. The aim of this study was to evaluate the clinicopathological significance of 4F2hc expression in pulmonary neuroendocrine (NE) tumors. Surgically-resected patient tumors including 16 large cell neuroendocrine carcinoma (LCNEC), 12 small cell lung cancer (SCLC), 1 atypical carcinoid (AC) and 5 typical carcinoid (TC) samples were included in this study. Tumor sections were immunohistochemically stained for 4F2hc (CD98), glucose transporter 1 (Glut1) and 3 (Glut3), hypoxia-inducible factor-1α (HIF-1α), hexokinase I, vascular endothelial growth factor (VEGF), microvessel density (CD34), epidermal growth factor receptor (EGFR), Akt/mammalian target of rapamycin (mTOR) signaling pathway (p-Akt, p-mTOR and p-S6K) and for a cell cycle regulator (p53). 4F2hc was overexpressed in 0% of the pulmonary carcinoids (TCs and ACs), 62.5% of the LCNECs and 50.0% of the SCLCs. A positive 4F2hc expression was significantly associated with age, histology and Glut1 expression. Moreover, a significant correlation was found between 4F2hc expression, and Glut1, HIF-1α, p-Akt, p-mTOR and p-S6K. The expression of 4F2hc was also significantly associated with poor overall survival. The expression of 4F2hc expression tended to increase from low-grade to high-grade pulmonary NE tumors. Our results suggest that 4F2hc may play a significant role in tumor progression, hypoxic conditions and poor outcome in patients with pulmonary NE tumors.     

Neurofilament and chromogranin expression in normal and neoplastic neuroendocrine cells of the human gastrointestinal tract and pancreas.

To differentiate neuroendocrine (NE) neoplasms arising at different levels of the gut and pancreas, the authors studied the expression of neurofilament (NF) proteins and chromogranin (CR) in normal and neoplastic NE cells of the human gastrointestinal tract (GIT) (14 ileal/jejunal carcinoids, six appendiceal carcinoids, 11 rectal carcinoids) and pancreas (23 islet cell tumors). Among pancreatic islet cell tumors, those with middle molecular weight (NF-M)-positive cells were more abundant than those with high molecular weight (NF-H)-positive cells; nearly all of these tumors expressed CR. Although NF-M was abundantly expressed in greater than 50% of tumor cells in a subset of these tumors, only one of these tumors exhibited diffuse immunoreactivity with NF-H. Among rectal carcinoid tumors, NF-M and NF-H-positive cells were present in approximately the same number of tumors, yet only diffuse immunoreactivity to NF-H could be detected. Chromogranin immunoreactivity in greater than 50% of tumor cells was present in 74% of islet cell tumors, 93% of ileojejunal carcinoids, and 83% of appendiceal carcinoids, but only in a minority of rectal carcinoids (36%). Although ileojejunal carcinoid tumors rarely expressed NF-M and did not express NF-H, diffuse immunoreactivity with CR was present in nearly all of these tumors. None of the appendiceal carcinoid tumors expressed NF-M or NF-H, yet all of these tumors demonstrated immunoreactivity with CR. Neurofilament immunoreactivity was not detected in normal GIT and pancreatic NE cells, whereas CR immunoreactivity was always present. These results suggest that for NE neoplasms of the GIT and pancreas the differential expression of NF subtypes appears to be related to tumor site; and CR is a marker of most GIT and pancreatic NE neoplasms although NF may discriminate subtypes of GIT and pancreatic NE tumors. Neurofilament subtyping may be useful in the evaluation of the origin of NE tumors presenting as metastatic lesions.     

Biological targeted therapies in patients with advanced enteropancreatic neuroendocrine carcinomas

Enteropancreatic (EP) neuroendocrine carcinomas (NECs) represent relatively rare and heterogeneous malignancies. They are the most common group among neuroendocrine tumors (NETs). In most cases they are advanced at diagnosis and slow-growing, therefore conditioning a better prognosis compared with non neuroendocrine carcinomas from the same sites. No standard medical therapy exists, except for somatostatin analogs in functioning tumors, and octreotide LAR in functioning or non functioning well differentiated NECs from small bowel. Several systemic therapeutic options exist, including chemotherapy, somatostatin analog, interferon, peptide receptor radionuclide therapy (PRRT), and molecular targeted drugs. Among them some therapies have specific biological tumor targets and can be defined as "biological targeted therapies". This review focuses on the status of EP NECs targeted therapies in the light of recent advances. Somatostatin receptors (SSTRs) are the first therapeutic target detected in EP NECs. Through them SS analogs and PRRT act, producing symptomatic, biochemical, and, to a lesser extent, antiproliferative effects. New SS analogs, covering a higher number of SSTR subtypes, were developed, including pasireotide (SOM230), which controls 25% of carcinoid syndromes resistant to full dose octreotide LAR. Chimeric analogs, which bind SSTR2/SSTR5 and dopamine-2 receptor subtype (D2), are in preclinical phase of development. Among the numerous molecular targeted agents investigated in NETs, mTOR inhibitors and VEGF/VEGFR/PDGFR inhibitors are in most advanced clinical phase of investigation. In particular, everolimus, sunitinib, and bevacizumab are all studied in phase III trials. Both everolimus and sunitinib produced significant survival benefit versus placebo in advanced progressing well-differentiated pancreatic NECs. Sunitinib data have been presented at the last ASCO in June 2010, and everolimus data will be presented at next ESMO in September 2010.     

Ultrastructural study of small cell carcinoma (author's transl)

Fifty bronchopulmonary tumors were studied by light and electron microscopy: 39 carcinomas (25 small cell carcinomas, 8 undifferentiated carcinomas, 6 poorly differentiated squamous cell carcinomas) and 11 carcinoid tumors (5 central, 4 peripheral, 1 atypical, 1 of the tumorlet type). The results indicate that small cell carcinoma is a precise entity characterized by the presence of neurosecretory granules in the cytoplasm. Ultrastructurally carcinoid tumor resemble small cell carcinomas and there is a continuous spectrum of differentiation between the less undifferentiated neuro-endocrine tumors, i.e. the small cell anaplastic carcinomas, and the higher differentiated types, i.e. the carcinoids. The diagnostic and prognostic value of the ultrastructural findings are discussed.     

Management of neuroendocrine tumors of unknown origin

Neuroendocrine tumors (NETs) of unknown origin account for more than 10% of all NETs. Most of these tumors are poorly differentiated and, thus, very aggressive. Establishing the location of the primary tumor can be challenging. Workup of these NETs of unknown origin includes a thorough family history, immunohistochemistry, imaging, and OctreoScan. If the location of the primary malignancy is not determined, treatment is often initiated based on the grade and level of differentiation of the tumor, with well- and moderately differentiated tumors treated as carcinoid tumors, whereas poorly differentiated tumors are treated similarly to small cell tumors. Therapy is chosen based on symptoms and with the goal of debulking tumor when feasible and safe.     

Expression of platelet-derived growth factor beta-receptors on stromal tissue cells in human carcinoid tumors

Carcinoid tumors of the midgut type are slowly growing neoplasms which often present clinically and histologically pronounced fibrosis around the tumors. Cryosections from 41 neuroendocrine tumors (31 midgut carcinoid tumors, 8 endocrine pancreatic carcinomas, 1 parathyroid carcinoma, and 1 pheochromocytoma) and 22 nonneuroendocrine carcinomas were examined for the presence of platelet-derived growth factor (PDGF) beta-receptor by immunohistochemistry using the monoclonal antibody PDGFR-B2. Twenty midgut carcinoid tumor tissues (66%) and 4 endocrine pancreatic carcinomas (50%) and the parathyroid carcinoma stained positively with the antibody. In contrast, only 2 nonneuroendocrine tumor tissues (10%) were stained, and the staining in these cases was weak. The immunoreaction in the carcinoid tumors was observed in connective tissue cells adjacent to tumor cell clusters but not in the tumor cells themselves. The degree of positive PDGF beta-receptor expression in the carcinoid tissues seems to correlate positively with the presence of macrophages as determined by the monoclonal antibody anti-Leu-M5, but not with other infiltrated lymphocytes identified with the monoclonal antibody anti-Leu-4, or with anti-HLA-DR antibodies. Stromal cells adjacent to tumor cells, including small capillaries, stained more strongly than the stromal cells which were distant from tumor cell clusters. Furthermore, carcinoid tumor metastases from lymph nodes as well as from liver showed stronger immunoreactivity in the stromal cells with the PDGF beta-receptor antibody than the corresponding primary tumors. Our data suggest that carcinoid tumor cells may directly or indirectly induce expression of PDGF beta-receptor on adjacent stromal cells in the tumor tissue, which may contribute to the fibrosis that is often seen around carcinoid tumors.     

Expression of platelet-derived growth factor and its receptors in neuroendocrine tumors of the digestive system.

Carcinoid tumors are slowly growing neuroendocrine neoplasms which often present pronounced fibrosis around the tumor cells. We have previously shown by immunohistochemistry that carcinoid tumors express platelet-derived growth factor (PDGF) beta-receptors on surrounding stromal cells. In this report, 22 midgut carcinoids and 5 endocrine pancreatic tumors were examined for the presence of PDGF with a monoclonal antibody raised against a peptide corresponding to a part of the B-chain of PDGF which reacts strongly with the B-chain and weakly with the A-chain. They were also examined for PDGF alpha-receptors with an affinity-purified polyclonal peptide antibody and for PDGF beta-receptor with the monoclonal antibody PDGFR-B2. PDGF was expressed on tumor cells and on adjacent stroma. PDGF alpha-receptor was seen on clusters of tumor cells and occasionally on adjacent stroma, whereas beta-receptors were seen only in the stroma. Tissue sections from some of these midgut carcinoids were also investigated by in situ hybridization for mRNA of PDGF A- and B-chains as well as alpha- and beta-receptors. By in situ hybridization, abundant expression of mRNA for PDGF beta-receptor and PDGF A-chain was observed in stromal cells adjacent to carcinoid tumor cell clusters, but the mRNA expression in the tumor cells themselves was at a low level. A few clustered tumor cells and stromal cells expressed mRNA for the PDGF alpha-receptor, thus consolidating the immunohistochemical findings. mRNA for the PDGF B-chain was detected in both tumor cells and stroma, but only at low levels. Our data suggest that PDGF is involved in the growth stimulation of the carcinoid tumor cells in an autocrine fashion and in the stimulation of stromal cell growth through paracrine and possibly autocrine mechanisms. Moreover, remarkably strong immunostaining of PDGF and the PDGF alpha-receptor was seen on peripheral nerve fibers.     

Argyrophilic carcinoma "carcinoid tumor" of the breast: case report with electron microscopic and immunohistochemical investigations

A rare primary argyrophilic carcinoma "carcinoid tumor" of the breast in a 48-year-old woman was investigated by light and electron microscopy, and immunohistochemistry. Light microscopy showed the greater part of the tumor to have characteristic histological features of carcinoid tumor and Grimerius' stain revealed the presence of numerous argyrophilic granules in the tumor cells. Numerous neurosecretory granules and bundles of intermediate filaments were observed ultrastructurally in the cytoplasm. In addition, carcinoembryonic antigen (CEA) and neuronespecific enolase (NSE) were detected in the tumor cells using the immunoperoxidase method. From the results, it is speculated that the tumor cells have the ability to produce CEA as well as NSE in the cytoplasm. The observation of ductal spreading in parts of the tumor, and the detection of CEA, suggest the tumor cells to be derived from mammary epithelial cells.     

Cutaneous metastases from neuroendocrine carcinoma of the cervix—An unusual metastatic lesion from an uncommon malignancy

Neuroendocrine carcinoma (NEC) is an uncommon and aggressive type of small cell cervical cancer. NECs mostly arise from gastro-entero-pancreatic tract and the lung, but rarely from other organs like cervix. NEC of the cervix is a rare malignancy and constitutes 0.9%-1.5% of cervical tumors. NECs of cervix are common in perimenopausal females and present with abnormal vaginal bleeding and mimic squamous cell cancers, usually with no distinguishing features. On Immunohistochemistry, presence of chromogranin, synaptophysin, and CD-56 is necessary to make a diagnosis of small cell carcinoma. These tumors are notorious for local as well as distant relapses in comparison to their squamous and adenocarcinoma counterpart. NECs are characterized by highly aggressive clinical behavior and carry a poor prognosis. They commonly metastases to lung, liver, brain, and bones even in early stages of the disease. Metastasis to skin is a rare occurrence. We herein report a case of a NEC of the uterine cervix with multiple cutaneous metastases. After the initial diagnosis of NEC of cervix, the patient received concurrent chemoradiation followed by intracavitary brachytherapy. On subsequent follow-up, the patient developed multiple cutaneous metastasis along with liver metastases. This case is reported in view of rarity of the case with skin metastases. To the best of our knowledge, only 3 cases of cutaneous metastases from NEC of the cervix are reported till date. Being a rare malignancy, evidence in the literature is in form of case reports and small case series. Thus, the optimal treatment strategy varies for these patients. Multimodality management with teamwork is necessary to manage individual patients.     

Growth characteristics of rectal carcinoid tumors

PURPOSE: Tissue growth depends on both cell proliferation and cell death. This study was designed to examine the growth characteristics of rectal carcinoid tumors. METHODS: Fifty rectal carcinoid tumors were studied clinicopathologically and experimentally. Expression of Ki-67, TGF-alpha, p53, and bcl-2 was examined immunohistochemically, and apoptotic cells were identified by the in situ DNA nick end labeling method. EGF receptor expression was examined by a colorimetric in situ mRNA hybridization technique. RESULTS: The median Ki-67 labeling index (LI) in all lesions was 0.62 +/- 0.59%. Ki-67 LI was significantly (p < 0.01) higher in lesions larger than 5 mm than in lesions smaller than 5 mm. TGF-alpha was expressed more frequently (p < 0.01) in lesions larger than 5 mm (100%) than in lesions smaller than 5 mm (65.2%). Ki-67 LI was significantly (p < 0. 05) higher in lesions with TGF-alpha expression than in lesions without TGF-alpha expression. The in situ hybridization revealed EGF receptor expression in all 46 lesions with intact mRNA (100%), and coexpression of TGF-alpha and EGF receptor was found in 39 of the 46 (84.8%) lesions. The median apoptotic index (AI) in all lesions was 0.15 +/- 0.12%. AI has increased with tumor size and was significantly (p < 0.05) higher in lesions with a higher Ki-67 LI than in lesions with a lower Ki-67 LI. p53 protein was detected in only 1 patient who had liver metastases, and the gene mutation was confirmed by polymerase chain reaction and single-strand conformation polymorphism analysis. bcl-2 expression was absent in all lesions. CONCLUSIONS: The Ki-67 LI indicated a low cellular proliferative activity in rectal carcinoid tumors. AI was very low, and was significantly correlated with proliferative rate. Inhibition of apoptosis by mutated p53 or bcl-2 may not have occurred in most of these tumors. TGF-alpha/EGF receptor autocrine mechanisms may play a possible role in tumor growth, and the cellular proliferative activity may increase as tumors grow larger.     

182例胰腺神经内分泌肿瘤的临床病理特征和预后分析

  目的  探讨胰腺神经内分泌肿瘤（pancreatic neuroendocrine neoplasm,PanNEN）的临床病理特征和预后因素。  方法  收集2011年1月至2018年12月天津医科大学肿瘤医院收治的胰腺NEN,依据世界卫生组织（WHO）消化系统肿瘤2019版分类进行复核,分析比较不同分类胰腺NEN临床病理特征的异同,并分别进行生存分析。  结果  在最终确诊的182例PanNEN中,神经内分泌瘤（neuroendocrine tumor,NET）G1、NET G2、NET G3、神经内分泌癌（neuroendocrine carcinoma,NEC）和混合性神经内分泌-非神经内分泌肿瘤（mixed neuroendocrine-non-neuroendocrine neoplasm,MiNEN）分别为78例（42.9%）、82例（45.1%）、5例（2.7%）、15例（8.2%）和2例（1.1%）。临床病理特征方面,胰腺NEN分级越高,神经/脉管侵犯、淋巴结/远处转移等侵袭性行为越多见,诊断时进展期患者的比例越高（均P < 0.05）。NEC的Ki-67指数均值显著高于NET G3（P < 0.001）,但二者在30%~60%区间有重叠。WHO2019版分类与总体生存（overall survival,OS）和无进展生存（progression-free survival,PFS）显著相关（均P < 0.05）。对于NET G1患者,诊断时为进展期是OS和PFS较差的独立预后因素（分别HR=12.472,P=0.002;HR=10.56,P < 0.0012）。对于NET G2患者,手术切除是OS较好的独立预后因素（HR=8.217,P=0.001）,诊断时即有远处转移是PFS较差的独立预后因素（HR=26.137,P < 0.001）。NEN G3的预后主要与Ki-67指数有关,但NET G3和NEC的截断值不同（NET G3:45%,NEC:70%）。  结论  胰腺NEN是一组异质性肿瘤,不同WHO分类的胰腺NEN的临床病理特征及预后均不同。胰腺NEN以分化好的NET为主,但是部分NET在诊断时即见转移,术后可以复发/转移。NET G3与NEC的鉴别要点主要是肿瘤分化、细胞增殖活性、p53免疫组织化学染色等分子检测。治疗方面仍无统一标准,尤其对于未明确NET G3或NEC的NEN G3患者,需综合评估分级、分期,并监测疾病进展情况。未来仍需多中心大样本的研究来制定更加全面细致的诊疗标准。