Clinicopathological features of small nonfunctioning pancreatic neuroendocrine tumors

AIM: To present our experiences in studying the clinicopathological features of small nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs).METHODS: The subjects included 9 patients with NF-pNETs who underwent pancreatectomy between April 1996 and September 2012. The surgical procedure, histopathological findings, and prognosis were assessed.RESULTS: All tumors were incidentally detected by computed tomography. The median diameter was 10 mm (5-32 mm). One patient was diagnosed with von Hippel-Lindau disease, and the others were sporadic cases. For the histopathological findings, 7 patients were G1; 1 patient was G2; and 1 patient, whose tumor was 22 mm, had neuroendocrine carcinoma (NEC). One patient who had a tumor that was 32 mm had direct invasion to a regional lymph node and 1 patient with NEC, had regional lymph node metastases. Six of the 7 patients with sporadic NF-pNETs, excluding the patient with NEC, had tumors that were smaller than 10 mm. Tumors smaller than 10 mm showed no malignancy and lacked lymph node metastasis.CONCLUSION: Sporadic NF-pNETs smaller than 10 mm tend to have less malignant potential. These findings suggest that lymphadenectomy may be omitted for small NF-pNETs after further investigation.     

Efficacy of endoscopic ultrasonography-guided fine needle aspiration for pancreatic neuroendocrine tumor grading

AIM: To evaluate the efficacy of endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) for grading pancreatic neuroendocrine tumors (PNETs).METHODS: A total of 22 patients were diagnosed with PNET by EUS-FNA between October 2001 and December 2013 at Fukushima Medical University Hospital. Among these cases, we targeted 10 PNET patients who were evaluated according to the World Health Organization (WHO) 2010 classification. Surgery was performed in eight patients, and chemotherapy was performed in two patients due to multiple liver metastases．Specimens obtained by EUS-FNA were first stained with hematoxylin and eosin and then stained with chromogranin, synaptophysin, CD56, and Ki-67. The specimens were graded by the Ki-67 index according to the WHO 2010 classification. Specimens obtained by surgery were graded by the Ki-67 index and mitotic count (WHO 2010 classification). For the eight specimens obtained by EUS-FNA, the Ki-67 index results were compared with those obtained by surgery. In the two cases treated with chemotherapy, the effects and prognoses were evaluated.RESULTS: The sampling rate for histological diagnosis by EUS-FNA was 100%. No adverse effects were observed. The concordance rate between specimens obtained by EUS-FNA and surgery was 87.5% (7/8). For the two cases treated with chemotherapy, case 1 received somatostatin analog therapy and transcatheter arterial infusion (TAI) targeting multiple liver metastases. Subsequent treatment consisted of everolimus. During chemotherapy, the primary tumor remained unconfirmed, although the multiple liver metastases diminished dramatically. Case 2 was classified as neuroendocrine carcinoma (NEC) according to the Ki-67 index of a specimen obtained by EUS-FNA; therefore, cisplatin and irinotecan therapy was started. However, severe adverse effects, including renal failure and diarrhea, were observed, and the therapy regimen was changed to cisplatin and etoposide. TAI targeting multiple liver metastases was performed. Although the liver metastases diminished, the primary tumor remained unconfirmed. These chemotherapy regimens had immediate effects for both unresectable neuroendocrine tumor (NET) and NEC cases. These two subjects are still alive.CONCLUSION: EUS-FNA was effective for PNET diagnosis and Ki-67 index grading for WHO 2010 classification, enabling informed decisions on unresectable PNET treatment by identifying NET or NEC.     

Advances in the diagnosis and treatment of pancreatic neuroendocrine neoplasms in Japan

Several new developments have occurred in the field of pancreatic neuroendocrine neoplasm (PNEN) recently in Japan. First, the utility of chromogranin A (CgA), useful for the diagnosis and monitoring of the treatment response of neuroendocrine neoplasm (NEN), has been demonstrated in Japan. For PNEN diagnosis and treatment, grading and correct histological diagnosis according to the WHO 2010 classification is important. Regarding the histological diagnosis, the advent of endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) has enabled correct pathological diagnosis and suitable treatment for the affected tissue. Furthermore, EUS-FNA has also facilitates the assessment of the presence or absence of gene mutations. In addition, patients who have a well-differentiated neuroendocrine tumor (NET) showing a Ki-67 index of higher than 20 % according to the WHO 2010 classification, have also been identified, and their responses to treatment were found to be different from those of patients with poorly differentiated neuroendocrine carcinoma (NEC). Therefore, the concept of NET G3 was proposed. Additionally, somatostatin receptor type 2 is expressed in several cases of NET, and somatostatin receptor scintigraphy (¹¹¹In-octreoscan) has also been approved in Japan. This advancement will undoubtedly contribute to the localization diagnosis, the identification of remote metastasis, and assessments of the treatment responses of PNEN. Finally, regarding the treatment strategy for PNEN, the management of liver metastasis is important. The advent of novel molecular-targeted agents has dramatically improved the prognosis of advanced PNEN. Multimodality therapy that accounts for the tumor stage, degree of tumor differentiation, tumor volume, and speed of tumor growth is required.

     

Short- and long-term outcomes of endoscopic resection of rectal neuroendocrine tumours: analyses according to the WHO 2010 classification

Objective Although the World Health Organisation (WHO) defined a novel classification of gastroenteropancreatic neuroendocrine tumours (NETs) in 2010, indications for endoscopic resection of rectal NETs in the guidelines were based on evidence accumulated for carcinoid tumours defined by a previous classification. This study was designed to clarify indications for endoscopic resection of rectal NETs corresponding to the new WHO classifications. Material and methods One hundred-seventy rectal NETs resected endoscopically from April 2001 to March 2012 were histologically re-classified according to the WHO 2010 criteria. The clinicopathological features of these lesions were analysed, and the short- and long-term outcomes of endoscopic resection were evaluated. Results Of the 170 rectal NETs, 166 were histopathologically diagnosed as NET G1 and four as NET G2. Thirty-eight tumours (22.4%) were positive for lymphovascular invasion, a percentage higher than expected. Although the curative resection rate was low (65.3%), en bloc (98.8%) and complete (85.9%) resection rates were high. Modified endoscopic mucosal resection (88.0%) and endoscopic submucosal dissection (92.2%) resulted in significantly higher complete resection rates than conventional endoscopic mucosal resection (36.4%). No patient experienced tumour recurrence, despite the low curative resection rate. Conclusion Despite the low curative resection rate, prognosis after endoscopic resection of rectal NETs was excellent. Prospective large-scale, long-term studies are required to determine whether NET G2 and tumours >1?cm should be included in the indication for endoscopic resection and whether tumours with lymphovascular invasion can be followed up without additional surgery.     

Clinicopathological characteristics of biliary neuroendocrine neoplasms: a multicenter study

Objectives: This study assessed the clinicopathological features, therapeutic approaches, and prognosis of patients with biliary neuroendocrine neoplasm (NENs).

Materials and methods: Multicenter retrospective study of patients with biliary tract NENs in the gallbladder, the extrahepatic bile duct, or the ampulla of Vater between 2005 and 2014.

Results: Total of 43 patients were included in the study. The median age was 62 years (range: 29–84 years) and 58.1% of the patients were male. The tumors occurred in the gallbladder (n?=?11), the extrahepatic bile duct (n?=?5) or the ampulla of Vater (n?=?27). The liver was the most common metastatic site. Based on the 2010 World Health Organization classification, more patients with gallbladder NENs (11/11 (100%)) had neuroendocrine carcinoma G3 than those with NENs in the ampulla of Vater (10/27 (37.1%)). The median progression free survival time (39.3 vs 5.1 months, p?=?0.001) and median overall survival time (46.9 vs 7.9 months, p?<?0.001) were significantly longer in patients with ampulla of Vater NENs than gallbladder NENs. A 2010 World Health Organization classification of neuroendocrine carcinoma G3 was independently related to poor overall survival (hazard ratio (HR), 27.1; 95% confidence intervals (CI), 2.81-260.68; p?=?0.004).

Conclusion: The 2010 World Health Organization classification of neuroendocrine carcinoma G3 was the only factor related to poor prognosis in patients with biliary neuroendocrine neoplasms.     

Gastric neuroendocrine neoplasms and precursor lesions: Case reports and literature review

Rationale:Gastric neuroendocrine neoplasms (g-NENs) represent a distinctive group of gastric tumors, stratified into different prognostic categories according to different histological characteristics, put forth in the 2018 World Health Organization classification system. The clinical presentations, as well as pathological features, represent important data in establishing the type of the tumor, in estimating the tumor behavior, and in selecting the best therapeutic strategy. In our case series we presented different clinical scenarios that may be encountered in practice regarding gastric NENs. We performed a literature review and discussed diagnostic strategy, current classification system, precursor lesions, and therapeutic options in g-NENs.Patient concerns:The first patient was a 41-year-old female with weight loss, persistent dyspeptic complaints and a history of pernicious anemia. In the second clinical case a 61-year-old man was admitted with heartburn, abdominal pain, diarrhea and mild iron deficiency anemia. The third patient was a 56-year-old male with a history of neoplasia, admitted for weight loss, dyspeptic complaints, and liver metastases.Diagnosis:All the 3 patients underwent upper endoscopy with targeted biopsies. Histopathological and laboratory evaluation, together with imagistic evaluation (abdominal ultrasound, endoscopic ultrasound, and magnetic resonance imaging) allowed the distinction between 3 different types of gastric tumors: type 1 enterochromaffin-like-cell G1 NET, type 2 enterochromaffin-like-cell G2 NET, and type 3 G2 NET with liver metastases.Interventions:Endoscopic polypectomy of the largest lesion was performed in patient with type 1 g-NET and autoimmune chronic atrophic gastritis, followed by regular endoscopic surveillance with biopsies. In type 2 g-NET associated with pancreatic gastrinoma, pancreaticoduodenectomy with total gastrectomy were performed. In type 3 g-NET, detected in metastatic stage, oncologic therapy was performed.Outcomes:The patients follow-up was selected according to tumor behavior, from regular endoscopic surveillance to oncology follow-up. The prognosis was good in case 1, whilst poorer outcomes were associated with more aggressive tumors in case 2 and case 3.Lessons:g-NENs are rare tumors with distinct clinical and histological features. Our case series emphasized the role of close collaboration between clinician and pathologist, as well as the importance of a detailed pathology report.     

Survival Analyses for Patients With Surgically Resected Pancreatic Neuroendocrine Tumors by World Health Organization 2010 Grading Classifications and American Joint Committee on Cancer 2010 Staging Systems

In 2010, World Health Organization (WHO) reclassified pancreatic neuroendocrine tumors (p-NETs) into 4 main groups: neuroendocrine tumor G1 (NET G1), neuroendocrine tumor G2 (NET G2), neuroendocrine carcinoma G3 (NEC G3), mixed adeno and neuroendocrine carcinoma (MANEC). Clinical value of these newly updated WHO grading criteria has not been rigorously validated. The authors aimed to evaluate the clinical consistency of the new 2010 grading classifications by WHO and the 2010 tumor-node metastasis staging systems by American Joint Committee on Cancer (AJCC) on survivals for patients with surgically resected p-NETs. Moreover, the authors would validate the prognostic value of both criteria for p-NETs.The authors retrospectively collected the clinicopathologic data of 120 eligible patients who were all surgically treated and histopathologically diagnosed as p-NETs from January 2004 to February 2014 in our single institution.The new WHO criteria were assigned to 4 stratified groups with a respective distribution of 62, 35, 17, and 6 patients. Patients with NET G1 or NET G2 obtained a statistically better survival compared with those with NEC G3 or MANEC (P < 0.001). Survivals of NET G1 was also better than those of NET G2 (P = 0.023), whereas difference of survivals between NEC G3 and MANEC present no obvious significance (P = 0.071). The AJCC 2010 staging systems were respectively defined in 61, 36, 12, and 11 patients for each stage. Differences of survivals of stage I with stage III and IV were significant (P < 0.001), as well as those of stage II with III and IV (P < 0.001); whereas comparisons of stage I with stage II and stage III with IV were not statistically significant (P = 0.129, P = 0.286; respectively). Together with radical resection, these 2 systems were both significant in univariate and multivariate analysis (P < 0.05).The newly updated WHO 2010 grading classifications and the AJCC 2010 staging systems could consistently reflect the clinical outcome of patients with surgically resected p-NETs. Meanwhile, both criteria could be independent predictors for survival analysis of p-NETs.     

Clinicopathological features and prognostic factors associated with gastroenteropancreatic mixed neuroendocrine non-neuroendocrine neoplasms in Chinese patients

BACKGROUND The incidence of mixed neuroendocrine-non-neuroendocrine neoplasms(MiNEN)is low.To improve our understanding of this rare tumor type and optimally guide clinical treatment,associated risk factors,clinical manifestations,and prognosis must be explored.AIM To identify risk factors that influence the prognosis of patients with gastroenteropancreatic MiNEN(GEP-MiNEN).METHODS We retrospectively analyzed the clinical data of 46 patients who were diagnosed with GEP-MiNEN at the First Affiliated Hospital of Bengbu Medical College(Anhui,China)between January 2013 and December 2017.Risk factors influencing the prognosis of the patients were assessed using Kaplan-Meier curves and cox regression models.We compared the results with 55 randomly selected patients with gastroenteropancreatic GEP neuroendocrine tumors,47 with neuroendocrine carcinomas(NEC),and 58 with poorly differentiated adenocarcinoma.RESULTS Among the 46 patients with GEP-MiNEN,thirty-five had gastric tumors,nine had intestinal tumors(four in the small intestine and five in the colon and rectum),and two had pancreatic tumors.The median age of the patients was 66(41-84)years,and the male-to-female ratio was 2.83.Thirty-three(71.7%)patients had clinical stage III and IV cancers.Distant metastasis occurred in 14 patients,of which 13 had metastasis to the liver.The follow-up period was 11-72 mo,and the median overall survival was 30 mo.Ki-67 index≥50%,high proportion of NEC,lymph node involvement,distant metastasis,and higher clinical stage were independent risk factors affecting the prognosis of patients with GEP-MiNEN.The median overall survival was shorter for patients with NEC than for those with MiNEN(14 mo vs 30 mo,P=0.001),but did not significantly differ from those with poorly differentiated adenocarcinoma and MiNEN(30 mo vs 18 mo,P=0.453).CONCLUSION A poor prognosis is associated with rare,aggressive GEP-MiNEN.Ki-67 index,tumor composition,lymph node involvement,distant metastasis,and clinical stage are important factors for patient prognosis.     

Natural history and clinical outcomes of pancreatic neuroendocrine neoplasms based on the WHO 2017 classification; a single-center experience of 30 years

Background/ObjectivesThis single-center study aimed to evaluate treatment outcomes and long-term prognosis of patients with pancreatic neuroendocrine neoplasms (PanNENs) based on the World Health Organization (WHO) 2017 classification.MethodsWe enrolled 245 patients with PanNENs treated at Kyushu University Hospital between January 1987 and March 2018. PanNENs were categorized according to the WHO 2017 classification or further subdivisions of Ki-67 index. Clinicopathological features, median survival time (MST), and prognostic factors were retrospectively analyzed.ResultsThe number of PanNENs, especially non-functioning PanNENs, has increased over the last decade. The mean MST of all patients was 202 months; which was longest in patients with NET G1 (n = 145, MST = 261 months) relative to NET G2 (n = 72, 132 months), NET G3 (n = 3, 34 months) and NEC G3 (n = 17, 9 months). Prognosis in patients with surgery as the first-line treatment was significantly better than in those with drug therapy. However, 26% of patients who underwent curative resection developed recurrence after a median time of 28.7 months. In unresectable PanNENs (n = 97), the MST and 5-year survival rate were 78 months and 55.8%, respectively. Poor differentiation, Ki-67 index of >10% and presence of liver metastasis were significant unfavorable predictors. Response to first-line therapy (stable disease/partial response) and three or more treatment regimens were significant favorable predictors for unresectable PanNENs according to multivariate analyses (p < 0.01).ConclusionsWe demonstrated the utility of the WHO 2017 classification for PanNENs in the real clinical setting. For better prognosis in PanNENs, the use of three or more regimens should be considered.     

Analysis of neuroendocrine tumour metastases in the liver using contrast enhanced ultrasonography

Background. Imaging of liver tumours might be improved by contrast-enhanced ultrasonography, which allows much better demonstration of the microvascular system. The aim of this study was to assess the sonographic morphology and vascularity of neuroendocrine liver metastases. Methods. Forty-eight patients with histologically proven neuroendocrine tumours (NET) and suspected liver metastases – as well as 50 consecutive patients with liver metastases of other origins – were included in a prospective study to evaluate tumour characteristics using B-mode, colour Doppler (CDI) and contrast-enhanced ultrasound (CEUS). Results. In 4/48 patients with NET, liver biopsy revealed hemangiomas. The typical B-mode appearance was that of both echo-rich and echo-poor combined, also inhomogeneous depending on the size, and often centrally cystic. With CDI, neuroendocrine metastases appeared hypervascular (66%) or isovascular (34%). Metastases of another origin were hypovascular in 82%. With CEUS, neuroendocrine metastases showed increased arterial enhancement in 38 patients and hypoechoic appearance in the portalvenous phase in 39 patients. In liver metastases of another origin, the sensitivity for malignancy due to a hypoechoic appearance during the portalvenous phase was 100%. In liver metastases of NET origin the sensitivity for malignancy was 39/48 (82%). Conclusions. Neuroendocrine tumour metastases might show characteristics which are similar to hemangiomas. In patients with liver cirrhosis and severe fatty liver disease the identification of NET with CEUS as a malignant lesion is more difficult. The sensitivity of CEUS in identifying malignancy based on the lack of portalvenous enhancement is higher for metastases of other origin.     

Occurrence of exocrine pancreatic insufficiency in patients with advanced neuroendocrine tumors treated with somatostatin analogs

BackgroundAlthough exocrine pancreatic insufficiency (EPI) has been described in patients with neuroendocrine neoplasia (NEN) treated with somatostatin analogs (SSAs), its role in the therapeutic management of these patients is not well established.AimTo determine the frequency of EPI in patients with NEN long-term treated with SSAs.MethodsThis is a prospective single-center study evaluating 35 patients treated with SSAs for >12 months due to unresectable/advanced nonpancreatic well-differentiated NEN. Clinical evaluation, biochemical parameters, and fecal elastases 1 (FE-1) were assessed to diagnose EPI.ResultsA total of 7 patients (20%) had EPI, given the presence of abdominal symptoms and a median FE-1 value of 180 mcg/g stool (150–198). No patient had severe EPI, defined as FE-1 < 100 mcg/g stool. Elevated glycated Hb levels were a significant predictor for developing EPI (OR 4.81, p = 0.01). No significant difference in terms of duration of SSA treatment was observed between patients with or without EPI diagnosed (84 months and 72 months, respectively; p = 0.950).ConclusionsMild-moderate EPI is a relatively common condition in patients receiving long-term treatment with SSAs. Specific clinical and biochemical evaluations, including FE-1, should be planned in these patients to diagnose this relevant condition early, which may deteriorate quality of life and cause malnutrition.     

Neuroendocrine neoplasms of liver-A 5-year retrospective clinico-pathological study applying World Health Organization 2010 classification

AIM To study the clinicopathological characteristics of neuroendocrine neoplasms(NEN) on liver samples and apply World Health Organization(WHO) 2010 grading of gastroenteropancreatic(GEP) NEN.METHODS Clinicopathological features of 79 cases of NEN of the liver diagnosed between January 2011 to December 2015 were analyzed. WHO 2010 classification of GEP NEN was applied and the tumors were graded as G1, G2 or G3. Two more categories, D1/2(discordant 1/2) and D2/3(discordant 2/3) were also applied. The D1/2 grade tumors had a mitotic count of G1 and Ki-67 index of G2. The D2/3 tumors had a mitotic count of G2 and Ki-67 index of G3. The follow up details which were available till the end of the study period(December 2015) were collected.RESULTS Of the 79 tumors, 16 each were G1 and G2, and 18 were G3 tumors. Of the remaining 29 tumors, 13 were assigned to D1/2 and 16 were D2/3 grade. Male preponderance was noted in all tumors except for G2 neoplasms, which showed a slight female predilection. The median age at presentation was 47 years(range 10-82 years). The most common presentation was abdominal pain(81%). Pancreas(49%) was the most common site of primary followed by gastrointestinal tract(24.4%) and lungs(18%). Radiologically, 87% of the patients had multiple liver lesions. Histopathologically, necrosis was seen in only D2/3 and G3 tumors. Microvascular invasion was seen in all grades. Metastasis occurred in all grades of primary NEN and the grades of the metastatic tumors and their corresponding primary tumors were similar in 67% of the cases. Of the 79 patients, 36 had at least one follow up visit with a median duration of follow up of 8.5 mo(range: 1-50 mo). This study did not show any impact of the grade of tumor on the short term clinical outcome of these patients.CONCLUSION Liver biopsy is an important tool for clinicopathological characterization and grading of NEN, especially when the primary is not identified. Eighty-seven percent of the patients had multifocal liver lesions irrespective of the WHO grade, indicating a higher stage of disease at presentation. Follow up duration was inadequate to derive any meaningful conclusion on long term outcome in our study patients.     

Presentation and outcome of mixed neuroendocrine non-neuroendocrine neoplasms of the pancreas

Background/objectivesMixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) of the pancreas and periampullary region are extremely rare and heterogeneous malignancies. Literature is sparse, clinical management is not standardized and little is known about survival outcomes. The aim of this study was to identify pathological and radiological features of MiNEN and assess the outcome of surgical management.MethodsPatients undergoing surgery for pancreatic and periampullary MiNEN between 2001 and 2019 were retrospectively analysed based on a prospective database. Histological, radiological and clinical features were assessed. Survival was analysed in a nested case-control study and matched-pair analyses with pure neuroendocrine neoplasms (pNEN) and ductal adeno- or acinar cell carcinomas of the pancreas. A literature review with focus on survival after surgical resection was additionally performed.ResultsOf 13 patients with MiNEN, 5 had acinar-MiNEN and 8 adeno-MiNEN. Two of 5 (40%) acinar-MiNEN and one adeno-MiNEN patients had liver metastases. All but one adeno-MiNEN (88%) showed preoperative radiological features of pancreatic adenocarcinoma, 3 of 5 (60%) acinar-MiNEN exhibited mainly neuroendocrine features. No surgical mortality was observed. The 5-year overall survival rate in all MiNEN was 40%. Five-year survival rate was 58% in adeno-MiNEN and comparable to that of matched ductal adenocarcinomas (36%) and pNEN (48%). Five-year overall survival rate was 20% in acinar-MiNEN, compared to 39% in acinar carcinoma patients and 59% in matched pNEN patients.ConclusionsMiNEN are rare and difficult to distinguish from pure adenocarcinoma or neuroendocrine neoplasm preoperatively. Surgical resection would therefore be the treatment of choice in localized tumors.     

Application of low dose pancreas perfusion CT combined with enhancement scanning in diagnosis of pancreatic neuroendocrine tumors

PurposeTo explore the diagnostic value of pancreatic perfusion CT combined with contrast-enhanced CT in one-time scanning (PCECT) in pancreatic neuroendocrine tumors (PNETs) and to evaluate the difference of perfusion parameters between different grades of PNETs.Materials and methodsFrom October 2016 to December 2018, forty consecutive patients with histopathological-proven PNETs were identified retrospectively that received PCECT for the preoperative PNETs evaluation. Two board certified radiologists who were blinded to the clinical data evaluated the images independently. The image characters of PNETs vs. tumor-free pancreatic parenchymal and different grades of PNETs were analyzed.ResultsOne-time PCECT scanning had a detection rate of 89.1% for PNETs, which was higher than the detection accuracy of the perfusion CT only (83.6%). The perfusion parameters of PNETs including blood volume (BV), blood flow (BF), mean slope of increase (MSI), and capillary surface permeability (PS) were significantly increased than those of tumor-free pancreatic parenchyma (p < 0.05, respectively). For differential comparison between grade I (G1) and grade II (G2) tumors, the parameters of BF and impulse residue function (IRF) of tumor tissue were significantly higher in the G2 tumors (p < 0.05, for both). In this study, the total radiation dose of the whole PCECT scan was 16.241 ± 2.289 mSv.ConclusionThe one-time PCECT scan may improve the detection of PNETs according to morphological features and perfusion parameters with a relative small radiation dose. The perfusion parameters of BF and IRF may be used to help distinguish G1 and G2 tumors in the preoperative evaluation.     

结直肠神经内分泌肿瘤25例临床分析

目的探讨结直肠神经内分泌肿瘤的临床特征、诊治方法及预后。 方法回顾分析湖北省肿瘤医院自2006年1月至2015年1月收治的25例结直肠神经内分泌肿瘤患者的临床资料。 结果肿瘤部位：阑尾3例,升结肠3例,乙状结肠2例,直肠17例。分级情况：NET（G1）11例,NET（G2）3例,NEC（G3）8例,MANEC 3例。免疫组织化学：Syn、CgA、NSE阳性表达率为96%,68%和92%。预后：结直肠神经内分泌肿瘤出现转移部位最多见为肝脏。9例Ⅰ期患者生存时间均长于5年。6例Ⅱ期患者,3年内死亡1例,5年内死亡3例,余1例仍在随访中。8例Ⅲ期患者,1年生存率75%,3年生存率50%,5年生存率25%。2例Ⅳ期患者,1例存活28月,另1例存活37月。 结论结直肠神经内分泌肿瘤缺乏特征性临床表现,主要通过内镜下活组织病理检查明确诊断。结直肠神经内分泌肿瘤治疗方法主要依靠手术治疗,早期预后良好,预后与分期和分级密切相关。     

The expression of versican and its role in pancreatic neuroendocrine tumors

BackgroundPancreatic neuroendocrine tumors (pNET) are rare and heterogeneous. New biomarkers are needed for better predicting the prognosis and for providing individualized treatment. Versican (VCAN) plays an important role in tumorigenesis. Therefore, we plan to investigate the role of VCAN in pNET prognosis.MethodThe clinical and pathological data of pNET patients who underwent surgery between 2005 and 2010 were collected and evaluated. Radiologic tumor assessments with contrast computed tomography or magnetic resonance imaging were performed at baseline and follow up. The radiologic response was classified according to the RECIST 1.1 criteria. VCAN expression was assessed by immunohistochemical staining (IHC).ResultAmong 155 pNET patients, 112 (72.3%) pNET patients were VCAN positive, and 43 (27.7%) were negative. Positive expression of VCAN in pNET was significantly associated with a longer disease-free survival (DFS) compared with VCAN negative pNET (p = 0.038, HR 0.462, 95% CI 0.218–0.978). Subgroup analysis showed that VCAN positive expression was associated with a longer DFS in the G1 subgroup (p = 0.031, HR 0.124, 95% CI 0.013–1.193), the tumor size>2 cm subgroup (p = 0.047, HR 0.458, 95% CI 0.207–1.012) and the NF-pNET subgroup (p = 0.003, HR 0.274, 95% CI 0.112–0.673). Multivariable analysis showed that VCAN negative expression, G2 and tumor size>2 cm were independent factors of poor prognosis of pNET (p = 0.041, p < 0.001, p = 0.008, respectively).ConclusionOur data indicate that VCAN positive expression may serve as an independent factor of predicting DFS in pNET; its expression in pNET tissues was correlated with a longer DFS.     

Differing Clinical Courses and Prognoses in Patients With Gastric Neuroendocrine Tumors Based on the 2010-WHO Classification Scheme

The aim of this study is to test the prognostic accuracy of the 2010-WHO classification for postsurgery survival in nonmetastatic gastric neuroendocrine tumor (NET) cases. Whether the 2010-WHO classification of NETs can predict relapse after surgical resection has not yet been established.We selected 175 nonmetastatic gastric NET patients at Asan Medical Center, Seoul, Korea between 1996 and 2013. All tumors were classified using the WHO-2010 scheme.Among 175 patients with gastric NETs, we diagnosed 39 cases as WHO grade 1, 13 cases as grade 2, 66 cases as grade 3 (neuroendocrine carcinomas; NECs), and 57 cases as mixed with adenocarcinoma. Patients with grade 3 had a lower relapse-free survival (RFS) and overall survival (OS) than those with WHO grade 1/2 and had a lower OS than patients with mixed type tumors. Patients with grade 1/2 had a better OS than patients with mixed type. There was no significant difference in RFS and OS between small and large cell type lesions. Among WHO grade 1/2 patients with ≤1 cm sized lesions, none exhibited lympho-vascular, perineural, mucosal, or submucosal invasion, and we detected no lymph node metastases or recurrences.Our findings strongly suggest that WHO grade 3 behaves more aggressively than adenocarcinoma. Additionally, the survival of cases with large and small cell NEC was similar. Among WHO grade 1/2 patients who had ≤1 cm lesions, none exhibited lympho-vascular, perineural, mucosal, or submucosal invasion and all could be treated by endoscopic resection or minimally invasive surgery without node dissection.     

Chronological improvement of pancreatectomy for resectable but advanced pancreatic neuroendocrine neoplasms

BackgroundProgress of non-surgical treatments in the last decade has improved the prognosis of pancreatic neuroendocrine neoplasms (PanNEN). However, the improvement of surgery for advanced PanNEN remains unknown. This study aimed to investigate the chronological changes of the clinical impact of pancreatectomy for PanNEN.MethodsPatients undergoing curative-intent pancreatectomy for PanNEN between 1991 and 2010 were categorized into the earlier period group, and those between 2011 and 2021 were into the later period group.Advanced PanNEN was defined as showing resectable synchronous liver metastases or invasion to portal venous systems or adjacent organs. The recurrence-free survival (RFS) and overall survival (OS) were analyzed among patients with non-advanced and advanced PanNENs. The independent prognostic risk factors were identified using a Cox proportional hazard model.ResultsA total of 189 patients (n = 54 in the earlier period and n = 135 in the later period) were included. The proportion of advanced PanNEN increased from 15% to 30% (P = 0.027). The RFS and OS of non-advanced PanNEN were similar between the periods. Whereas, among patients with advanced PanNEN, the later period group showed improved prognosis; The 5-year RFS of the earlier period vs. the later period was 0% vs. 27%, and the 5-year OS was 38% vs. 82% (p = 0.013).ConclusionsA radical surgical treatment for advanced PanNEN has shown prognostic improvement in this decade. However, more careful perioperative examinations and possibly, additional treatments are required for PanNEN with portal vein invasion.     

Hepatic micrometastases outside macrometastases are present in all patients with ileal neuroendocrine primary tumour at the time of liver resection

Abstract

Background: Neuroendocrine tumours (NETs) in the ileum grow slowly but metastasise to the liver at an early stage. After resection of the primary tumour and mesenteric lymph nodes, selected patients with liver metastases have been operated with curative intention. Recurrence-free survival seems low, suggesting that micrometastases are present in the liver at the time of surgery. We have therefore examined whether NET metastases could be detected in perceived normal liver tissue at the time of liver resection.

Material and methods: Liver tissue outside the macrometastases from patients (n?=?10) operated by liver resection due to metastases from ileal NETs G1/2, were examined for NE cells by immunohistochemistry. Liver tissue from patients operated for metastatic colon cancer was used as control (n?=?6). Groups of ≥3 NE cells ≥3?mm from macrometastases were considered micrometastases. Clinical course was recorded retrospectively.

Results: Ten of 10 patients had micrometastases, consisting of multiple groups of NE cells. None of the control patients had NE cells in the liver tissue. After median follow-up time of 5.5 (0.8–18.7) years 6 of 10 patients had developed recurrent NET metastases detected by cross-sectional imaging. The follow-up time of the four patients without detectable metastases was 4.8 (0.8–7.5) years vs. with detectable metastases 7.9 (3.2–18.7) years.

Conclusions: All patient had micrometastases outside macrometastases at the time of liver resection, suggesting that subsequently recurrent liver metastases develop from NET depositions in the liver already present at the time of surgery. The likelihood of curation by hepatic resection appears very low.     

Pancreatic grade 3 neuroendocrine tumors behave similarly to neuroendocrine carcinomas following resection: a multi-center,international appraisal of the WHO 2010 and WHO 2017 staging schema for pancreatic neuroendocrine lesions

BackgroundIn 2017, the WHO updated their 2010 classification of pancreatic neuroendocrine tumors, introducing a well-differentiated, highly proliferative grade 3 tumor, distinct from neuroendocrine carcinomas. The aim of this study was to investigate the clinical significance of this update in a large cohort of resected tumors.MethodsUsing a multicenter, international dataset of patients with pancreatic neuroendocrine lesions, patients were classified both according to the WHO 2010 and 2017 schema. Multivariable survival analyses were performed, and the models were evaluated for discrimination ability and goodness of fit.ResultsExcluding patients with a known germline MEN1 mutation and incomplete data, 544 patients were analyzed. The performance of the WHO 2010 and 2017 models was similar, however surgically resected grade 3 tumors behaved very similarly to neuroendocrine carcinomas.ConclusionThe addition of a grade 3 NET classification may be of limited utility in surgically resected patients, as these lesions have similar postoperative survival compared to carcinomas. While the addition may allow for a more granular evaluation of novel treatment strategies, surgical intervention for high grade tumors should be considered judiciously.