Complications of Gastrostomy Tubes in Patients With Head and Neck Cancer.

OBJECTIVES: Head and neck cancers (HNCs) include various malignant tumors of the upper aerodigestive tract. Due to their anatomical location, HNCs can cause obstruction, odynophagia, or trismus, leading to dysphagia. In addition, this patient group may be vulnerable to treatment side effects both by surgery and oncological treatment, exposing the patients to an even higher risk of malnutrition. The risk of malnourishment is often resolved by applying a feeding gastrostomy tube. The present study aims to identify complication rates after percutaneous endoscopic gastrostomy (PEG) and open gastrostomy (OG) in patients treated for HNC in a high-volume center. STUDY DESIGN: Retrospective cohort study. METHODS: A retrospective cohort study of all patients treated for a new diagnosis of HNC at the Department of Otorhinolaryngology and Head and Neck Surgery at Karolinska University Hospital between January 1, 2000 and December 31, 2018 in whom gastrostomy was performed. RESULTS: Regarding tumor location, 165 (56.7%) were in the pharynx, 68 (23.4%) in the oral cavity, 57 (19.6%) in the larynx, and 1 (0.3%) in the nasal cavity. PEG was performed in 240 (82.5%) and OG in 51 (17.5%) patients. The overall complication rate was 28.2%: 64 (26.7%) among PEG patients and 18 (35.3%) among OG patients. The incidence of major complications was 3.1%. CONCLUSIONS: Our study confirms that enteral feeding via gastrostomy is a safe method, regardless of the technique used (PEG or OG), with a low rate of major complications and no mortality linked to the procedure. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:1778-1784, 2022.

A Critical Appraisal of Contemporary and Novel Biomarkers in Pheochromocytomas and Adrenocortical Tumors.

Pheochromocytomas/Paragangliomas (PPGLs) and adrenocortical tumors are rare neoplasms with significant heterogeneity in their biologic and clinical behavior. Current diagnostic and predictive biomarkers include hormone secretion, as well as histopathological and genetic features. PPGL diagnosis is based on biochemical measurement of catecholamines/metanephrines, while histopathological scoring systems have been proposed to predict the risk of malignancy. Adrenocortical tumors are mostly benign, but some can be malignant. Currently, the stage of disease at diagnosis and tumor grade, appear to be the most powerful prognostic factors. However, recent genomic and proteomic studies have identified new genetic and circulating biomarkers, including genes, immunohistochemical markers and micro-RNAs that display high specificity and sensitivity as diagnostic or prognostic tools. In addition, new molecular classifications have been proposed that divide adrenal tumors in distinct subgroups with different clinical outcomes.

Effectiveness of percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis.

BACKGROUND: Weight loss and dysphagia are frequent features of amyotrophic lateral sclerosis (ALS) and influence prognosis. The aim of this study was to determine complications and outcomes in patients with percutaneous endoscopic gastrostomy (PEG) insertion in a high-volume center. METHODS: A single center retrospective study on a prospectively collected cohort of 187 consecutive patients who have undergone PEG placement due to ALS was performed. Demographic and clinical parameters were analyzed. RESULTS: There were 51.3% male; mean age at insertion was 65.7 years. Major complications occurred in 5 (2.7%) patients: 3 with local infections requiring intravenous antibiotic treatment, 1 patient with PEG dislocation required laparotomy and a new surgically introduced gastrostomy and 1 patient with buried-bumper syndrome. Improvement in Body Mass Index (BMI) and serum albumin levels were recorded in 37.3% and 51.9%, respectively. Mortality after 30 days, 6 months and 12 months was 5.3%, 38% and 64.3%, respectively. At the time of data collection, 78.9% of the patients had died. Mean survival after ALS diagnosis was 20.5 months. CONCLUSIONS: PEG placement is as an effective, safe nutritional method with a low complication rate in patients with ALS, with or without non-invasive ventilation. The BMI and albumin levels stabilize after PEG placement, indicating benefits of early placement.

Clinical importance of main pancreatic duct variants and possible correlation with pancreatic diseases.

Background: Except for pancreas divisum (PD), the prevalence of anatomic variants of the main pancreatic duct (MPD) seems to be insufficiently investigated. To date, their role in the occurrence of pancreatic exocrine insufficiency (PEI) and morphological changes suggestive of chronic pancreatitis (CP) has remained unclear.Methods: A systematic review was performed, searching MEDLINE and Web of Science, limited to articles published between 1960 and 1 June 2019.Results: Our review included a total number of 3234 subjects. The most common variant of MPD was type 3, followed by type 1, indicating MPD drainage pattern into major papilla (MP) as the most frequent. A sub-variant of type 3, known as 'reverse pancreas divisum' had a prevalence of 2.2%. Type 4 variant- PD, was found in 6.4% of all cases. The most common sub-variant of PD was complete PD, followed by incomplete PD and variant with MPD as only pancreatic duct. Type 5 variant (including ansa pancreatica) was present in 2.9% of subjects. Apart from one study with a significantly higher frequency of morphological changes suggestive of CP in patients with ansa pancreatica, the studies stated no significant association between pancreatic disease and MPD variants. Furthermore, only one study examined the influence of MPD variants on exocrine pancreatic function. Although equivocal, this association is most likely found to be insignificant.Conclusion: To elucidate linkage between MPD variants and the occurrence of chronic pancreatitis and impairment of pancreatic exocrine function, further clinical investigations are warranted.

Increased autophagy/mitophagy levels in primary tumours of patients with pancreatic neuroendocrine neoplasms.

BACKGROUND/AIMS: We assessed the levels of autophagy and mitophagy, that are linked to cancer development and drug resistance, in well differentiated pancreatic neuroendocrine neoplasms (PanNENs) and correlated them with clinico-pathological parameters. METHODS: Fluorescent immunostaining for the autophagy markers LC3Β and p62/or LAMP1 was performed on 22 PanNENs and 11 controls of normal pancreatic tissues and validated through Western blotting. Autophagy quantitative scoring was generated for LC3B-positive puncta and analysed in relation to clinico-pathological parameters. TOMM20/LC3B qualitative assessment of mitophagy levels was undertaken by fluorescent immunostaining. The presence of autophagy/mitophagy was validated by transmission electron microscopy. RESULTS: Autophagy levels (LC3B-positive puncta/cell) were discriminative for normal vs. NEN pancreatic tissue (p = 0.007). A significant association was observed between autophagy levels and tumour grade (Ki67 < 3% vs. Ki67 ≥ 3%; p = 0.021), but not functionality (p = 0.266) size (cut-off of 20 mm; p = 0.808), local invasion (p = 0.481), lymph node- (p = 0.849) and distant metastases (p = 0.699). Qualitative assessment of TOMM20/LC3B demonstrated strong mitophagy levels in PanNENs by fluorescent immunostaining as compared with normal tissue. Transmission electron microscopy revealed enhanced autophagy and mitophagy in PanNEN tissue. Response to molecular targeted therapies in metastatic cases (n = 4) did not reveal any patterns of association to autophagy levels. CONCLUSIONS: Increased autophagy levels are present in primary tumours of patients with PanNENs and are partially attributed to upregulated mitophagy. Grade was the only clinico-pathological parameter associated with autophagy scores.

Chronic pancreatitis and the heart disease: Still terra incognita?

BACKGROUND: It has been suggested that chronic pancreatitis (CP) may be an independent risk factor for development of cardiovascular disease (CVD). At the same time, it seems that congestive heart failure (CHF) and CP share the responsibility for the development of important clinical conditions such as sarcopenia, cachexia and malnutrition due to development of cardiac cachexia and pancreatic exocrine insufficiency (PEI), respectively. AIM: To explore the evidence regarding the association of CP and heart disease, more specifically CVD and CHF. METHODS: A systematic search of MEDLINE, Web of Science and Google Scholar was performed by two independent investigators to identify eligible studies where the connection between CP and CVD was investigated. The search was limited to articles in the English language. The last search was run on the 1st of May 2019. The primary outcomes were: (1) Incidence of cardiovascular event [acute coronary syndrome (ACS), chronic coronary disease, peripheral arterial lesions] in patients with established CP; and (2) Incidence of PEI in patients with CHF. RESULTS: Out of 1166 studies, only 8 were eligible for this review. Studies regarding PEI and CHF showed an important incidence of PEI as well as associated malabsorption of nutritional markers (vitamin D, selenium, phosphorus, zinc, folic acid, and prealbumin) in patients with CHF. However, after substitution of pancreatic enzymes, it seems that, at least, loss of appetite was attenuated. On the other side, studies investigating cardiovascular events in patients with CP showed that, in CP cohort, there was a 2.5-fold higher incidence of ACS. In another study, patients with alcohol-induced CP with concomitant type 3c diabetes had statistically significant higher incidence of carotid atherosclerotic plaques in comparison to patients with diabetes mellitus of other etiologies. Earlier studies demonstrated a marked correlation between the clinical symptoms in CP and chronic coronary insufficiency. Also, statistically significant higher incidence of arterial lesions was found in patients with CP compared to the control group with the same risk factors for atherosclerosis (hypertension, smoking, dyslipidemia). Moreover, one recent study showed that PEI is significantly associated with the risk of cardiovascular events in patients with CP. CONCLUSION: Current evidence implicates a possible association between PEI and malnutrition in patients with CHF. Chronic pancreatic tissue hypoxic injury driven by prolonged splanchnic hypoperfusion is likely to contribute to malnutrition and cachexia in patients with CHF. On the other hand, CP and PEI seem to be an independent risk factor associated with an increased risk of cardiovascular events.

Gastric neuroendocrine neoplasms type 1: A systematic review and meta-analysis.

BACKGROUND: To date, the histopathological parameters predicting the risk of lymph node (LN) metastases and local recurrence, associated mortality and appropriateness of endoscopic or surgical resection in patients with gastric neuroendocrine neoplasms type 1 (GNENs1) have not been fully elucidated. AIM: To determine the rate of LN metastases and its impact in survival in patients with GNEN1 in relation to certain clinico-pathological parameters. METHODS: The PubMed, EMBASE, Cochrane Library, Web of Science and Scopus databases were searched through January 2019. The quality of the included studies and risk of bias were assessed using the Newcastle-Ottawa Scale (NOS) in accordance with the Cochrane guidelines. A random effects model and pooled odds ratios (OR) with 95%CI were applied for the quantitative meta-analysis. RESULTS: We screened 2933 articles. Thirteen studies with 769 unique patients with GNEN1 were included. Overall, the rate of metastasis to locoregional LNs was 3.3% (25/769). The rate of LN metastases with a cut-off size of 10 mm was 15.3% for lesions > 10 mm (vs 0.8% for lesions < 10 mm) with a random-effects OR of 10.5 (95%CI: 1.4 -80.8; heterogeneity: P = 0.126; I 2 = 47.5%). Invasion of the muscularis propria was identified as a predictor for LN metastases (OR: 17.2; 95%CI: 1.8-161.1; heterogeneity: P = 0.165; I 2 = 44.5%), whereas grade was not clearly associated with LN metastases (OR: 2; 95%CI: 0.3-11.6; heterogeneity: P = 0.304; I 2 = 17.4%). With regard to GNEN1 local recurrence, scarce data were available. The 5-year disease-specific survival for patients with and without LN metastases was 100% in most available studies irrespective of the type of intervention. Surgical resection was linked to a lower risk of recurrence (OR: 0.3; 95%CI: 0.1-1.1; heterogeneity: P = 0.173; I 2 = 31.9%). The reported complication rates of endoscopic and surgical intervention were 0.6 and 3.8%, respectively. CONCLUSION: This meta-analysis confirms that tumor size ≥ 10 mm and invasion of the muscularis propria are linked to a higher risk of LN metastases in patients with GNEN1. Overall, the metastatic propensity of GNEN1 is low with favorable 5-year disease-specific survival rates reported; hence, no clear evidence of the prognostic value of LN positivity is available. Additionally, there is a lack of evidence supporting the prediction of local recurrence in GNEN1, even if surgery was more often a definitive treatment.

Synaptic Vesicle Protein 2 and Vesicular Monoamine Transporter 1 and 2 Are Expressed in Neuroblastoma.

Neuroblastoma (NB), the most common extracranial cancer in childhood, exhibits neuroendocrine (NE) differentiation. Two well-established NE markers, chromogranin A (CgA) and synaptophysin (syn), are used in the histopathological diagnostics. Our aims were to explore if the NE markers synaptic vesicle protein 2 (SV2) and vesicular monoamine transporter 1 (VMAT1) and 2 (VMAT2) also are expressed in human NB and if so, evaluate their usefulness in NB histopathological diagnostics. Tumor specimens from 21 NB patients, before and/or after chemotherapy, were immunostained for CgA, syn, SV2, VMAT1, and VMAT2. Clinical data was extracted from patients' records. SV2 was highly expressed in NB, as was CgA while syn was less frequently expressed compared to the other two. Both VMATs were expressed in several NB, VMAT2 in more cases than VMAT1 and its expression was similar to syn. Chemotherapy did not affect the immunoreactivity in an obvious way. SV2 was highly expressed in NB and can thus be useful marker in NB diagnostics. VMAT1 and VMAT2 were also expressed in NB but similar to syn less reliable as tumor markers.

Magnetic Resonance Imaging or Endoscopic Ultrasonography for Detection and Surveillance of Pancreatic Neuroendocrine Neoplasms in Patients with Multiple Endocrine Neoplasia Type 1?

Our aim was to compare the clinical utility of Magnetic Resonance Imaging (MRI) and Endoscopic Ultrasonography (EUS) in identifying Pancreatic Neurondocrine Neoplasms (PanNENs) and monitoring size alterations in Multiple Endocrine Neoplasia type 1 (MEN1) patients. Thirty-one MEN1 patients with PanNENs and concurrent screening by EUS and abdominal MRI were included and 129 pancreatic lesions were detected in total. MRI detected fewer lesions than EUS (n=73 vs. 110, p=0.006). MRI sensitivity and specificity compared to EUS at 20 and 10 mm cut-offs of maximal lesion diameter were 96 and 88% (20 mm cut-off) and 90 and 82%(10 mm cut-off), respectively (concordance rates of 97 and 87% and Cohen's kappa=0.912 and 0.718, respectively). Lesions<1 cm were more often detected with EUS (p=0.025). Data from sequential concurrent imaging on lesion growth rate [n=7 (mean±SD: 2 mm/year±3.4 mm vs. 1.9 mm/year±3.6 mm)] over a period of at least two years as well as pathology data in connection to preoperative concurrent imaging were available in a small number of patients (n=7, p=0.933 for mean differences in maximal lesion diameter). MRI of the pancreas was more readily available and less expensive than EUS in an outpatient setting. In conclusion, MRI performs well compared to EUS for the detection and subsequent surveillance of MEN1-related panNENs larger than 10 mm and seems to be cost-effective. Both modalities could be used at initial assessment and MRI alone could be utilized thereafter in patient surveillance. EUS retains its value in surgical planning and the detection of small mostly functional PanNENs.

Endocrine paraneoplastic syndromes in patients with neuroendocrine neoplasms.

OBJECTIVE: Our aim was to assess the prevalence of endocrine paraneoplastic syndromes (EPNS) in neuroendocrine neoplasms (NENs) and estimate its impact on patient outcomes. DESIGN: This is a retrospective analysis of 834 patients with NENs (611 gastrointestinal, 166 thoracic, 57 of unknown and various other primary origin). We included 719 consecutive NEN patients treated at EKPA-Laiko Hospital, Athens, Greece and 115 patients with lung carcinoid (LC) treated at Uppsala University Hospital, Uppsala, Sweden. EPNS diagnosis was based on standard criteria. METHODS: Twenty-one patients with EPNS were detected: 16 with ectopic Cushing's syndrome (ECS), one with hypercalcaemia due to parathyroid hormone-related protein (PTHrP) secretion, three with hypercalcitonaemia and one patient with dual secretion of calcitonin and beta-human chorionic gonadotropin (ß-HCG). All tumours were well-differentiated; 10 patients had Stage IV disease at diagnosis. RESULTS: The prevalence of EPNS in the Greek cohort was 1.9%, whereas that of ECS among LC patients in both centres was 6.7%. Median overall survival (OS) for patients with EPNS was 160.7 months (95%CI, 86-235.4) and median event-free survival (EFS) was 25.9 months (95%CI, 0-57.2). Patients presenting with EPNS prior to NEN diagnosis had longer EFS compared to patients with synchronous or metachronous EPNS (log-rank P = 0.013). Patients with ECS of extra-thoracic origin demonstrated shorter OS and EFS compared to patients with ECS of lung or thymic origin (log-rank P = 0.001 and P < 0.001, respectively). LC patients with and without ECS were comparable in 5-year and 10-year OS rates (66.7% and 33.3% versus 89.8% and 60.2%, respectively; 95%CI [189.6-300.4 months], log-rank P = 0.94) and in median EFS, 67 versus 183 months, 95%CI [50.5-207.5], log-rank P = 0.12). CONCLUSION: EPNS are relatively rare in patients with NENs and mainly concern well-differentiated tumours of the foregut. Among patients with EPNS, LC-related ECS may not adversely affect patient outcomes when diagnosed prior to NEN and effectively been treated.

Lung Carcinoids: Long-Term Surgical Results and the Lack of Prognostic Value of Somatostatin Receptors and Other Novel Immunohistochemical Markers.

BACKGROUND/AIMS: Lung carcinoids (LCs) are often diagnosed at an early stage and surgical intervention becomes the next phase of treatment. To date, there is lack of long-term follow-up data after surgery and prognostication based on WHO classification criteria and evolving prognostic markers, particularly the expression of somatostatin receptors (SSR). METHODS: We included 102 consecutive patients (72 women; age at baseline 51 ± 16 years [mean ± SD]) with LCs, who underwent thoracic surgery (n = 99) and/or laser treatment (n = 8). Hospital charts were reviewed for clinico-pathological parameters. Immunohistochemical (IHC) expression of SSR1-5 and other novel markers were studied with regard to their prognostic value. RESULTS: Five- and 10-year overall survival (OS) was 96 and 83% respectively; relative survival (RS) was 101 and 93% respectively; and event-free survival (EFS) was 80 and 67% respectively. Independent prognostic factors for OS, RS and/or EFS were age at diagnosis, histopathological type and the presence of ipsilateral mediastinal subcarinal lymph node metastases. Macro-radicality of resective surgery and its extent were associated with increased OS and EFS. The IHC expression of SSR1-5 and other novel markers was not associated with OS or EFS. CONCLUSION: The long-term outcome of surgically treated patients with LCs is favourable. Age, histopathological type and ipsilateral mediastinal subcarinal lymph node status at baseline were independent prognostic factors for survival and disease recurrence or progression. The extent of surgery and operative macro-radicality also had an impact on prognosis. None of the IHC markers tested appeared to be associated with disease prognosis.

Upfront surgery of small intestinal neuroendocrine tumors. Time to reconsider?

Small intestinal neuroendocrine tumors (SI-NETs) may demonstrate a widely variable clinical behavior but usually it is indolent. In cases with localized disease, locoregional resective surgery (LRS) is generally indicated with a curative intent. LRS of SI-NETs is also the recommended treatment when symptoms are present, regardless of the disease stage. Concerning asymptomatic patients with distant metastases, prophylactic LRS has been traditionally suggested to avoid possible future complications. Even the current European Neuroendocrine Tumor Society guidelines emphasize a possible effect of LRS in Stage IV SI-NETs with unresectable liver metastases. On the contrary, the 2017 National Comprehensive Cancer Network Guidelines on carcinoid tumors do not support the resection of a small, asymptomatic, relatively stable primary tumor in the presence of unresectable metastatic disease. Furthermore, a recent study revealed no survival advantage for asymptomatic patients with distant-stage disease who underwent upfront LRS. At the aforementioned paper, it was suggested that delayed surgery as needed was comparable with the upfront surgical approach in terms of postoperative morbidity and mortality, the length of the hospital stay and the rate of incisional hernia repairs but was associated with fewer reoperations for bowel obstruction. On the other hand, it is also important to note that some patients might benefit from a prophylactic surgical approach and our attention should focus on identifying this patient population.

Can insulin-like growth factor 1 (IGF-1), IGF-1 receptor connective tissue growth factor and Ki-67 labelling index have a prognostic role in pulmonary carcinoids?

INTRODUCTION: Altered expression of Insulin-like Growth Factor-1 (IGF-1), its receptor (IGF-1R), Connective Tissue Growth Factor (CTGF) and Hypoxia Inducible Factor-1 (HIF-1), has been implicated in tumorigenesis. So far, these factors have not been studied systematically in Pulmonary Carcinoids (PCs). AIMS: To examine IGF-1, IGF-1R, CTGF and HIF-1 expression in PCs, and assess their prognostic value over established factors. MATERIALS & METHODS: Retrospective study of 121 PCs (104 Typical and 17 Atypical). The expression of growth factors was studied immunohistochemically and tumors were considered positive if immunoreactivity appeared in >50% of cells. RESULTS: All studied parameters were expressed in the majority of tumors (IGF-1, IGF-1R, CTGF and HIF-1, in 78.5%, 67%, 72% and 78%, respectively). Their expression tended to be more frequent in TCs and in tumors with Ki-67≤2% (significant only for HIF-1; 82 vs. 53%; p=0.023 and 83 vs. 63%; p=0.025 respectively). CTGF was the only factor correlated with more extensive disease (larger size; presence of lymph node and distant metastases). According to logistic regression analysis, only advanced age, Ki-67≥3.4% and lymph node involvement could predict the development of distant metastases. CONCLUSIONS: IGF-1, IGF-1R, CTGF and HIF-1 are avidly expressed in PCs; however, their presence did not appear to be of statistically significant value over established prognostic factors.

Clinical prediction rule to determine the need for repeat ERCP after endoscopic treatment of postsurgical bile leaks.

BACKGROUND AND AIMS: In patients who have undergone ERCP with biliary stenting for postsurgical bile leaks, the optimal method (ERCP or gastroscopy) and timing of stent removal is controversial. We developed a clinical prediction rule to identify cases in which a repeat ERCP is unnecessary. METHODS: Population-based study of all patients who underwent ERCP for management of surgically induced bile leaks between 2000 and 2012. Multivariate and binary recursive partitioning analyses were performed to generate a rule predicting the absence of biliary pathology on repeat endoscopic evaluation. RESULTS: A total of 259 patients were included. On multivariate analysis, postsurgical normal alkaline phosphatase (ALP; OR, 2.26; 95% CI, 1.03-4.99), time from surgery to first ERCP < 8 days (OR, 2.47; 95% CI, 1.15-5.31), and minor leak with no other pathology on initial ERCP (OR, 6.74; 95% CI, 1.75-25.89) were independently associated with the absence of persistent bile leak and other pathology on repeat ERCP. The derived rule included laparoscopic cholecystectomy, normal postsurgical ALP, minor leak with no other pathology on initial ERCP, and an interval from initial to repeat ERCP between 4 and 8 weeks. When all 4 criteria were met, the rule had a sensitivity of 94% (95% CI, 83%-99%) and a negative predictive value of 93% (95% CI, 81%-99%). Optimism-adjusted sensitivity and negative predictive value were 88% (95% CI, 76%-96%) and 86% (95% CI, 73%-96%), respectively. CONCLUSIONS: This clinical decision rule identifies patients who can have their biliary stents removed via gastroscopy, which may improve patient safety and healthcare utilization.

Differential diagnosis between pancreatic neuroendocrine and solid pseudopapillary neoplasms on endoscopic ultrasound-guided fine-needle aspiration. An immunohistochemical study.

OBJECTIVES: To evaluate the role of applying a limited panel of immunohistochemical stains on the cellblock preparation from samples obtained by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in the aim of differentiating solid pseudopapillary neoplasms (SPNs) from neuroendocrine tumors (NETs).  METHODS: We retrospectively retrieved all the EUS-FNAs of the pancreas that have a diagnosis of NET or SPN that were performed at 2 tertiary care hospitals in Riyadh, Kingdom of Saudi Arabia from May 2004 to December 2014. Diff-Quik, Papanicolaou, and Immunohistochemistry stains on cellblock preparations were performed.   RESULTS: Twenty cases were available (16 pancreatic neuroendocrine tumors (pNETs) and 4 SPNs). The pNETs were immunoreactive for synaptophysin, chromogranin A and CD56 while E-cadherin was diffusely to focally cytoplasmic positive. ß-catenin was negative or showed focal cytoplasmic immunoreactivity. In comparison, SPNs were positive for vimentin, CD10, CD-56, focally positive for progesterone receptors and synaptophysin, and revealed nuclear immunostaining for ß-catenin. They were negative for chromogranin A and E-cadherin.  CONCLUSION: Based on EUS-FNA samples, nuclear immunoreactivity for ß-catenin with loss of membranous immunostaining for E-Cadherin can potentially facilitate differentiating SPNs from pNETs.

Histidine decarboxylase and urinary methylimidazoleacetic acid in gastric neuroendocrine cells and tumours.

AIM: To study histidine decarboxylase (HDC) expression in normal and neoplastic gastric neuroendocrine cells in relationship to the main histamine metabolite. METHODS: Control tissues from fundus (n = 3) and corpus (n = 3) mucosa of six patients undergoing operations for gastric adenocarcinoma, biopsy and/or gastric surgical specimens from 64 patients with primary gastric neuroendocrine tumours (GNETs), as well as metastases from 22 of these patients, were investigated using conventional immunohistochemistry and double immunofluorescence with commercial antibodies vs vesicular monoamine transporter 2 (VMAT-2), HDC and ghrelin. The urinary excretion of the main histamine metabolite methylimidazoleacetic acid (U-MeImAA) was determined using high-performance liquid chromatography in 27 of the 64 patients. RESULTS: In the gastric mucosa of the control tissues, co-localization studies identified neuroendocrine cells that showed immunoreactivity only to VMAT-2 and others with reactivity only to HDC. A third cell population co-expressed both antigens. There was no co-expression of HDC and ghrelin. Similar results were obtained in the foci of neuroendocrine cell hyperplasia associated with chronic atrophic gastritis type A and also in the tumours. The relative incidence of the three aforementioned markers varied in the tumours that were examined using conventional immunohistochemistry. All of these GNETs revealed both VMAT-2 and HDC immunoreactivity, and their metastases showed an immunohistochemical pattern and frequency similar to that of their primary tumours. In four patients, increased U-MeImAA excretion was detected, but only two of the patients exhibited related endocrine symptoms. CONCLUSION: Human enterochromaffin-like cells appear to partially co-express VMAT-2 and HDC. Co-expression of VMAT-2 and HDC might be required for increased histamine production in patients with GNETs.

Somatostatin and dopamine receptor expression in neuroendocrine neoplasms: correlation of immunohistochemical findings with somatostatin receptor scintigraphy visual scores.

CONTEXT: The expression of somatostatin (sstr1-5) and dopamine (DR) receptors in neuroendocrine neoplasms (NENs) facilitates diagnosis by tumour visualization with somatostatin receptor scintigraphy (SRS) and directs towards specific treatment with peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues. OBJECTIVE: To investigate the co-expression of sstrs, D2R in relation to pre-operative SRSs in NENs. DESIGN: Prospective two-centre study. PATIENTS AND MEASUREMENTS: We analysed pre-operative SRS of 60 patients [44 with gastrointestinal (GI) NENs and 16 with lung NENs] and compared SRS results with immunohistochemical (IHC) reactivity for sstr2, sstr3, sstr5 in sample tissues from primary (n = 54) and metastatic (n = 27) lesions and IHC reactivity for D2R in 23 samples from primary GI-NENs lesions. RESULTS: Sstr2 was the commonest sstr expressed (65·4%) and was co-expressed with sstr3 and sstr5 in 32·1% and 24·7% of the specimens, respectively. In 67 of 81 specimens (82·7%), there was concordance of sstr2 immunohistochemistry with SRS findings (P < 0·001). D2R was expressed in only 8 of 23 (34·8%) GI-NENs while was co-expressed with sstr2 in all cases. SRS grade, as per Krenning scale, was higher in metastatic foci, large-size (>2 cm) tumours and GI-NENs, whereas sstr2 intensity was greater in GI compared to lung NENs. SRS grade showed higher correlation with sstr2 (r = 0·6, P < 0·001) and D2R (r = 0·5, P < 0·001) IHC intensity scores than tumour size (r = 0·4, P < 0·001) and sstr3 (r = 0·4, P < 0·001) intensity score. CONCLUSIONS: Sstr2 IHC expression and SRS are useful tools for the diagnosis and management of NENs because they display a high concordance. IHC expression of DR2 seems to be of potential clinical significance in GI-NENs tumours.

Expression of Somatostatin Receptors 1-5 and Dopamine Receptor 2 in Lung Carcinoids: Implications for a Therapeutic Role.

OBJECTIVE: The expression of somatostatin receptors (SSTRs) and dopamine receptor 2 (DR2) in neuroendocrine tumors is of clinical importance as somatostatin analogues and dopamine agonists can be used for their localization and/or treatment. The objective of this study is to examine the expression of the five SSTR subtypes and DR2 in lung carcinoids (LCs). METHODS: We conducted a retrospective study of 119 LCs from 106 patients [typical carcinoids (TCs): n = 100, and atypical carcinoids (ACs): n = 19]. The expression of all five SSTR subtypes and DR2 was evaluated immunohistochemically and correlated to clinicopathological data. In a subgroup of cases, receptor expression was further analyzed using semiquantitative RT-PCR. RESULTS: SSTR2A was the SSTR subtype most frequently expressed immunohistochemically (72%), followed by SSTR1 (63%), SSTR5 (40%), and SSTR3 (20%), whereas SSTR4 was negative. DR2 was expressed in 74% and co-expressed with SSTR1 in 56%, with SSTR2A in 59%, with SSTR3 in 19%, and with SSTR5 in 37% of the tumors. Receptor expression was not related to the histological subtype, tumor aggressiveness (disease extent/grading) or functionality; however, DR2 was expressed more frequently in ACs than TCs (95 vs. 70%, p = 0.017). In a subset of patients, RT-PCR findings highly suggested that the expression of SSTR2A, SSTR3, DR2, and to a lesser extent that of SSTR1 and SSTR5 is the outcome of increased gene transcription. CONCLUSIONS: The high and variable immunohistochemical expression of the majority of SSTRs along with their co-expression with DR2 in LCs provides a rationale for their possible treatment with agents that target these receptors.

Incremental benefit of preoperative EUS for the detection of pancreatic neuroendocrine tumors: a meta-analysis.

BACKGROUND: Current guidelines recommend CT scan or magnetic resonance imaging as the initial imaging modalities for the work-up of suspected pancreatic neuroendocrine tumors (PNETs). OBJECTIVE: To determine the incremental benefit of preoperative EUS (IBEUS) for the detection of suspected PNETs after other investigative modalities have been attempted. DESIGN: This systematic review searched MEDLINE, EMBASE, bibliographies of included articles, and conference proceedings for studies reporting original data regarding the preoperative detection of PNETs. Pooled IBEUS was calculated by using random effects models. Heterogeneity was explored by using stratified meta-analysis and meta-regression. Evidence of small-study effects was assessed by using funnel plots and the Begg test. PATIENTS: Patients with suspected PNETs. INTERVENTIONS: EUS evaluation. MAIN OUTCOME MEASUREMENTS: The pooled IBEUS for the detection of PNETs after CT scan, with or without additional investigative modalities. RESULTS: Among 4505 citations identified, we included 17 cohort studies (612 patients). EUS identified PNETs in 97% of cases. Improved PNET identification with EUS was observed in all of the studies. After adjusting for small-study effects, meta-analysis showed that EUS alone could identify PNETs in approximately 1 in 4 patients (adjusted IBEUS 26%; 95% confidence interval, 17%-37%). The pooled IBEUS varied based on the study design, study size, type of CT scan used, and the number of modalities used prior to EUS. LIMITATIONS: The majority of included studies were retrospective. Small-study effects were observed. CONCLUSION: Preoperative EUS is associated with an increase in PNET detection after other modalities are attempted.

Current concepts in the diagnosis and management of type 1 gastric neuroendocrine neoplasms.

The vast majority of gastrin-related gastrointestinal neuroendocrine neoplasms (GI-NENs) develop in the context of chronic atrophic gastritis (type 1), a condition closely related to autoimmune thyroid diseases. These neoplasms are defined as gastric NENs type 1 (GNEN1) and have recently been shown to constitute the commonest GI-NENs in a prospective study. GNEN1s are usually multiple and follow a relative indolent course, raising questions regarding the extent that such patients should be investigated and the appropriate therapeutic interventions needed. Recently, a number of consensus statements and guidelines have been published from various societies dealing with the diagnosis and management of GI-NENs. Endocrinologists are among the many different medical specialties involved in GNEN1s diagnosis and management. However, despite recent advances, few randomized trials are available, and thus existing evidence remains relatively weak compared to other malignancies. The purpose of this review is to provide recent evidence along with currently employed modalities addressing the diagnosis, management, long-term follow-up and potential comorbidities of GNEN1s.