Chromogranin A Measurement Research Articles

Role of Chromogranin A in the Diagnosis and Follow-up of Neuroendocrine Tumors

The aim of this study was to assess the utility of serum chromogranin A (CgA) along the clinical pathway of patients with neuroendocrine tumors (NETs). A retrospective review of medical records was conducted of patients with NET who had at least 1 measurement of CgA between January 2015 and April 2021 at a large metropolitan Australian hospital. Chromogranin A was classified as increased or decreased if there was at least a 25% change in sequential levels and was compared with disease response by anatomical or functional imaging if within 6 weeks (considered concurrent). Of 102 patients with NETs, 67 had at least 1 serum CgA level: 50 had been ordered during diagnostic workup, of which 33 were elevated (sensitivity: 66%; 95% confidence interval, 51%-79%). Of 129 CgA results concurrent with imaging, the sensitivity for detecting progressive disease was 28% (95% confidence interval, 15%-44%). Our findings support previous concerns that CgA adds little value in clinical decision-making.

Awareness of drug laboratory test interactions is important for prevention of unnecessary additional diagnostics: An example

BackgroundElevated levels of Chromogranin A (CgA) may be indicative of a neuroendocrine tumour (NET), but increased levels are also observed after intake of proton pump inhibitors (PPIs). The incidence of diagnostic confusion because of this drug-laboratory test interaction (DLTI) was examined. MethodsMedical records of 238 patients with elevated CgA concentrations were obtained from three hospitals. The following data were extracted: PPI prescription at the time of CgA measurement, medical decision making based on elevated CgA concentrations, final diagnosis, comorbidity and other prescribed drugs. ResultsFrom 238 patients with elevated CgA concentrations, 132 used PPIs. Of these patients, 57 patients did not have a NET. In 9 of these 57 patients (16%), diagnostic work up revealed no medical cause of an elevated CgA concentration. Somatostatin receptor imaging was ordered in 4 out of 9 cases, with no abnormalities observed. In 6 out of 9 cases, CgA measurement was repeated after PPI discontinuation resulting in normalisation of CgA concentrations. ConclusionIn this retrospective patient record study we observed that part of the elevated CgA concentrations in patients could be caused by the usage of PPIs causing unnecessary diagnostic work-up for the exclusion of a NET. These observations illustrate the need for better DLTI awareness.

Use of Chromogranin A for Monitoring Patients With Pancreatic Neuroendocrine Neoplasms.

We aimed to assess the role of serum chromogranin A (CgA) in monitoring disease status and treatment response in patients with pancreatic neuroendocrine neoplasms (pNENs). We included posttherapy pNENs patients with measured serum CgA levels who underwent 68Ga-labeled tetraazacyclododecanetetraacetic acid-peptide positron emission tomography (PET) imaging between April 2017 and January 2020. Serum CgA levels were determined by enzyme-linked immunosorbent assay. Tumor response was assessed according to the PET response evaluation criteria in solid tumors. Seventy-seven patients with 101 events were included in this study. Serum CgA levels were significantly higher in patients with active disease and metastasis. The optimal cutoff values for CgA for active and metastatic pNENs diagnosis after treatment were 52.39 (77.8% sensitivity, 80.7% specificity) and 60.18 ng/mL (73.9% sensitivity, 73.1% specificity), respectively. Based on 18 patients with serial CgA measurements and PET imaging, the optimal changes in CgA levels for predicting disease remission and progression were a 28.5% decrease (71.4% sensitivity, 88.2% specificity) and a 21.0% increase (100.0% sensitivity, 75.0% specificity), respectively. We concluded that serum CgA levels are associated with disease status and treatment response and may thus provide a helpful biomarker for the monitoring and clinical management of patients with pNENs.

Myocardial perfusion SPECT as a potential mediator on circulating chromogranin A in patients with old myocardial infarction.

Chromogranin A (CgA) is a soluble polypeptide stored within and released from secretory granules of endocrine and other cell types (including cardiomyocytes); CgA appears to be a marker of the overall neuroendocrine activity. Increased levels of serum CgA have been found not only in patients with neuroendocrine neoplasms but also with other malignancies, hypertension, myocardial infarction, heart, or renal failure. A population of 307 patients (202 males, 105 females) was enrolled. The study group consisted of 118 individuals (38.4%) with myocardial infarction more than one year old (MI group); the remaining 189 (61.6%) had no known heart disease (control group). All patients underwent myocardial perfusion scintigraphy (MPS) after blood withdrawal for serum CgA measurement. To test whether a possible effect of old infarction on serum CgA is mediated by MPS findings, we employed analysis of covariance for three distinct categories of left ventricular (LV) perfusion deficits as dichotomous predictors: (1) any-type deficits (abnormal MPS); (2) reversible deficits (ischemia); and (3) fixed deficits (scar). In all three MPS conditions, the effect of age, gender, and LV ejection fraction (EFLV) on serum CgA was statistically significant: women exhibited higher CgA levels than men (P=0.008-0.023), whereas increasing age and decreasing EFLV were associated with increasing CgA (all P<0.001). Conversely, no statistically significant differences in mean CgA levels were found between MI patients and normal controls with either abnormal MPS, scar, or ischemia, or their degree and extent. Although serum CgA is significantly associated with age, gender, and EFLV in patients with an old MI, no association was found between CgA levels and either old MI history or MPS findings. The verified involvement of circulating CgA in the acute/subacute phase of infarction appears to be blunted in infarctions older than a year.

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.

Early response assessment and prediction of overall survival after peptide receptor radionuclide therapy

BackgroundResponse after peptide receptor radionuclide therapy (PRRT) can be evaluated using anatomical imaging (CT/MRI), somatostatin receptor imaging ([68Ga]Ga-DOTA-TATE PET/CT), and serum Chromogranin-A (CgA). The aim of this retrospective study is to assess the role of these response evaluation methods and their predictive value for overall survival (OS).MethodsImaging and CgA levels were acquired prior to start of PRRT, and 3 and 9 months after completion. Tumour size was measured on anatomical imaging and response was categorized according to RECIST 1.1 and Choi criteria. [68Ga]Ga-DOTA-TATE uptake was quantified in both target lesions depicted on anatomical imaging and separately identified PET target lesions, which were either followed over time or newly identified on each scan with PERCIST-based criteria. Response evaluation methods were compared with Cox regression analyses and Log Rank tests for association with OS.ResultsA total of 44 patients were included, with median follow-up of 31 months (IQR 26–36 months) and median OS of 39 months (IQR 32mo-not reached)d. Progressive disease after 9 months (according to RECIST 1.1) was significantly associated with worse OS compared to stable disease [HR 9.04 (95% CI 2.10–38.85)], however not compared to patients with partial response. According to Choi criteria, progressive disease was also significantly associated with worse OS compared to stable disease [HR 6.10 (95% CI 1.38–27.05)] and compared to patients with partial response [HR 22.66 (95% CI 2.33–219.99)]. In some patients, new lesions were detected earlier with [68Ga]Ga-DOTA-TATE PET/CT than with anatomical imaging. After 3 months, new lesions on [68Ga]Ga-DOTA-TATE PET/CT which were not visible on anatomical imaging, were detected in 4/41 (10%) patients and in another 3/27 (11%) patients after 9 months. However, no associations between change in uptake on 68Ga-DOTA-TATE PET/CT or serum CgA measurements and OS was observed.ConclusionsProgression on anatomical imaging performed 9 months after PRRT is associated with worse OS compared to stable disease or partial response. Although new lesions were detected earlier with [68Ga]Ga-DOTA-TATE PET/CT than with anatomical imaging, [68Ga]Ga-DOTA-TATE uptake, and serum CgA after PRRT were not predictive for OS in this cohort with limited number of patients and follow-up time.

Chromogranin Serves as Novel Biomarker of Endocrine and Gastric Autoimmunity.

The glycoprotein chromogranin A (CgA) is expressed by endocrine and neuroendocrine cells. High levels of serum CgA serve as markers of neuroendocrine tumors (NET), but its role in autoimmunity has not been assessed. To investigate CgA utility as a marker of endocrine autoimmunity. CgA serum levels were evaluated in 807 consecutive unselected participants (cross-sectional study) with the time-resolved amplified cryptate emission technology. Serum CgA concentrations were increased in 66%, 39%, 38%, and 24% of patients with NET, type 1 diabetes (T1D), autoimmune gastritis (AG) and autoimmune polyendocrinopathy (AP), respectively. Compared with healthy participant controls (C), the odds of positive CgA measurement were up to 28 times higher in the disease groups. In detail, the odds ratios (ORs) for positive CgA levels were 27.98, 15.22, 7.32 (all P < 0.0001) and 3.89 (P = 0.0073) in patients with NET, T1D, AG, and AP, respectively. In AG, CgA and serum gastrin correlated positively (r = 0.55; P < 0.0001). The area under the receiver operating characteristic curve to predict AG was higher for parietal cell antibody (PCA) positivity than for CgA (0.84 vs 0.67; P < 0.0001). However, in combination with PCA and intrinsic factor autoantibodies, CgA independently improved prediction of AG (OR 6.5; P = 0.031). An impact of age on CgA positivity and on CgA value was detected (P < 0.0001) while current smoking significantly increased CgA serum levels by 25% (P = 0.0080). CgA qualifies as a novel biomarker for T1D, AP, and AG.

Chromogranin A and serotonin for evaluation of treatment efficacy of neuroendocrine tumors

Background: The utility of biochemical markers in the monitoring of treatment efficacy in patients with neuroendocrine tumors (NETs) goes beyond any doubt. However, there are still no clear criteria for the assessment of clinically significant abnormalities of the main NET biomarkers chromogranin A (CgA) and serotonin. Aim: To evaluate the value of serial measurement of serum CgA and serotonin in the monitoring of the treatment effect in NET patients. Materials and methods: Serum CgA and serotonin levels were measured in 107 patients with NETs at baseline and at 3–4 weeks after the end of treatment (chemotherapy, biotherapy), as well as in 60 healthy controls. We used enzyme immunoassay based on Chromogranin A NEOLISA (Euro Diagnostica) and Serotonin ELISA (IBL International GmbH) test systems. Results: There was an association between CgA levels and the efficacy of chemotherapy in NET patients. With progression of the disease, median CgA increased significantly from 412 to 2679 ng/mL (p = 0.012), whereas in the patients with partial response it decreased from 811 to 254 ng/mL (p = 0.023). The ROC analysis showed the 33% cut-off for significant CgA changes for progression, with sensitivity of 80.0% and specificity of 95.6%. A decrease (of more than 33% compared to baseline levels) or absence of significant CgA changes was associated with stabilization of the disease or with partial response to treatment. Significantly decreased CgA levels were found in 75.0% cases of partial response and 43.48% of stabilized patients, whereas the absence of any significant changes in 25 and 66.7%, respectively. There was no association between serotonin levels and the disease behavior under treatment.Conclusion: CgA could be used as a sensitive marker of NET progression on chemotherapy.

Prospective Study of Chromogranin A as a Predictor of Progression in Patients with Pancreatic, Small-Intestinal, and Unknown Primary Neuroendocrine Tumors

Background: Retrospective studies are conflicting but most of them report that an increase in plasma chromogranin A (CgA) predicts tumor progression in neuroendocrine tumor (NET) patients. Prospectively, we investigated if a change in plasma CgA is associated with tumor burden changes in NET patients with disseminated disease. Methods: We included 239 patients treated at 5 NET centers from December 2010 to December 2013. CgA was measured within 6 weeks of a CT or MRI in a patient undergoing at least 2 scan examinations performed over a period of 1–24 months. In a post hoc analysis, CgA measured 3–6 months prior to the CT/MRI was analyzed. Changes in tumor size were evaluated by RECIST1.1. A 25% change in CgA was chosen to discriminate between increased, decreased, or unchanged levels. Results: In 671 events (2 CT/MRI scans and 2 corresponding CgA measurements), we found a weak positive correlation between the RECIST 1.1 responses and change in plasma CgA from baseline (Spearman’s rank correlation coefficient: 0.15; p < 0.05). Of 304 events in the post hoc analysis, 58 showed progression, 228 showed stable disease, and 18 showed regression, with a median change in CgA of 19% (IQR: 57 to –20%), –12% (23 to –38%), and –73% (–55 to –83%), respectively. The correlation coefficient for all sites was 0.17 (p = 0.003), and it was 0.16 (p = 0.07), 0.18 (p = 0.04), and 0.20 (p = 0.21) for small-intestinal (n = 137), pancreatic (n = 123), and unknown primary NET (n = 40), respectively. In the 58 patients showing tumor progression, the sensitivity and specificity of an increased CgA concentration were 36 and 82%, respectively, with positive and negative predictive values of 32 and 85%. Conclusions: In this prospective study of gastroenteropancreatic NET patients, we observed only a weak association between a change in plasma CgA and changes in tumor burden. CgA as a single biomarker was thus inadequate to predict tumor progression.

Blood Chromogranin A Is Not Effective as a Biomarker for Diagnosis or Management of Bronchopulmonary Neuroendocrine Tumors/Neoplasms

Background: Identification of circulating tumor markers for clinical management in bronchopulmonary (BP) neuroendocrine tumors/neoplasms (NET/NEN) is of considerable clinical interest. Chromogranin A (CgA), a “universal” NET biomarker, is considered controversial as a circulating biomarker of BPNEN. Aim: Assess utility of CgA in the diagnosis and management of BPNEN in a multicentric study. Material and Methods: CgA diagnostic metrics were assessed in lung NET/NENs (n = 200) and controls (n = 140), randomly assigned to a Training and Test set (100 BPC and 70 controls in each). Assay specificity was evaluated in neoplastic lung disease (n = 137) and nonneoplastic lung disease (n = 77). CgA efficacy in predicting clinical status was evaluated in the combined set of 200 NET/NENs. CgA levels in bronchopulmonary neuroendocrine tumor (BPNET) subtypes (atypical [AC] vs. typical [TC]) and grade was examined. The clinical utility of an alteration of CgA levels (±25%) was evaluated in a subset of 49 BPNET over 12 months. CgA measurement was by NEOLISA^TM kit (EuroDiagnostica). Results: Sensitivity and specificity in the training set were 41/98%, respectively. Test set data were 42/87%. Training set area under receiver operator characteristic analysis differentiated BPC from control area under the curve (AUC) 0.61 ± 0.05 p = 0.015. Test set the data were AUC 0.58 ± 0.05, p = 0.076. In the combined set (n = 200), 67% BPNET/NEN (n = 134) had normal CgA levels. CgA levels did not distinguish histological subtypes (TC vs. AC, AUC 0.56 ± 0.04, p = 0.21), grade (p = 0.45–0.72), or progressive from stable disease (AUC 0.53 ± 0.05 p = 0.47). There was no correlation of CgA with Ki-67 index (Pearson r = 0.143, p = 0.14). For nonneoplastic diseases (chronic obstructive pulmonary disorder and idiopathic pulmonary fibrosis), CgA was elevated in 26–37%. For neoplastic disease (NSCLC, squamous cell carcinoma), CgA was elevated in 11–16%. The neuroendocrine SCLC also exhibited elevated CgA (50%). Elevated CgA was not useful for differentiating BPNET/NEN from these other pathologies. Monitoring BPNET/NEN over a 12-month period identified neither CgA levels per se nor changes in CgA were reflective of somatostatin analog treatment outcome/efficacy or the natural history of the disease (progression). Conclusions: Blood CgA levels are not clinically useful as a biomarker for lung BPNET/NEN. The low specificity and elevations in both nonneoplastic as well as other common neoplastic lung diseases identified limited clinical utility for this biomarker.

MON-334 Hooke Effect for Chromogranin A in Immunofluorescence Assay, a Pitfall Revealed by Targeted Proteomics

Introduction: Chromogranin A (CGA) is a glycoprotein secreted by several neuroendocrine tissues; therefore, it is a good marker for neuroendocrine tumors, with high specificity for diagnosis and good correlation with disease progression, recurrence and treatment response. Several conditions may lead to "falsely elevated" values ​​of this marker, but reports of occurrence of "falsely low" values ​​due to the hook effect are rare. We report this effect detected in the laboratory evaluation of a patient with neuroendocrine tumor who presented conflicted results of CGA using two different techniques: a traditional immunofluorescence assay and a new directed proteomics method using liquid nanocromatography associated with high-resolution mass spectrometry. Case report: A 64-year-old male patient with chronic renal insufficiency undergoing treatment for a neuroendocrine lung tumor, during treatment progression the patient presented CGA of 359 ng / mL (RR <93 ng / mL) and 179 ng / mL (RR less than 93 ng / mL), both performed using immunofluorescence assay. Later on the follow up a new CGA measurement using guided proteomics methodology resulted in 204,538 ng / mL (RR less than 93 ng / mL), this same sample measurement performed using immunofluorescence assay was 261 ng / mL. This result discrepancy led to the suspicion of a hook effect, what was confirmed after the dilution of the samples (1: 25 and 1: 100) showed results higher than 80,000 ng / mL, which clearly demonstrated that the immunofluorescence assay underestimated the result by more than two orders of magnitude. Discussion and conclusion: The hook effect is a technical pitfall, characterized by the presence of falsely low levels of a substance, which is present in a very elevated concentration, much higher than expected. The most characterized hook effect is with prolactin and to the best of our knowledge; this is the first description of this effect in relation to CGA. The detection of falsely low value of CGA was only possible due to the use of this new technique. Targeted proteomics method is innovative, and proved to be able to give greater accuracy to the CGA result, leading to more appropriate treatment and follow-up for this patient.

Limited role of Chromogranin A as clinical biomarker for pancreatic neuroendocrine tumors

BackgroundSerum Chromogranin A (CgA) is widely used as a biomarker for pancreatic neuroendocrine tumors (PanNETs). The aim of this study was to investigate the value of CgA as a diagnostic and prognostic marker for well-differentiated PanNETs. MethodsPatients with well-differentiated PanNET and a baseline CgA measurement, between 2011 and 2016 were reviewed. The diagnostic value was determined by comparing CgA values from patients with PanNETs to those with other pancreatic neoplasms and healthy controls. The Kaplan–Meier method was used to investigate the CgA prognostic significance. ResultsNinety-nine patients met inclusion criteria. As a diagnostic marker, CgA had a sensitivity of 66%, specificity of 95%, and overall accuracy of 71%. The use of PPIs was associated with a higher CgA level (p = 0.015). When excluding patients on PPIs, CgA accuracy in distinguishing PanNETs from other pancreatic neoplasms was 66%, the sensitivity and specificity were 60% and 75% respectively. Elevated CgA (p = 0.004), Ki67% (p < 0.001), tumor grade (p < 0.001) and stage of disease (p = 0.036) were associated with disease-specific survival. ConclusionCgA has a limited role as a diagnostic biomarker for well-differentiated PanNETs. An elevated CgA level may have prognostic value but its role should be further investigated with respect to other known pathological factors.

An Italian program of external quality control for chromogranin A (CgA) assay: State of the art of CgA measurement

Chromogranin A (CgA) is a secretory protein produced by many neuroendocrine cells. Circulating levels of CgA have been found to be elevated in a variety of neuroendocrine tumors and may facilitate the diagnosis and management of patients with functioning as well as non-functioning forms. However, up to now the analytical methods used for assaying intact CgA and CgA-derived peptides in the circulation of patients have not been monitored in Italy by an external quality control program. Within the framework of a Ministry of Health project an external quality control program was developed to investigate the state of the art of CgA determination in Italy and to monitor the performance of laboratories carrying out this assay. This paper deals primarily with the former of these aspects. Every laboratory received the study protocol together with a questionnaire to be returned before receipt of the samples to be assayed. Serum and plasma samples obtained from a pool of routine specimens were prepared at three different concentrations of CgA, aliquoted, frozen at -80 degrees C and mailed in dry ice to the participating laboratories. Of the 43 laboratories, 21 used IRMA, 21 used ELISA and one used RIA. There was a wide range in the time of kit utilization and the number of samples assayed per year, which indicated that the participating group was heterogeneous with regard to their experience in the determination of CgA. Most laboratories routinely used serum and plasma for IRMA and ELISA, respectively, and different data fitting approaches were employed. Further analyses will investigate the possible influence of these preanalytical factors on laboratory performance.

Tumor markers in pancreatic cystic fluids for diagnosis of malignant cysts.

Early diagnosis of premalignant or malignant pancreatic cysts is essential to improve prognosis. Sampling of pancreatic cyst fluid by fine-needle aspiration during endoscopic ultrasonography (EUS) enables cytopathological examination combined with biochemical analysis. This study aimed to provide an aid based on biological markers for the preoperative management of patients with pancreatic cysts. Pancreatic fluids obtained by EUS-guided fine-needle aspiration from 115 patients with cystic lesions were assayed for amylase, lipase, carcinoembryonic antigen (CEA), CA 19-9 and CA 72-4. In addition, chromogranin A (CgA) and neuron-specific enolase (NSE) were measured in 28 fluid samples. ROC curve analysis of the different markers for diagnosis of mucinous cysts showed that CEA had the highest area under the curve (0.93, 95% CI 0.87-0.97), with a sensitivity and specificity of 89% and 93%, respectively, at the cutoff value of 317 µg/L. The CgA and NSE concentrations in 5 NET cysts (median values of 210 [63-492] and 68.5 [9-496] µg/L, respectively) were higher than in 23 other cysts (median values of 8 [7-828] and 2.7 [0.5-35.8] µg/L, respectively) (p = 0.0015 and p = 0.0045, respectively). CEA is the best marker for identifying a cyst as mucinous. In case of low levels of CEA, our results suggest that CgA and NSE measurements may be helpful in the diagnosis of a neuroendocrine tumor and therefore deserve further investigation.

BIOCHEMICAL MARKERS IN SERUM AND URINE IN THE WORKUP OF PATIENTS WITH NEUROENDOCRINE TUMORS

This review summarizes current data on neuroendocrine tumors (NET), which, unlike other neoplasms, are able to produce biologically active substances (hormones, vasoactive peptides, amines). It is exactly their main characteristic that allows to unify this heterogeneous group and that may determine their clinical course. We present integrated recommendations for biochemical diagnosis and confirmation of over-secretion syndromes based on a panel assessment of NET biochemical markers. Data from the literature are reviewed on evaluation of clinical significance of generic and specific NET markers, as well as the results of the studies performed by the authors themselves. Three hundred and thirty patients were examined with NETs of various localization (pancreas, stomach, small intestine and large intestine, lungs) and with metastatic NET disease with unknown primary location, who were treated in the N.N. Blokhin Russian Cancer Research Center. The control group included 115 healthy individuals. Before and during the treatment, plasma and serum chromogranin A (CgA) and serotonin levels, as well as 5-hydroxyindoleacetic acid (5-HIAA) in a 24-hour urine sample were measured with standardized immunoenzyme plate-based assays (“Chromogranin A ELISA kit”, Dako A/S; “Serotonin ELISA and 5-HIAA ELISA”, IBL International GMBH). We evaluated clinical importance of CgA as a generic NET marker, as well as that of serotonin and its metabolite 5-HIAA as specific markers of the carcinoid syndrome. CgA was shown to be the most efficient biochemical marker for diagnosis, assessment of prevalence and monitoring of NETs. CgA has a high diagnostic sensitivity (63.4 to 88.9%) in various NETs. An association between CgA secretion and prevalence and biological activity of the tumor was confirmed. CgA measurement is particularly important in functionally inactive tumors, where serotonin and 5-HIAA have lower sensitivity, being specific markers of the carcinoid syndrome.

Chromogranin A

The review summarizes the utility and limitations of chromogranin A (CgA) as a circulating biomarker for neuroendocrine tumors (NETs). Blood CgA measurement has numerous clinical limitations including poor assay reproducibility, low sensitivity (meta-analysis: 73%, 95% confidence interval: 0.71-0.76), and a paucity of prospective validation studies. A recent study noted elevation in 27% of NETs with a predictive value of 50% for metastases. These findings are consistent with its efficacy primarily as a monoanalyte secretory rather than multidimensional neoplastic marker. An automated CgA assay (KRYPTOR) exhibits similar metrics to the DAKO assay but is only useful in serum and routine storage diminishes its accuracy. Current studies indicate that CgA is more effective as a biomarker for cardiac disease. Given the diverse limitations of CgA, NET biomarker focus has evolved toward measurement of multiple analytes, for example, transcripts. Multianalyte algorithmic analyses perform significantly better as diagnostic (>95%) and prognostic markers (>90%) than CgA (30-74 and ∼50%, respectively) since they delineate different aspects of the biological behavior of NETs, (e.g., proliferome and metabolome). CgA is neither a reliable nor robust NET biomarker. As a monoanalyte, it is restricted by poor metrics and has limited predictive value. Its current clinical utility appears optimal in cardiovascular disease. The significance of CgA in NET disease is diminishing as other analytical approaches, particularly transcript multianalyte assays or other strategies, evolve to supersede it.

Routine measurement of plasma chromogranin B has limited clinical utility in the management of patients with neuroendocrine tumours.

Chromogranin A (CgA) and B (CgB) are markers for monitoring disease status in patients with gastroenteropancreatic neuroendocrine tumours (NETs). These are specialized diagnostic tests often necessitating referral of specimens to a supraregional assay service (SAS) laboratory for analysis. The aim of this audit was to assess whether measurement of either plasma CgA or CgB alone provides sufficient clinical information in comparison with the current practice of measuring both markers together. A retrospective analysis was undertaken for all chromogranin tests requested for patients with a known NET diagnosis. Results were categorized based on whether plasma concentrations were elevated for one or both CgA and CgB. A total of 325 sequential patients with a NET diagnosis had plasma chromogranin levels measured during the period of review. Baseline CgA was elevated in 60·9% of patients. Isolated elevations in CgA (with normal CgB) were found in 44·9% of patients, whilst combined elevations in both CgA and CgB were found in 16% of patients. Combined CgA and CgB concentrations within the normal range were observed for 38·5% of patients. Only two patients (0·6%) had an isolated elevation in CgB at baseline. Both patients had a diagnosis of pancreatic NET and were radiologically stable. Plasma CgA and CgB corresponded with disease stage (localized vs metastatic). CgB in addition to CgA did not provide any significant improvement in diagnostic performance for identification of metastatic disease compared to CgA alone. Based on this NET population and specific assay performance characteristics, CgA alone provides sufficient information for the management of NET patients; the routine estimation of CgB in all patients is not informative in clinical practice.

Standard Pre- and Postoperative Determination of Chromogranin A in Resectable Non-Functioning Pancreatic Neuroendocrine Tumors - Diagnostic Accuracy: NF-pNET and Low Tumor Burden

Background: Chromogranin A (CgA) is often used in metastatic patients with nonfunctioning pancreatic neuroendocrine tumors (NF-pNET). The aim of this study is to assess the diagnostic accuracy of CgA in patients with low tumor burden. Methods: Resectable patients with NF-pNET without metastases at time of diagnosis were included between 2002 and 2013 in the Academic Medical Center of Amsterdam. CgA was determined at time of diagnosis and during follow-up according to a standardized method. The upper reference range was 94 µg/l. Results: Overall, 47 patients were included in this study. CgA was elevated preoperatively in only 10 patients (27%). In the detection of metastases during follow-up, the positive predictive value for CgA was 50% and negative predictive value was 81%. In 50% of the patients with an elevated CgA during follow-up, this test result was false-positive. Conclusions: The diagnostic accuracy of CgA was low preoperatively in patients with resectable NF-pNET and low tumor burden. In the detection of recurrent disease after curative resection of NF-pNET, the diagnostic accuracy of CgA was moderate (50%). We conclude that the routine measurement of CgA at time of diagnosis or during follow-up after curative resection had limited value in patients with resectable NF-pNET.

Chromogranin-A levels measured with automated immunoassay.

Measurement of chromogranin-A (CgA) levels is relevant for the diagnosis of neuroendocrine neoplasms. The use of CgA testing for risk stratification of cardiovascular diseases is also increasing. The objective of our study was to determine the performances and reference values of a novel automated assay for CgA testing. The new method was compared with an enzyme-linked immunosorbent assay. Our results showed that the performances of the automated assay were satisfactory and that the agreement between the two methods was excellent. The automation of CgA testing also reduced the turnaround time of analysis and, therefore, might contribute to a faster delivery of the results to physicians.

Chromogranin A as a marker for diagnosis, treatment, and survival in patients with gastroenteropancreatic neuroendocrine neoplasm.

Chromogranin A (CgA) not only plays an important role in pathologic diagnosis, but is also used as a circulating biomarker in patients with gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN). However, the relationship between immunohistochemistry (IHC) expression and serum levels of CgA has not been investigated. The value of CgA for evaluating treatment response and prognosis is still not well understood. We conducted this study to assess the significance of CgA in GEP-NEN in terms of diagnosis, curative effects evaluation and prognosis.One hundred forty-five patients comprising 88 patients with active disease and 57 disease-free patients were enrolled in this study from January 2011 to November 2013. The expression of CgA was assessed by IHC, and serial serum CgA levels were measured by enzyme linked immunosorbent assay.The overall expression rate of CgA was 69.0% (100/145). CgA expression was associated with tumor site and stage (P < 0.05), but not correlated with prognosis (P = 0.07). Serum CgA levels were significantly higher in GEP-NEN patients with active disease when compared with disease-free patients (P = 0.001) or healthy participants (P < 0.001). A CgA cutoff value of 95 ng/ml discriminated between healthy subjects or disease-free patients and patients with active disease (sensitivity 51.2% and specificity 87.5%, respectively). There was a correlation between the CgA IHC expression and high serum CgA levels (R = 0.320, P = 0.002). Serum CgA levels were much higher in patients who classified as neuroendocrine carcinoma, mixed adenoendocrine carcinoma (P = 0.035) and who were on stage IV (P = 0.041). Changes in CgA levels normalization or ≥30% decrease suggested that patients had tumor response. Furthermore, patients with serum CgA levels higher than 95 ng/ml had a significantly shorter survival compared with patients with levels lower than 95 ng/ml (P < 0.001).CgA is a reliable pathologic and circulating maker for diagnosis of GEP-NEN. We further confirmed that serial measurement of CgA may be useful for evaluating the efficacy of different kinds of therapies in patients during follow-up, and serum CgA level ≥95 ng/ml may serve as a predictor of overall survial.