Surgery in Patients with Gastro-Entero-Pancreatic Neuroendocrine Carcinomas, Neuroendocrine Tumors G3 and High Grade Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms.

OPINION STATEMENT: In the 2019 WHO guidelines, the classification of gastro-entero-pancreatic neuroendocrine neoplasms (GEP NEN) has changed from one being based on Ki-67 proliferation index alone to one that also includes tumor differentiation. Consequently, GEP NENs are now classified as well-differentiated neuroendocrine tumor (NET), NET G1 (Ki-67 <3%), NET G2 (Ki-67 3-20%) and NET G3 (Ki-67 >20%), and poorly differentiated neuroendocrine carcinoma (NEC) (Ki-67 >20%). It has been suggested that NET G3 should be treated as NET G2 with respect to surgery, while surgical management of NEC should be expanded from local disease to also include patients with advanced disease where curative surgery is possible. High grade mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) have a neuroendocrine and a non-neuroendocrine component mostly with a poor prognosis. All studies evaluating the effect of surgery in NEC and MiNEN are observational and hold a risk of selection bias, which may overestimate the beneficial effect of surgery. Further, only a few studies on the effect of surgery in MiNEN exist. This review aims to summarize the data on the outcome of surgery in patients with GEP NET G3, GEP NEC and high grade MiNEN. The current evidence suggests that patients with NEN G3 and localized disease and NEN G3 patients with metastatic disease where curative surgery can be achieved may benefit from surgery. In patients with MiNEN, it is currently not possible to evaluate on the potential beneficial effect of surgery due to the low number of studies.

Long-term outcomes after video-assisted thoracoscopic surgery in pulmonary large-cell neuroendocrine carcinoma.

BACKGROUND: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare subtype of lung cancer with dismal prognosis. Long-term outcomes after primarily video-assisted thoracoscopic surgery (VATS) have not yet been described in LCNEC. This study aims to determine overall survival and recurrence-free survival after VATS as well as to identify prognostic factors for survival and recurrence. METHODS: Data were obtained from a prospective institutional database. Kaplan-Meier estimates of overall survival and recurrence-free survival were determined and compared across prognostic factors using log-rank analysis and the Cox proportional hazards model. RESULTS: Data from 82 consecutive patients undergoing surgical resection from 2009 to 2020 were included. All patients underwent surgical resection with curative intent, of whom 96.3% were by a VATS approach. Morbidity was low without any conversions or 30-day mortality. Lobectomy was performed in 87.8% of patients, followed by wedge resection in 4.9% and segmentectomy in 3.7%. No pneumonectomies were performed. Radical resection (R0) was achieved in 97.6%. Thirty-four patients (41.5%) had adjuvant platinum-based chemotherapy and high proportion completed at least four series (76.7%). The mean follow-up was 5.1 years. The 1-year, 3-year, and 5-year overall survival rates were 86%, 54%, and 45%, while the corresponding recurrence-free survival rates were 67%, 45%, and 35%. Advanced age was an independent predictor of poor overall survival (HR 2.08; 95% CI 1.04-4.17; p = 0.038). CONCLUSION: A 96.3% VATS rate was feasible in LCNEC and associated with a low morbidity rate and a high compliance with adjuvant chemotherapy. Overall survival and recurrence-free survival was comparable to previous series using thoracotomy.

Incidence, Clinical Presentation and Trends in Indication for Diagnostic Work-Up of Small Intestinal and Pancreatic Neuroendocrine Tumors.

BACKGROUND: The incidence of small intestinal (SI) and pancreatic neuroendocrine tumors (siNETs and pNETs) seems to have increased. The increased frequency of incidental findings might be a possible explanation. The study aimed to examine (1) changes in incidence and the stage at diagnosis (2010-2011 vs. 2019-2020), (2) changes in the initial indication for diagnostic workup and 3) the differences in stage between incidentally discovered vs. symptomatic disease during the entire study period. METHODS: We performed a retrospective study, that includes consecutive siNET and pNET patients referred to the Copenhagen ENETS center of excellence in 2010-2011 and 2019-2020. RESULTS: The annual incidence of siNET per 100,000 increased from 1.39 to 1.84, (p = 0.05). There was no change in the stage at diagnosis, and in both periods approximately 30% of patients were incidentally diagnosed (p = 0.62). Dissemination was found in 72/121 (60%) of symptomatic vs. 22/50 (44%) of incidentally discovered SI tumors in the entire cohort, (p = 0.06). The annual incidence of pNET increased from 0.42 to 1.39 per 100,000, (p < 0.001). The proportion of patients with disseminated disease decreased from 8/21 (38%) to 12/75 (16%), (p = 0.02) and the number of incidental findings increased from 4/21 (19%) to 43/75 (57%), (p = 0.002). More symptomatic patients had disseminated disease compared to patients with incidentally discovered tumors (15/49 (31%) vs. 5/47 (11%), (p = 0.01)). CONCLUSION: The incidence of siNET and pNETs increased over the past decade. For siNETs, the stage of disease and the distribution of symptomatic vs. incidentally discovered tumors were unchanged between the two periods. Patients with pNETs presented with more local and incidentally discovered tumors in the latter period. Patients with incidentally discovered siNETs had disseminated disease in 44% of the overall cases. The vast majority of incidentally found pNETs were localized.

Increase of Ki-67 index and influence on mortality in patients with neuroendocrine neoplasms.

An increase in the Ki-67 index in neuroendocrine neoplasms over time in relation to prognosis has scarcely been investigated. We aimed to assess whether the Ki-67 index changed over time and also whether a change influenced prognosis. Second, we investigated the difference in the Ki-67 index between primary tumour and metastases. From 1 January 1995 to 31 December 2019, 108 consecutive patients with gastroenteropancreatic tumours were included. Patients were followed with regard to an increase in the Ki-67 index and all-cause mortality. Ki-67 determination of the primary tumour at diagnosis and at the time of radiological progression, including developed metastases, was performed. A significant increase in the Ki-67 index was defined as a doubling of the value at disease progression compared to the value at diagnosis. In addition, in 14 patients, the Ki-67 index of the primary tumour and present metastases at the time of diagnosis was investigated. At diagnosis, there were no differences in the Ki-67 index between primary tumours and metastases (P = .41). Sixty-five patients had a doubling of the Ki-67 index. The median Ki-67 index at the time of progression 17% (1%-90%) vs 5% (1%-60%) at the time of diagnosis (P = .006). A doubling of the Ki-67 index was independently associated with all-cause mortality (hazard ratio = 2.7 [1.3-6.3], P = 0.02), after adjustment for relevant co-variables including the Ki-67 index at baseline. Doubling of the Ki-67 index at the time of disease progression was associated with a significantly higher risk of all-cause mortality. We recommend that a Ki-67 index is obtained whenever disease progression is recorded by demonstrated progression because it may have impact on the choice of treatment.

Long-term survival and recurrence after resection of bronchopulmonary carcinoids: A single-center cohort study of 236 patients.

OBJECTIVE: The aim of this study was to determine overall survival and recurrence-free survival after resection of bronchopulmonary carcinoids by means of predominantly minimally invasive surgery and lung-sparing resections. In addition, we aimed to identify prognostic factors for overall survival. MATERIALS AND METHODS: Retrospective review of consecutive patients operated for bronchopulmonary carcinoids between January 2009 and October 2020 identified from a prospectively collected database. RESULTS: A total of 236 patients representing 240 cases of bronchopulmonary carcinoids were included. Of these, 212 (88.3 %) were typical carcinoids, while 28 (11.7 %) were atypical carcinoids. A Video-Assisted Thoracoscopic Surgery (VATS) approach was used in 75 % of cases. There was no 30-day mortality. The median follow-up was 5.6 years for overall survival and 4.7 years for recurrence-free survival. 5- and 10-year overall survival rates were 89 % and 71 %, while 5- and 10-year recurrence-free survival rates were 84 % and 71 %. Patients with atypical carcinoids had significantly reduced overall survival and recurrence-free survival rates (HR 3.4; 95 % CI 1.5-7.6; p = 0.003 and HR 5.4; 95 % CI 2.6-11.4; p < 0.001). Independent predictors of overall survival included atypical carcinoid (HR 2.7; 95 % CI 1.2-6.0; p = 0.018) and age > 60 years (HR 2.9; 95 % CI 1.2-7.3; p = 0.021). CONCLUSION: Surgery for bronchopulmonary carcinoids by means of predominantly VATS and lung-sparing resections provides favorable long-term survival. Atypical carcinoids and age > 60 years are independent predictors of poor overall survival.

Nordic guidelines 2021 for diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms.

BACKGROUND: The diagnostic work-up and treatment of patients with gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) has undergone major advances and new methods are introduced. Furthermore, an update of the WHO classification has resulted in a new nomenclature for GEP-NEN that is implemented in the clinic. AIM: These Nordic guidelines summarise the Nordic Neuroendocrine Tumour Group's current view on how to diagnose and treat GEP-NEN patients and aims to be useful in the daily practice for clinicians.

Surgery of the primary tumour in 201 patients with high-grade gastroenteropancreatic neuroendocrine and mixed neuroendocrine-non-neuroendocrine neoplasms.

The benefit of surgery in high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) is uncertain. The present study aimed to investigate outcomes after tumour surgery in patients with high-grade (Ki-67 > 20%) GEP NEN or MiNEN stage I-III or stage IV. We analysed data from patients treated in the period 2007-2015 at eight Nordic university hospitals. Overall survival (OS) and progression-free survival (PFS)/disease-free survival (DFS) were analysed by Kaplan-Meier estimates. Prognostic factors were evaluated using Cox regression. We included 201 surgically resected patients, 143 stage I-III and 58 stage IV, with 68% having neuroendocrine carcinoma, 23% MiNEN, 5% neuroendocrine tumour G3 and 4% uncertain NEN G3. Primary tumours were located in colon/rectum (52%), oesophagus/cardia (19%), pancreas (10%), stomach (7%), jejunum/ileum (5%), duodenum (4%), gallbladder (2%) and anal canal (1%). For patients with stage I-III, median DFS was 12 months (95% confidence interval [CI] = 5.5-18.5) and median OS was 32 months (95% CI = 24.0-40.0). For patients with stage I-III and an R0 resection, median DFS was 21 months (95% CI = 4.9-37.1) and median OS was 39 months (95% CI = 25.0-53.0). For patients with stage IV, median PFS/DFS was 4 months (95% CI = 1.9-6.1) and median OS was 11 months (95% CI = 4.8-17.2). For patients with stage IV and an R0 resection, median DFS was 6 months (95% CI = 0-16.4) and median OS was 32 months (95% CI = 25.5-38.5). Performance status > 1 and colorectal primary were associated with poor prognosis. There was no difference in survival between patients with high-grade GEP NEN and MiNEN. Surgery of the primary tumour in patients with loco-regional high-grade GEP NEN or MiNEN led to good long-term results and should be considered if an R0 resection is considered achievable. Highly selected patients with stage IV disease may also benefit from surgery.

Neuroendocrine neoplasms of the appendix: Characterization of 335 patients referred to the Copenhagen NET Center of Excellence.

INTRODUCTION: Neuroendocrine neoplasms (NEN) of the appendix are often incidentally discovered after appendectomy. Appropriate management is debated. The purpose was to characterize a cohort of 335 appendix NEN and evaluate the risk of recurrence. METHODS: Retrospective collection of data from 335 patients referred to the Neuroendocrine Tumor Center at Rigshospitalet 2000-2019. Appendix goblet cell carcinoids and mixed neuroendocrine non-neuroendocrine neoplasms were excluded. Patients were followed until December 31st, 2019. No patients were lost to follow-up. RESULTS: Sixty-three percent of the patients were female. The median (range) age at diagnosis was 34 (9-92) years. Median follow-up was 66 (1-250) months. Median tumor size was 7 (1-45) mm with 10 (3%) tumors >20 mm. In 18 specimens (5%) resection margins were positive. Mesoappendiceal invasion was found in 113 (35%). Sixty-three (19%) patients underwent right-sided completion hemicolectomy (RHC) after appendectomy according to ENETS guidelines. Among these, 11 (17%) had lymph node metastases in the resected tissue. Further, one patient who underwent initial RHC due to colonic adenocarcinoma had lymph node metastases. All lymph node metastases were detected in patients with serotonin positive tumors. No patients with glucagon positive tumors (n = 85) had lymph node metastases. Mesoappendiceal invasion >3 mm and positive resection margins were associated with presence of lymph node metastases. No recurrences were recorded. CONCLUSION: Following ENETS guidelines may lead to overtreatment of patients with respect to completion RHC. The risk of over- and undertreatment needs to be further evaluated.

Immunohistochemical Staining With Neuroendocrine Markers is Essential in the Diagnosis of Neuroendocrine Neoplasms of the Esophagogastric Junction.

Neuroendocrine neoplasms (NENs) of the esophagogastric junction (EGJ) are uncommon and the classification of these tumors has been revised several times. Since 2016, at the Department of Pathology, Rigshospitalet, Denmark, all adenocarcinomas and poorly differentiated carcinomas of the EGJ have been stained routinely with the neuroendocrine markers, synaptophysin and chromogranin A, to detect a possible neuroendocrine component. This study aimed to determine if routine immunohistochemical staining is necessary to detect neuroendocrine differentiation of the EGJ tumors by evaluating how often a neuroendocrine component of the tumors was correctly identified or missed on routine hematoxylin and eosin-stained slides, and by evaluating the interobserver agreement among several pathologists. Of 262 cases a NEN was identified in 24 (9.2%). Up to 22.7% of all EGJ NENs would have been missed without routinely performed neuroendocrine staining in all EGJ tumors. The interobserver agreement between 3 pathologists was slight to moderate. In conclusion, immunohistochemical staining with neuroendocrine markers is essential for the diagnosis of NENs, and to detect all NENs, we recommend to perform this routinely on all resected tumors of the EGJ.

A Consensus-Developed Morphological Re-Evaluation of 196 High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms and Its Clinical Correlations.

High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are classified according to morphology as well-differentiated neuroendocrine tumours (NETs) G3 or poorly differentiated neuroendocrine carcinomas (NECs). Little data exist concerning which morphological criteria this subdivision should be based on. Uncertainty exists if the NEC group should be further subdivided according to proliferation rate. Clinical data on NET G3 and NEC with a lower Ki-67 range are limited. A total of 213 patients with high-grade GEP-NEN (Ki-67 >20%) were included from the Nordic NEC Registries. Four experienced NET pathologists re-evaluated the cases to develop the best morphological criteria to separate NET G3 from NEC, assuming longer survival in NET G3. Organoid growth pattern, capillary network in direct contact to tumour cells, and absence of desmoplastic stroma were found to best separate NET G3 from NEC. Of 196 patients with metastatic disease, NET G3 was found in 12.3%, NEC with a Ki-67 <55% (NEC < 55) in 29.6%, and NEC with a Ki-67 ≥55% (NEC ≥ 55) in 56.6%. Only in 1.5%, the morphology was ambiguous. Of 164 patients receiving first-line chemotherapy, 88% received platinum/etoposide treatment. Response rate was higher for NEC ≥ 55 (44%) than that of NEC < 55 (25%) and NET G3 (24%) (p = 0.025 and p = 0.026). Median progression-free survival was 5 months for all groups. Median overall survival was 33 months for NET G3 compared to 11 months for both NEC < 55 and NEC ≥ 55 (p = 0.004 and 0.003). Specific morphological criteria can separate NET G3 from NECs and show prognostic significance. High-grade GEP-NEN patients stratified by morphology and proliferation rate demonstrate significant differences in response to chemotherapy and survival.

18F-FDG PET is Superior to WHO Grading as a Prognostic Tool in Neuroendocrine Neoplasms and Useful in Guiding PRRT: A Prospective 10-Year Follow-up Study.

Accurate grading of patients with neuroendocrine neoplasms (NENs) is essential for risk stratification and optimal choice of therapy. Currently, grading is based on histologically assessed degree of tumor proliferation. The aim of the present study was to assess the long-term prognostic value of 18F-FDG PET imaging for risk stratification of NENs and compare it with tumor grading (World Health Organization 2010 classification). Methods: We conducted a prospective cohort study evaluating the prognostic value of 18F-FDG PET imaging and compared it with histologic grading. Enrolled were 166 patients of all grades and with histologically confirmed NENs of gastroenteropancreatic origin. The primary endpoint was overall survival (OS). Progression-free survival (PFS) was a secondary endpoint. In addition, OS in relation to peptide receptor radionuclide therapy (PRRT) was analyzed as an exploratory endpoint. The median follow-up time was 9.8 y. Results: Analysis of the whole cohort revealed that a positive 18F-FDG PET scan was associated with a shorter OS than a negative 18F-FDG PET scan (hazard ratio: 3.8; 95% CI: 2.4-5.9; P < 0.001). In G1 and G2 patients (n = 140), a positive 18F-FDG PET scan was the only identifier of high risk for death (hazard ratio: 3.6; 95% CI, 2.2-5.9; P < 0.001). In multivariate analysis, 18F-FDG PET, G3 tumor, ≥2 liver metastases, and ≥2 prior therapies were independent prognostic factors for OS, and 18F-FDG PET, G3 tumor, and ≥3 liver metastases were independent prognostic factors for PFS. For patients receiving PRRT, 18F-FDG-negative cases had a significantly longer survival than 18F-FDG-positive cases, whereas no difference was identified for tumor grading. 18F-FDG-positive patients receiving PRRT had a significantly longer median survival than patients not receiving PRRT (4.4 vs. 1.4 y, P = 0.001), whereas no difference was seen for 18F-FDG-negative patients. Conclusion:18F-FDG PET is useful for risk stratification of all NEN grades and is superior to histologic grading. 18F-FDG PET could differentiate G1 and G2 tumors into low- and high-risk groups. In the selection of therapy and for risk stratification of NEN patients, 18F-FDG PET status should be considered.

PD-L1 expression in gastroenteropancreatic neuroendocrine neoplasms grade 3.

Gastroenteropancreatic neuroendocrine neoplasms grade 3 (GEP-NENs G3) are rare tumors. These highly aggressive neoplasms are traditionally treated with platinum-based chemotherapy in combination with etoposide. Immune checkpoint proteins such as programmed cell death ligand (PD-L1) may have a role in different cancers allowing them escape the immune system and hence, progress. We aimed to investigate the immunohistochemical expression of PD-L1 in GEP-NEN G3 and evaluate its correlation to clinical parameters. In a cohort of 136 patients, 14 (10%) expressed PD-L1 immunoreactivity; four (3%) patients in the tumor cells and 10 (7%) had immunoreactive immune cells. PD-L1 expression did not correlate to clinical parameters, progression-free survival or overall survival. We conclude that PD-L1 expression is present only in a subset of GEP-NEN G3 patients. Further studies are needed to fully understand the role of PD-L1 in patients with GEP-NEN G3, including the future possibility for treatment with immune checkpoint inhibitors.

Limited Diagnostic Utility of Chromogranin A Measurements in Workup of Neuroendocrine Tumors.

BACKGROUND: Plasma chromogranin A (CgA) is related to tumor burden and recommended in the follow-up of patients diagnosed with neuroendocrine tumors (NETs). The use of CgA in the workup of a suspected NET is more questionable. OBJECTIVE: To assess the positive predictive value (PPV) of CgA plasma concentrations above the upper reference limit (URL) in patients with suspected NET. METHOD: Patients referred to the NET Centre, Rigshospitalet, Copenhagen from 2015 to 2019 with clinically suspected NET were included if a CgA measurement was performed prior to referral. The utility of CgA was assessed by comparing pre-referral CgA concentrations to the outcome of a thorough workup. In 47 selected cases with continuously unexplained elevated CgA concentrations, a processing-independent analysis (PIA) for CgA was performed. RESULTS: A total of 197 patients were included. NET was ultimately diagnosed in 25 patients. CgA plasma concentrations were above the URL (elevated) in 19/25 patients diagnosed with NET. In total, 167/197 had elevated CgA concentrations at referral. The positive predictive value (PPV) of elevated CgA concentration was 11% (19/167). Proton pump inhibitor (PPI) treatment was identified as the possible cause of CgA elevation in 55/148 patients with falsely elevated CgA. CgA concentration was normal in 28/47 patients when using PIA. CONCLUSION: Our data do not support using measurement of CgA for screening when NET is suspected since the PPV was rather low. PPI treatment is a common cause of increased CgA concentrations and should always be discontinued before CgA measurement. PIA of CgA could be a way of excluding NET when suspicion is based primarily on elevated CgA.

Isolated tumor cells in the regional lymph nodes in patients with squamous cell carcinoma of the esophagus are rarely observed but often represent part of a true metastasis.

The most common malignancy of the esophagus is squamous cell carcinoma (SCC) and regional lymph node metastases are an important prognostic factor. Isolated tumor cells (ITCs) are defined as single tumor cells or small clusters of tumor cells not exceeding 0.2 mm. The prognostic role of ITCs is not clear. This study aimed to determine the prevalence of ITCs in regional lymph nodes in patients with esophageal SCC and to investigate how frequently ITCs represent part of a true metastasis. Surgical specimens from 100 patients with SCC of the esophagus were included. All original H&E stained slides containing lymph nodes were reviewed by two gastrointestinal pathologists. In lymph nodes containing ITCs, additional levels were cut and stained with a H&E- and a cytokeratin stain. Areas of tumor cells that measured >0.2 mm on the deeper sections were classified as metastases. A total of 2460 lymph nodes were examined. ITCs were detected in 10 lymph nodes (0.4%) from nine patients (9%). Deeper sections revealed metastases in five out of the 10 lymph nodes (50%). ITCs in regional lymph nodes of patients with SCC of the esophagus is a rare finding compared with patients with adenocarcinoma of the esophagogastric junction. However, deeper sections often revealed metastases. Therefore, in patients with SCC of the esophagus, we recommend additional sectioning and immunohistochemical examination of lymph nodes when ITCs are detected on the first slide.

Acinar cystic transformation of the pancreas: Report of a case and a review of the literature.

Acinar cystic transformation (ACT) is a rare cystic lesion of the pancreas lately reclassified as a non-neoplastic entity. This is a presentation of a case of ACT and a review of the literature. A systematic PubMed search was conducted, yielding a result of 24 publications. Including our case report, 75 cases of ACT have been reported in the literature. The patients are mainly females with initial symptoms of abdominal pain. The cysts are primarily located in the head of the pancreas and are often multilocular on cross section and have a mean size of 53.2 mm. Microscopically, the cysts are lined by an acinar epithelium with abortive acinar formations. The cells are immunohistochemically positive in stains for trypsin, chymotrypsin and CK7. The Ki67-index is low; 1-2 %. No genetic alterations indicative of a neoplastic pathogenesis have been found. The mean follow up time is 37.4 months and no malignant transformation has been observed. A preoperative diagnosis is difficult to establish, but microbiopsies seem a promising tool. The indication for surgical intervention should be founded on the symptoms of the patients since no malignant transformation has ever been reported.

P53, Somatostatin receptor 2a and Chromogranin A immunostaining as prognostic markers in high grade gastroenteropancreatic neuroendocrine neoplasms.

BACKGROUND: High grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) with a Ki67 proliferation index > 20%, include well-differentiated tumours grade 3 (NET G3) and poorly differentiated (PD) neuroendocrine carcinomas (NEC). Abnormal p53-expression is a feature of PD tumours, while expression of chromogranin A (CgA) and somatostatin-receptor 2a (SSTR-2a) may be a feature of well-differentiated tumours. The aim of this study was to elucidate the expression and prognostic value of these three markers in 163 GEP-NEN patients with a Ki67-index > 20%. METHOD: Clinical data, histopathology and overall survival were analysed according to Kaplan-Meier's method and Cox regression. The expression of SSTR-2a, CgA and synaptophysin was analysed in tumour specimens by immunohistochemistry, and semi-quantitatively scored as negative (< 5%), heterogeneously positive (5-30%) or strongly positive (> 30%). P53 was defined as normal when scored as heterogeneously positive (1-30%), and abnormal when negative (0%) or strongly positive (> 30%). RESULTS: In multivariate analysis, better survival was observed among patients with heterogeneously positive p53 compared to strongly positive (p < 0.001). When dichotomised, tumours with a heterogeneously positive p53 vs. negative and strongly positive p53 also showed a significantly better survival (p = 0.002). Survival was significantly worse for negative CgA compared to heterogeneously positive CgA (p = 0.02). Strongly positive SSTR-2a expression was found in 26% of the 163 included patients. Well-differentiated morphology correlated with strong expression of SSTR-2a and CgA, and heterogeneously positive p53-staining, and was more frequent in pancreatic primaries. In pancreatic primaries, strongly positive SSTR-2a was associated with longer survival (univariate analysis, p = 0.02). A significantly lower Ki67 proliferation index was found in patients with a heterogeneously positive p53, a positive SSTR-2a and CgA expression. CONCLUSION: Our results suggest that abnormal p53-expression is an independent negative prognostic marker in GEP-NEN with a Ki67-index > 20%. Patients with heterogeneously positive p53 had the best prognosis. SSTR-2a was a positive prognostic marker in pancreatic NEN. Negative CgA was associated with a significantly worse OS compared to heterogeneously positive CgA-expression in a multivariate sub-analysis. Lower Ki67 index correlated significantly with heterogeneously positive p53, positive SSTR-2a and CgA expression.

Solid pseudopapillary neoplasm of the pancreas: Clinical-pathological features and management, a single-center experience.

Solid pseudopapillary neoplasm of the pancreas is a rare tumor of low malignancy that occurs most often in females. The study describes the clinicopathologic characteristics of the tumor and common differential diagnoses. Data were collected from a prospectively maintained database. Of 1661 patients operated for pancreatic tumors between January 2001 and September 2018, 15 patients were recorded. Patients included 12 females and 3 males, median age 40 (range 10 -87) years. Computed tomography or magnetic resonance imaging was diagnostic in eight patients and a preoperative biopsy in eight out of 10 patients. Median tumor size was 5 cm (range 2 -16 cm), 12 tumors were in the head, six in the body, and three in the tail of the gland. All patients except one had radical resection including one with hepatic and lymph node metastases, no patient underwent oncologic treatment. All patients are alive from 17.5 to 209.4 months postoperatively and without recurrence. Radical operation is usually curative and should also be offered to patients with metastases or recurrence as oncologic treatment has limited effect.

Isolated tumor cells in regional lymph nodes in patients with adenocarcinoma of the esophagogastric junction might represent part of true metastases.

Regional lymph node metastases in patients with carcinoma of the esophagogastric junction (EGJ) are an important prognostic factor. According to the tumor, node, and metastasis classification, isolated tumor cells (ITCs) are single tumor cells or small clusters of tumor cells not exceeding 0.2 mm. Tumor clusters >0.2 mm are classified as metastases. The significance of lymph nodes with ITCs is unclear, although not contributing to the pN category. The aim of this study was to determine the prevalence of regional lymph nodes with ITCs on the primary hematoxylin and eosin-stained slide and to examine how often deeper sections reveal a true metastasis. The study included surgical specimens of 126 patients with adenocarcinoma of the EGJ. Lymph nodes with ITCs were identified. Additional sections were cut and stained with hematoxylin and eosin and with cytokeratin. All slides were evaluated for the presence of tumor cells, and it was determined whether the criteria for a metastasis were met on the additional sections. ITCs were detected in 59 (1.7%) of 3454 lymph nodes and in 41 (32.5%) of 126 patients. In 29 (49.2%) lymph nodes with ITCs on the primary slide, further sections resulted in a changed status from ITCs to a metastasis. In 7 (17.1%) of 41 patients, the pN category was changed. In patients with adenocarcinoma of the EGJ, the presence of ITCs in regional lymph nodes is a common observation. ITCs often represent part of a real metastasis. To obtain a pN category as accurate as possible, we strongly recommend thorough examination of regional lymph nodes with additional sections when ITCs are observed.

Surgical Management, Preoperative Tumor Localization, and Histopathology of 80 Patients Operated on for Insulinoma.

INTRODUCTION: Diagnosis and pathological classification of insulinomas are challenging. AIM: To characterize localization of tumors, surgery outcomes, and histopathology in patients with insulinoma. METHODS: Patients with surgically resected sporadic insulinoma were included. RESULTS: Eighty patients were included. Seven had a malignant tumor. A total of 312 diagnostic examinations were performed: endoscopic ultrasonography (EUS; n = 59; sensitivity, 70%), MRI (n = 33; sensitivity, 58%), CT (n = 55; sensitivity, 47%), transabdominal ultrasonography (US; n = 45; sensitivity, 40%), somatostatin receptor imaging (n = 17; sensitivity, 29%), 18F-fluorodeoxyglucose positron emission tomography/CT (n = 1; negative), percutaneous transhepatic venous sampling (n = 10; sensitivity, 90%), arterial stimulation venous sampling (n = 20; sensitivity, 65%), and intraoperative US (n = 72; sensitivity, 89%). Fourteen tumors could not be visualized. Invasive methods were used in 7 of these 14 patients and localized the tumor in all cases. Median tumor size was 15 mm (range, 7 to 80 mm). Tumors with malignant vs benign behavior showed less staining for insulin (3 of 7 vs 66 of 73; P = 0.015) and for proinsulin (3 of 6 vs 58 of 59; P < 0.001). Staining for glucagon was seen in 2 of 6 malignant tumors and in no benign tumors (P < 0.001). Forty-three insulinomas stained negative for somatostatin receptor subtype 2a. CONCLUSION: Localization of insulinomas requires many different diagnostic procedures. Most tumors can be localized by conventional imaging, including EUS. For nonvisible tumors, invasive methods may be a useful diagnostic tool. Malignant tumors showed reduced staining for insulin and proinsulin and increased staining for glucagon.