Sensitivity Of Chromogranin A Research Articles

Low sensitivity of chromogranin A in the diagnosis of insulinoma: a single-center study

Background: Insulinoma is a neuroendocrine tumor (NET), with its main clinical manifestation being the hypoglycemic syndrome. The symptoms of hypoglycemia are nonspecific, and therefore, in most cases, the diagnosis is made untimely. The Russian clinical guidelines for the diagnosis and treatment of NET suggest as a diagnostic test that the universal circulating marker of all NET, chromogranin A (CgA) be determined. However, the literature data on the sensitivity of CgA in the diagnosis of insulinoma are contradictory. Aim: To evaluate the diagnostic effectiveness of the CgA test in the diagnosis of insulinoma. Materials and methods: This was a hospital-based single-center, cross-sectional comparative (first step) and prospective non-comparative (second step) study conducted from 2016 to 2022. During the first part of the study, we determined serum CgA in 120 patients with suspected non-diabetic hypoglycemia and compared its levels in the patients with and without confirmed insulinoma (n = 87 and n = 33, respectively). During the second study step, CgA was measured in the insulinoma patients at 6 [4.0; 7.0] months after surgery. The CgA levels at baseline and post-surgery were analyzed in 74 patients (those with recurring non-diabetic hypoglycemia were excluded from the analysis). Results: In the study subjects without insulinoma, the median CgA level was 0.7 [0.5; 1.1] (range, 0.1 to 2.0) nmol/l and the difference (with Bonferroni adjustment) from its levels in the patients with insulinoma before surgery was non-significant (1.0 [0.7; 1.4], range, 0.1 to 8.5 nmol/l, р = 0.045). The CgA concentration in the insulinoma patients after surgery was 0.9 [0.7; 1.2], range, 0 to 1.9 nmol/l and significantly differed from that at baseline (1.0 [0.7; 1.4], range, 0.1 to 8.5 nmol/l, p = 0.012, Wilcoxon test). In the patients with insulinoma before surgery the CgA levels exceeding the generally accepted reference range ( 2 nmol/l) was found in 11.5% (n = 10), with its median level of 2.5 [2.3; 4.1], range 2.3 to 8.5 nmol/l. There were no significant associations between the CgA levels and localization, tumor numbers, their size and malignization grade, insulin and proinsulin values, and duration of fasting. The sensitivity and specificity of the CgA test were 12% [95% confidence interval [CI]: 6%–20%] and 100% [95% CI: 97%–100%], respectively. The prognostic value of a positive result (PVPR) was 100% [95% CI: 69%–100%] and the prognostic value of a negative result (PVNR) 30% [95% CI: 28%–32%]. Conclusion: As a diagnostic test, CgA has high specificity and prognostic value of a positive result. However, the uncertainty of the prognostic value of a negative result is unacceptably high. A special study is required to clarify the operational characteristics of CgA in insulinoma.

Chromogranin A as surveillance biomarker in patients with carcinoids: CASPAR.

e16242 Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare cancers with highly heterogeneous growth rates, yielding very broad ranges of radiographic imaging intervals in standard guidelines, with a multitude of risk for patients. Better tools are needed to reduce risks for these patients. Chromogranin A (CgA) is released by GEP-NET cells and has been associated with increased tumor burden. The European Neuroendocrine Tumor Society (ENETS) considers CgA to be the most practical and useful general serum tumor marker in patients with NETs. However, clinical utility has been limited by the lack of prospective validation studies and by different sensitivity of CgA according to NET tumor type and volume. Accordingly, expert consensus guidelines have offered varying advice regarding the use of CgA to practicing clinicians. The aim was to evaluate the performance of the B·R·A·H·M·S CgA II KRYPTOR immunoassay to monitor the course of disease in patients with well-differentiated GEP-NETs (grade 1 and grade 2). This is the first prospective validation of a clinical algorithm for the interpretation of CgA values in patients with advanced GEP-NETs. Methods: This prospective, multi-center, observational study was designed to validate the performance of the B·R·A·H·M·S CgA II KRYPTOR assay in monitoring disease progression in a defined population of GEP-NET patients with minimal confounding from end organ dysfunction or concomitant medications (e.g. PPIs). Patients were followed for up to 36 months including the evaluation of tumor burden with RECIST 1.1 categorization by imaging (CT/MRI scans). A clinical cut-off for changes in CgA levels over time to indicate the risk that a tumor progression occurred was derived from a retrospective, bicentric observational pilot study. A change in CgA levels between visits was considered positive, if the CgA concentration increased by more than 50% to an absolute value of >100 ng/ml. Results: A total of 175 adult patients were enrolled, and 153 patients had measurable disease at baseline and ≥1 follow-up visit. Using the cut-off for CgA increase defined above resulted in a sensitivity of 34.4% (95%-CI: 25.6% - 44.3%, p < 0.001) and a specificity of 93.4% (95%-CI: 90.4% – 95.5%, p < 0.001). Positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+) and negative likelihood ratio (LR-) to diagnose whether a tumor progression occurred according RECIST 1.1 criteria were 57.9% (95% CI: 45.0-69.8), 84.3% (95% CI: 80.5-87.6), 5.20 (95% CI: 3.23-8.36), and 0.70 (95% CI: 0.61-0.81), respectively. The AUC was estimated at 0.731 (95% CI: 0.670-0.793). Conclusions: B·R·A·H·M·S CgA II KRYPTOR can be used in conjunction with other clinical methods as an aid in monitoring of disease progression during the course of disease and treatment in patients with gastroentero-pancreatic neuroendocrine tumors (GEP-NETs, grade 1 and grade 2).

Chromogranin A and chromogranin B in pancreatic neuroendocrine tumors

For the first time in Russia a comparative study of chromogranin A (CgA) and chromogranin B (CgB) in neuroendocrine tumors (NETs) of the pancreas was performed. We examined 50 primary patients with pancreatic NETs and 42 healthy people. The determination of CgA and CgB was performed in blood serum using standard enzyme-linked immunoassay test-systems (Chromogranin A NEOLISA, Eurodiagnostica; Human Chromogranin B, USCN). The levels of CgA and CgB in pancreatic NETs significantly differed from the control group. There was found the association between CgA levels and the dissemination of the process, while CgB demonstrated the properties of a marker independent from the tumor dissemination. The diagnostic sensitivity of CgA was 76 %, CgB – 68 %. Complex determination of CgA and CgB enhanced the diagnostic sensitivity to 84 %. Our data indicate the potential usefulness of complex CgA and CgB in the diagnosis of pancreatic NETs.

Chromogranin A: Is It a Useful Marker of Neuroendocrine Tumors?

We evaluated the pattern of chromogranin A (CgA) plasma levels in a large number of patients with neuroendocrine tumors (NETs), in a series of patients with chronic atrophic gastritis (CAG) with and without enterochromaffin-like (ECL) cell hyperplasia, and in healthy participants (HPs). Two hundred thirty-eight patients with NETs, 42 patients with CAG with or without ECL cell hyperplasia, and 48 HPs were studied. All patients underwent a baseline visit, biochemical routine check-up, imaging techniques, endoscopy, and histologic determination. CgA plasma levels were higher in patients with NETs compared with CAG patients or HPs (P < .001). In the NET group, we observed higher CgA levels in patients with diffuse disease compared with patients with local or hepatic disease (P < .001). CgA plasma levels were significantly higher in patients with Zollinger-Ellison syndrome compared with other types of endocrine tumors (P < .001). We found the best cutoff range between HPs and NET patients to be 18 to 19 U/L (sensitivity, 85.3%; specificity, 95.8%). Comparing all participants without neoplasia (HPs, CAG patients, and disease-free patients) and patients with endocrine tumors, the best cutoff range was 31 to 32 U/L (sensitivity, 75.3%; specificity, 84.2%). Setting the specificity at 95%, the cutoff range was 84 to 87 U/L (sensitivity, 55%). Our study confirms the high specificity and sensitivity of CgA in diagnosing an endocrine tumor. It is necessary to use a cutoff range of 84 to 87 U/L to obtain a high specificity in diagnosing NETs, with the aim of excluding patients in whom the CgA was elevated as a result of other non-neoplastic diseases.

Accuracy and Clinical Correlates of Two Different Methods for Chromogranin A Assay in Neuroendocrine Tumors

Measurement of chromogranin A (CgA) plays a major role in the management of neuroendocrine tumors (NET); however, reliable assaying of CgA is made difficult by the rapid hydrolysis following its release into the bloodstream. This study was aimed at the assessment of two assays for CgA in NET patients. CgA was measured in 93 patients by means of an enzyme-linked immunosorbent assay (ELISA) and an immunoradiometric assay (IRMA). The specificity and sensitivity of CgA were evaluated in relation to tumor histology. The clinical accuracy of the two assays was evaluated by receiver-operating characteristic (ROC) curve analysis. Regression analysis demonstrated different immunoreactivity for CgA of the antibodies used in the two kits (r=0.61). The two assays had different accuracy also in classifying patients according to their clinical condition (91% vs 64% specificity and 79% vs 79% sensitivity for the ELISA and IRMA assay, respectively) and tumor histology (81% vs 85% sensitivity for the ELISA and IRMA assays, respectively, in carcinoids; 92% vs 67% sensitivity for the ELISA and IRMA assays, respectively, in pancreatic islet cell tumors). The different clinical accuracy of the two assays was confirmed by the ROC analysis (AUC=0.90 vs AUC=0.87 for the ELISA and IRMA assays, respectively). In conclusion, because of the poor standardization of the commercially available measurement tools the clinical accuracy of CgA measurement depends on the assay used. This makes it difficult to compare CgA values measured with different kits and affects the clinical accuracy of the different assays for CgA.

Accuracy and clinical correlates of two different methods for chromogranin A assay in neuroendocrine tumors

Measurement of chromogranin A (CgA) plays a major role in the management of neuroendocrine tumors (NET); however, reliable assaying of CgA is made difficult by the rapid hydrolysis following its release into the bloodstream. This study was aimed at the assessment of two assays for CgA in NET patients. CgA was measured in 93 patients by means of an enzyme-linked immunosorbent assay (ELISA) and an immunoradiometric assay (IRMA). The specificity and sensitivity of CgA were evaluated in relation to tumor histology. The clinical accuracy of the two assays was evaluated by receiver-operating characteristic (ROC) curve analysis. Regression analysis demonstrated different immunoreactivity for CgA of the antibodies used in the two kits (r = 0.61). The two assays had different accuracy also in classifying patients according to their clinical condition (91% vs 64% specificity and 79% vs 79% sensitivity for the ELISA and IRMA assay, respectively) and tumor histology (81% vs 85% sensitivity for the ELISA and IRMA assays, respectively, in carcinoids; 92% vs 67% sensitivity for the ELISA and IRMA assays, respectively, in pancreatic islet cell tumors). The different clinical accuracy of the two assays was confirmed by the ROC analysis (AUC = 0.90 vs AUC = 0.87 for the ELISA and IRMA assays, respectively). In conclusion, because of the poor standardization of the commercially available measurement tools the clinical accuracy of CgA measurement depends on the assay used. This makes it difficult to compare CgA values measured with different kits and affects the clinical accuracy of the different assays for CgA.

Evaluation of chromogranin A expression in serum and tissues of breast cancer patients.

Human chromogranin A (CgA) is a member of the granin family and is widely distributed in large dense core granules of endocrine and neuroendocrine cells. A variety of non-neuroendocrine carcinomas arising in various tissues show patterns of neuroendocrine differentiation. Expression of CgA has been documented in epithelial cells of normal mammary gland as well as in breast cancers, and elevation of serum CgA has been detected in patients with breast cancer. Our study was undertaken to evaluate the relationship between serum CgA levels and neuroendocrine features in breast cancer. In addition, we evaluated the expression of serum CgA in patients affected by breast cancer compared to controls and the relationship between serum CgA and tumor histology, extent of disease, lymph node status, tumor stage and serum CA 15.3 levels. We enrolled 266 patients with infiltrating ductal or lobular breast carcinoma and a group of 100 age-matched healthy women serving as controls. Serum CgA and CA 15.3 were assayed by specific immunoradiometric methods. The overall sensitivity of CgA and CA 15.3 was 0.06 and 0.34, respectively (chi2 19.1, p<0.0005). No relationship was found between serum levels of CgA and tumor histology, extent of disease, lymph node status or tumor stage while serum levels of CA 15.3 were strongly correlated with all these variables but tumor histology. No relationship was found between serum levels of CgA and CA 15.3. Immunostaining against CgA, CgB, NSE and synaptophysin was performed on primary tumor tissue of 14 serum CgA-positive and 24 serum CgA-negative patients and was negative in all cases. We also evaluated eight cases of pathologically-proven neuroendocrine breast cancer: only four and two of these showed positive CgA immunostaining and increased serum CgA concentration, respectively. In conclusion, serum CgA assay offers no additional information regarding the presence, the extent and the histology of breast cancer compared to the CA 15.3 assay. Moreover, serum CgA was not an accurate marker to identify or exclude the rare neuroendocrine differentiation of breast cancer. We therefore conclude that CgA is not useful as a serum marker in breast cancer.