Chromogranin A is a reliable serum diagnostic biomarker for pancreatic neuroendocrine tumors but not for insulinomas
- Xin-Wei Qiao†1,
- Ling Qiu†2,
- Yuan-Jia Chen1, 3Email author,
- Chang-Ting Meng4,
- Zhao Sun4,
- Chun-Mei Bai4,
- Da-Chun Zhao5,
- Tai-Ping Zhang6,
- Yu-Pei Zhao3, 6,
- Yu-Li Song1,
- Yu-Hong Wang7,
- Jie Chen7 and
- Chong-Mei Lu1
© Qiao et al.; licensee BioMed Central Ltd. 2014
Received: 18 February 2014
Accepted: 30 July 2014
Published: 7 August 2014
Pancreatic neuroendocrine tumors (PNETs) are a group of rare tumors. Chromogranin A (CgA) was considered as the most practical and useful serum tumor marker in PNET patients. But peripheral blood levels of CgA are not routinely tested in Chinese patients with PNETs. This study was to assess the diagnostic value of CgA in Chinese patients with PNETs especially in patients with insulinomas.
Eighty-nine patients with PNETs including 57 insulinomas and 32 non-insulinoma PNETs as well as 86 healthy participants were enrolled in this study between September 2003 and June 2013. Serum levels of CgA were measured by ELISA method. Expression of CgA protein was detected in 26 PNET tissues including 14 insulinomas by immunohistochemical staining.
Serum levels of CgA in 89 PNET patients were significantly higher than that in healthy controls (P = 7.2 × 10−9). Serum levels of CgA in 57 patients with insulinomas (median 64.8 ng/ml, range 25–164) were slightly higher than the levels in healthy controls (median 53.4 ng/ml, range 39–94) but much lower than the levels in 32 patients with non-insulinoma PNETs (median 193 ng/ml, range 27–9021), P = 0.001. The serum CgA levels were reduced in 16 of 17 patients with insulinomas after tumor resection. ROC curve showed that CgA values at 60 ng/ml distinguished patients with insulinomas from healthy controls but its sensitivity and specificity were 66.7% and 73.3%, respectively. In contrast, CgA values at 74 ng/ml distinguished patients with non-insulinoma PNETs from healthy controls, and the sensitivity and specificity were 65.6% and 91.9%, respectively. Except for two insulinomas with negative staining of CgA, 12 insulinoma tissues showed positive staining of CgA.
CgA is a reliable serum diagnostic biomarker for PNETs but not for insulinomas.
Pancreatic neuroendocrine tumors (PNETs) are a group of rare tumors. The prevalence and incidence have increased over the past 3 decades [1–5]. The clinical presentations of PNETs are very complicated due to excess of gut peptides produced by functioning PNETs while symptoms of nonfunctioning PNETs (NF) are obscure [1, 3]. In addition, most of PNETs could be biologically aggressive [1, 3, 6]. Thus, the earlier and accurate diagnosis of PNET is important to facilitate surgical resection and/or to initiate appropriate medical management such as molecular targeted therapy, biotherapy and other intensive care.
Chromogranin A (CgA) is a 46-kDa glycoprotein, member of the granin family, exists within all type of neurons, normal neuroendocrine cells and is expressed in NET cells [7, 8]. Over the past 2 decades, many studies reported and confirmed that CgA was a reliable diagnostic biomarker for NETs including gastroentero-pancreatic NETs (GEP-NET) [1, 3, 5–20] and also might be a prognostic biomarker for NETs . Moreover, several studies showed that peripheral blood levels of CgA were increased in endocrine-associated tumors, for example, breast cancer  and prostate cancer [23, 24]. Recently, elevated serum/plasma levels of CgA were found in a number of non-endocrine solid tumors, such as hepatic carcinomas [25, 26] and pancreatic cancer . Examination of CgA levels could be used not only for diagnosis but also for prognostic evaluation in these tumors [21, 23, 25, 27].
In recent ENETS and NANETS consensus guidelines, CgA was considered as the most practical and useful serum tumor marker in PNET patients [28, 29]. Some studies suggested that testing blood CgA should be mandatory for NET diagnosis . However, few attention has been paid to the insulinoma which is the most common type of functioning PNETs [7, 8, 14, 15, 17, 19, 21, 30–32]. In addition, peripheral blood levels of CgA are not routinely tested in Chinese patients with GEP-NET. Using CgA for clinical diagnosis has not been officially approved by Sino Food Drug Administration (SFDA) because little data have been reported.
Thus, the present study is to verify the utility of CgA in diagnosis of PNETs, focusing on its diagnostic value in insulinoma. We found that serum levels of CgA were not significantly elevated in patients with insulinomas, compared to the higher levels of CgA in other PNETs. This finding was rarely reported in previous studies.
This study was approved by the Scientific Ethics Committee of Peking Union Medical College Hospital and the First Affiliated Hospital of Sun Yat-sen University. Participants provided their written informed consent to participate in this study. The Scientific Ethics Committee of both hospitals approved the consent procedure.
Patients and samples collection
Eighty-nine Chinese patients with PNETs including 57 insulinomas (one with extensive hepatic metastases), and 32 non-insulinoma PNETs (8 gastrinomas, 4 glucagonomas, 1 VIPoma and 19 NF) as well as 86 healthy participants were enrolled in this study at Peking Union Medical College Hospital and the First Affiliated Hospital of Sun Yat-sen University, between September 2003 and June 2013. The diagnostic criteria for PNETs were reported previously [33–39]. Briefly, the tumors were mainly localized by computed tomography with contrast, magnetic resonance imaging, endoscopic ultrasound and somatostatin receptor scintigraphy. All patients did not suffer with inflammatory diseases (such as inflammatory bowel disease, chronic atrophic gastritis), and the renal, hepatic or cardiac insufficiency was excluded. The patients did not take proton pump inhibitors (PPIs) or histamine 2 receptor blockers as well as somatostatin analogues. The pathological diagnosis was made by 2 experienced pathologists. We analyzed tumor grade in 54 tumors according to ENETS-WHO guideline  and analyzed stage in 84 patients according to the ENETS guideline .
Before surgery or treatment, blood samples were obtained in 89 fasted patients with PNETs. In 17 patients with insulinomas, blood samples were postoperatively collected during 3rd to 7th days after resection. The blood samples from 86 healthy participants (median age 43 years, 38 male) were collected after overnight fasting. Serum were isolated and stored in −80°C.
Detecting of serum levels of CgA
Serum levels of CgA of patients with PNETs and healthy controls were measured by ELISA method with a commercial kit (Chromoa assay; CIS Bio International, France), according to the manufacturer’s protocol. Most of samples were duplicated tested, and some of samples were checked in another experiment. Ten samples were double examined in two different labs (one in Beijing and another lab in Guangzhou).
Detecting of CgA expression in tumor tissues
Expression of CgA protein was detected in 26 sections of paraffin-embedded PNETs tissues, including 14 insulinomas, 2 gastrinomas and 10 NF as well as their paired pancreatic (duodenal) tissues by immunohistochemical staining (IHC) with anti-CgA (AC-0037, clone EP38, Epitomics, Inc, Burlingame, CA) at a 1:100 dilution. The criteria of semi-quantitative grading of IHC was similar to our previous report [36, 39], i.e. (−) means no positive staining in tumor cells; (±) < 20% tumor cells shown positive staining, (+) ≥20% but < 50% tumor cells shown positive staining; (++) ≥50% but < 75% tumor cells shown positive staining; (+++) ≥ 75% tumor cells shown positive staining. We defined < 20% tumor cells with staining of CgA as negative staining, i.e. (−) and (±).
To verify the diagnostic value of serum CgA, receiver operating characteristic (ROC) curves were plotted, and the area under the curve (AUC) was calculated. SPSS statistics software version 13.0 was used for statistical analysis. Mann–Whitney method was used to compare the CgA levels between each group of patients and healthy controls. Fisher exact test or Chi’s test were used to analyze our data. Two-tailed test was used in all of statistic analysis. P < 0.05 was considered statistically significant.
Clinicopathological characteristics of PNET patients
Clinicopathological features of patients with PNETs
Gender n = 89 (%)
Male : Female
Age (years) at diagnosis, n = 87
PNET subtype n = 89 (%)
Inherited or sporadic PNETs, n = 89 (%)
Surgery or not, n = 89 (%)
Primary tumor location, n = 77 (%)
Tumor size (cm) median (range) n = 82
Insulinoma n = 56
Non-insulinoma n = 26
Metastasis or not, n = 83 (%)
Grade, n = 54 (%)
Stage, n = 84 (%)
Clinicopathological features of patients with insulinomas
Gender n = 57 (%)
Male : Female
Age (years) at diagnosis, n = 57
Inherited or sporadic PNETs, n = 57 (%)
Surgery or not, n = 57 (%)
Primary tumor location, n = 56 (%)
Tumor size (cm) median (range) n = 56
Metastasis or not, n = 57 (%)
Grade, n = 35 (%)
CgA Serum Levels in PNET Patients and ROC curves
Correlation of CgA levels with clinicopathological characteristics in patients with PNETs and insulinomas
Correlation of CgA levels with clinicopathological features in patients with PNETs and insulinomas
Clinicopathological features of patients with PNETs
CgA levels (ng/ml) median (range)
Male, n = 36
Female, n = 53
≤48, n = 49
>48, n = 38
Primary tumor location on pancreas
Head/neck, n = 41
Body/tail, n = 36
Tumor size (cm)
n = 82, 0.8 - 8,
r = 0.068,
G1, n = 37
G2, n = 15
G3, n = 2
I, n = 39
II, n = 22
III, n = 5
IV, n = 18
Clinicopathological features of patients with insulinomas
CgA levels (ng/ml) median (range)
Male, n = 25
Female, n = 32
≤48, n = 32
>48, n = 25
Primary tumor location on pancreas
n = 30
n = 26
Tumor size (cm)
n = 56, 0.8 - 4,
r = 0.01
G1, n = 31
G2, n = 4
Stage I, n = 39
Stage II, n = 15
The CgA levels in patients with localized insulinomas and in patients with localized non-insulinomas
The expression of CgA in PNETs tissues
Circulating CgA levels have been confirmed to be useful diagnostic marker for NETs, with a high specificity and sensitivity [1, 3, 5–19, 28]. In the present study, we verified the diagnostic value of serum CgA in a series of patients with non-insulinoma PNETs, in agreement with previous studies. The sensitivity and specificity were 65.6% and 91.9%, respectively, similar to the rate of 67% and 96% when using CIS Bio kits, as Ardill and Erikkson described . Similar to previous studies [9–11, 14, 16, 41, 42], we found that CgA levels in patients with gastrinomas were much higher than those in patients without gastrin-secreting PNETs.
The interesting finding in the study was that serum CgA levels were not elevated in patients with insulinomas, including one patient with extensive liver metastases (48 ng/ml). Most of previous studies on PNETs did not clarify this unusual biochemical feature of insulinoma, the most common subtype of PNETs [7, 8, 13–16, 19, 20, 31] but Wouter de Herder pointed out in a review that blood levels of CgA were rarely slightly elevated in subjects with insulinomas  and Portela-Gomes GM et al. mentioned in a review that well-differentiated NETs expressed CgA epitopes except insulinomas . A recently published guideline which was revised by the UK and Ireland Neuroendocrine Tumor Society and the British Society of Gastroenterology addressed that CgA would not raised in benign insulinomas . Moreover, Nobels et al. studied more than 200 NETs and found that serum CgA levels were rarely slightly elevated in patients with insulinomas (elevated in 2 of 21 patients, range 63–236 ng/ml, upper cut-off value was 220 ng/ml) . Another study showed that CgA levels were not elevated in 5 cases of insulinomas . In present study, we focused on insulinomas and our findings were very similar to their data which showed only a small part of patients with insulinomas (7/57, 12%) had a slightly increased level of CgA (>100 ng/ml, the highest level: 164 ng/ml). With a relatively low specificity (73%), serum CgA was not a reliable and practicable biomarker for diagnosis of insulinoma. This finding is important. Some studies suggested that testing CgA levels should be mandatory for PNETs diagnosis . Furthermore, according to recent North American Neuroendocrine Tumor Society (NANETS) and European Neuroendocrine Tumor Society (ENETS) consensus guidelines [28, 29] as well as ESMO guidelines for NETs diagnosis , CgA was considered as a general biomarker for NETs, and CgA can be used as a marker in patients with both Functional PNET and NF-PNET [28, 29]. Insulinoma is the most common subtype of functioning PNETs [31, 35, 37, 46]. However, whether serum levels of CgA should be tested in patients with insulinomas has not been well clarified in those guidelines for NETs diagnosis. Our data and previous reports [9, 13] showed that insulinoma could be an exception for measuring serum levels of CgA for diagnostic purpose. It maybe not necessary to test CgA levels in patients with insulinomas although this issue needs to be further validated in more cases and in multiple clinical centers. In addition, using different commercial kits or assay could be useful to further validate our findings because the antibodies used in different assay were raised against the different domain or epitopes of the CgA molecular [12, 15, 17, 47].
The underlying mechanism of low CgA levels in patients with insulinomas is not clear. Nobels et al. speculated the serum levels of CgA were only slightly elevated in subjects with small NETs, such as insulinomas, pituitary adenomas . However, there is disagreement in the literatures whether the serum CgA levels correlate with the extent of NETs or size of these tumors [7, 21, 32, 48]. In present study, we did not observe the correlation between the tumor size and CgA levels in PNETs (P = 0.545) and in insulinomas alone (P = 0.942). Some of non-insulinoma PNETs with relatively small size still had very high serum levels of CgA, for example, CgA level was 4572 ng/ml in a gastrinoma of 1.5 cm in size, and the highest CgA level in present study was more than 9000 ng/ml in a glucagonoma of 2.5 cm in size. Furthermore, one patient with a NF of 3.5 cm in size had a CgA level of 5772 ng/ml whereas another patient with a NF of 8 cm in size had a CgA level of 59 ng/ml.
Many previous studies [10, 13, 15, 41, 42, 49] and our present data showed that CgA levels in patients with NETs metastases were much higher than that in patients with localized NETs. Thus, it may hypothesized that few metastases in insulinomas would be the reason for low serum level of CgA in insulinomas (only one metastatic insulinoma in our serial). We found CgA levels in localized insulinomas were similar to that in localized non-insulinomas, P = 0.693. This might imply the above hypothesis could be partly true. In fact, most of insulinomas (>90%) are benign, absent metastasis in majority of insulinomas is one of the main characteristics of this unique tumor, and in our hospital, more than 95% of insulinomas are benign . However, we noticed that the rate of elevated CgA levels in patients with localized non-insulinomas was significantly higher than that in patients with localized insulinomas, P = 0.015. In addition, one report showed that in 9 of the 10 patients with gastrinoma, CgA values were raised, even in the absence of metastasis . These data suggested that metastasis could be one of determinant factors for high levels of CgA in PNETs, but not the only one. The tumor subtype could be another important determinant for CgA serum levels. Nevertheless, more patients with metastatic insulinomas were needed to validate the low levels of CgA in insulinomas although it might be quite difficult to do so due to the limited numbers of malignant insulinomas.
It was reported that pancreastatin, a CgA-derived peptide (CgA residues 250–301) with biological activity, inhibited the releasing of insulin by islet beta cells [7, 50] and insulinoma cell line . Gayen et al.  observed an inverse relationship between pancreastatin and insulin. This CgA-derived peptide might antagonize the effect of insulin via the Akt/FOXO-1 and, administration of insulin could result in low plasma levels of pancreastatin in mice (the basal pancreastatin level dropped significantly following insulin injection). In majority of insulinomas, a great deal amount of insulin is secreted by tumor cells. We speculate that high levels of insulin in patients with insulinomas might inhibit the secretion of CgA in these tumor cells. A recent study demonstrated that insulin and proinsulin were released in patients with insulinomas in response to arterial calcium stimulation, whereas CgA was not released .
One research suggested that CgA targeted to secretory granules in association with protein secretogranin III, a member of granin family, in pituitary and pancreatic endocrine cells . If other proteins such as secretogranin III were broken down, the secretion of CgA would be disrupted. The mechanisms of hormones and peptides secretion were very complicated, it maybe concerned with molecular cellular biology and the alterations of tumor cell functions.
Other than the low blood levels of CgA in insulinomas, the biomedical behaviors of insulinomas were quite different from other PNETs. For example, its low rate of malignancy (<10%), the relatively low rate of positive Octreotide scintigraphy can be identified in benign insulinomas comparing with non-insulinoma PNETs because many insulinomas do not express somatostatin receptor subtypes . All of these unusual features of insulinomas indicated that unique molecular cellular aspects and/or functions existed in insulinoma cells.
In this study, we have observed that most of insulinoma tissues (12/14) were shown strong positive staining for CgA, indicating that insulinoma cells were able to synthesize the CgA protein. This aspect of insulinoma was similar to non-insulinoma PNETs. However, only small part of the protein might be secreted into blood by the insulinoma cells because the CgA levels were not elevated and, the CgA levels were significantly reduced in 16 patients after tumor resection (from median 64.8 ng/ml to median 50.4 ng/ml, P = 0.003).
It is hard to explain why the serum level of CgA was postoperatively elevated in one patient who had normal liver and kidney functions. This patient did not suffer with other disease or take PPI or H2 receptor blocker. The sample was detected repeatedly and the same results were obtained.
In conclusion, our findings suggested that CgA is not a reliable biomarker for insulinomas, hence, examination of blood CgA levels could not be recommended in patients with insulinoms according to Nobels’  and our data. The mechanisms underlying low serum levels of CgA in insulinomas would appear to warrant further investigation.
The study revealed that the circulating CgA levels in patients with insulinomas were not obviously elevated, although we did validate the diagnostic value of serum CgA in a series of patients with non-insulinoma PNETs.
We thank Norvatis (China) Co. Ltd. for offering Chromogranin A ELISA kits.
- Rindi G, Wiedenmann B: Neuroendocrine neoplasms of the gut and pancreas: new insights. Nat Rev Endocrinol. 2012, 8 (1): 54-64.View ArticleGoogle Scholar
- Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evans DB: One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008, 26 (18): 3063-3072.View ArticlePubMedGoogle Scholar
- Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, Thakker RV, Caplin M, Delle Fave G, Kaltsas GA, Krenning EP, Moss SF, Nilsson O, Rindi G, Salazar R, Ruszniewski P, Sundin A: Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2008, 9 (1): 61-72.View ArticlePubMedGoogle Scholar
- Lawrence B, Gustafsson BI, Chan A, Svejda B, Kidd M, Modlin IM: The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am. 2011, 40 (1): 1-18. viiView ArticlePubMedGoogle Scholar
- Oberg K, Knigge U, Kwekkeboom D, Perren A, Group EGW: Neuroendocrine gastro-entero-pancreatic tumors: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012, 23 (Suppl 7): vii124-vii130.PubMedGoogle Scholar
- Oberg K, Eriksson B: Endocrine tumours of the pancreas. Best Pract Res Clin Gastroenterol. 2005, 19 (5): 753-781.View ArticlePubMedGoogle Scholar
- Modlin IM, Gustafsson BI, Moss SF, Pavel M, Tsolakis AV, Kidd M: Chromogranin A–biological function and clinical utility in neuro endocrine tumor disease. Ann Surg Oncol. 2010, 17 (9): 2427-2443.View ArticlePubMedGoogle Scholar
- Singh S, Law C: Chromogranin A: a sensitive biomarker for the detection and post-treatment monitoring of gastroenteropancreatic neuroendocrine tumors. Expert Rev Gastroenterol Hepatol. 2012, 6 (3): 313-334.View ArticlePubMedGoogle Scholar
- Nobels FR, Kwekkeboom DJ, Coopmans W, Schoenmakers CH, Lindemans J, De Herder WW, Krenning EP, Bouillon R, Lamberts SW: Chromogranin A as serum marker for neuroendocrine neoplasia: comparison with neuron-specific enolase and the alpha-subunit of glycoprotein hormones. J Clin Endocrinol Metab. 1997, 82 (8): 2622-2628.PubMedGoogle Scholar
- Bashir S, Gibril F, Ojeaburu JV, Asgharian B, Entsuah LK, Ferraro G, Crafa P, Bordi C, Jensen RT: Prospective study of the ability of histamine, serotonin or serum chromogranin A levels to identify gastric carcinoids in patients with gastrinomas. Aliment Pharmacol Ther. 2002, 16 (7): 1367-1382.View ArticlePubMedGoogle Scholar
- Abou-Saif A, Gibril F, Ojeaburu JV, Bashir S, Entsuah LK, Asgharian B, Jensen RT: Prospective study of the ability of serial measurements of serum chromogranin A and gastrin to detect changes in tumor burden in patients with gastrinomas. Cancer. 2003, 98 (2): 249-261.View ArticlePubMedGoogle Scholar
- Ardill JE, Erikkson B: The importance of the measurement of circulating markers in patients with neuroendocrine tumours of the pancreas and gut. Endocr Relat Cancer. 2003, 10 (4): 459-462.View ArticlePubMedGoogle Scholar
- Nehar D, Lombard-Bohas C, Olivieri S, Claustrat B, Chayvialle JA, Penes MC, Sassolas G, Borson-Chazot F: Interest of Chromogranin A for diagnosis and follow-up of endocrine tumours. Clin Endocrinol (Oxf). 2004, 60 (5): 644-652.View ArticleGoogle Scholar
- Campana D, Nori F, Piscitelli L, Morselli-Labate AM, Pezzilli R, Corinaldesi R, Tomassetti P: Chromogranin A: is it a useful marker of neuroendocrine tumors?. J Clin Oncol. 2007, 25 (15): 1967-1973.View ArticlePubMedGoogle Scholar
- Zatelli MC, Torta M, Leon A, Ambrosio MR, Gion M, Tomassetti P, De Braud F, Delle Fave G, Dogliotti L, Degli Uberti EC, Italian CromaNet Working Group: Chromogranin A as a marker of neuroendocrine neoplasia: an Italian Multicenter Study. Endocr Relat Cancer. 2007, 14 (2): 473-482.View ArticlePubMedGoogle Scholar
- Metz DC, Jensen RT: Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology. 2008, 135 (5): 1469-1492.View ArticlePubMedPubMed CentralGoogle Scholar
- Lawrence B, Gustafsson BI, Kidd M, Pavel M, Svejda B, Modlin IM: The clinical relevance of chromogranin A as a biomarker for gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am. 2011, 40 (1): 111-134. viiiView ArticlePubMedGoogle Scholar
- Oberg K: Circulating biomarkers in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer. 2011, 18 (Suppl 1): S17-S25.View ArticlePubMedGoogle Scholar
- Chou WC, Hung YS, Hsu JT, Chen JS, Lu CH, Hwang TL, Rau KM, Yeh KY, Chen TC, Sun CF: Chromogranin A is a reliable biomarker for gastroenteropancreatic neuroendocrine tumors in an Asian population of patients. Neuroendocrinology. 2012, 95 (4): 344-350.View ArticlePubMedGoogle Scholar
- Walter T, Chardon L, Chopin-laly X, Raverot V, Caffin AG, Chayvialle JA, Scoazec JY, Lombard-Bohas C: Is the combination of chromogranin A and pancreatic polypeptide serum determinations of interest in the diagnosis and follow-up of gastro-entero-pancreatic neuroendocrine tumours?. Eur J Cancer. 2012, 48 (12): 1766-1773.View ArticlePubMedGoogle Scholar
- Arnold R, Wilke A, Rinke A, Mayer C, Kann PH, Klose KJ, Scherag A, Hahmann M, Muller HH, Barth P: Plasma chromogranin A as marker for survival in patients with metastatic endocrine gastroenteropancreatic tumors. Clin Gastroenterol Hepatol. 2008, 6 (7): 820-827.View ArticlePubMedGoogle Scholar
- Giovanella L, Marelli M, Ceriani L, Giardina G, Garancini S, Colombo L: Evaluation of chromogranin A expression in serum and tissues of breast cancer patients. Int J Biol Markers. 2001, 16 (4): 268-272.PubMedGoogle Scholar
- Ranno S, Motta M, Rampello E, Risino C, Bennati E, Malaguarnera M: The chromogranin-A (CgA) in prostate cancer. Arch Gerontol Geriatr. 2006, 43 (1): 117-126.View ArticlePubMedGoogle Scholar
- Sciarra A, Di Silverio F, Autran AM, Salciccia S, Gentilucci A, Alfarone A, Gentile V: Distribution of high chromogranin A serum levels in patients with nonmetastatic and metastatic prostate adenocarcinoma. Urol Int. 2009, 82 (2): 147-151.View ArticlePubMedGoogle Scholar
- Malaguarnera M, Vacante M, Fichera R, Cappellani A, Cristaldi E, Motta M: Chromogranin A (CgA) serum level as a marker of progression in hepatocellular carcinoma (HCC) of elderly patients. Arch Gerontol Geriatr. 2010, 51 (1): 81-85.View ArticlePubMedGoogle Scholar
- Biondi A, Malaguarnera G, Vacante M, Berretta M, D’Agata V, Malaguarnera M, Basile F, Drago F, Bertino G: Elevated serum levels of Chromogranin A in hepatocellular carcinoma. BMC Surg. 2012, 12 (Suppl 1): S7-View ArticlePubMedPubMed CentralGoogle Scholar
- Malaguarnera M, Cristaldi E, Cammalleri L, Colonna V, Lipari H, Capici A, Cavallaro A, Beretta M, Alessandria I, Luca S, Motta M: Elevated chromogranin A (CgA) serum levels in the patients with advanced pancreatic cancer. Arch Gerontol Geriatr. 2009, 48 (2): 213-217.View ArticlePubMedGoogle Scholar
- O’Toole D, Grossman A, Gross D, Delle Fave G, Barkmanova J, O’Connor J, Pape UF, Plockinger U, Mallorca Consensus Conference p, European Neuroendocrine Tumor S: ENETS consensus guidelines for the standards of care in neuroendocrine tumors: biochemical markers. Neuroendocrinology. 2009, 90 (2): 194-202.View ArticlePubMedGoogle Scholar
- Vinik AI, Woltering EA, Warner RR, Caplin M, O’Dorisio TM, Wiseman GA, Coppola D, Go VL, North American Neuroendocrine Tumor S: NANETS consensus guidelines for the diagnosis of neuroendocrine tumor. Pancreas. 2010, 39 (6): 713-734.View ArticlePubMedGoogle Scholar
- Grant CS: Insulinoma. Best Pract Res Clin Gastroenterol. 2005, 19 (5): 783-798.View ArticlePubMedGoogle Scholar
- Mathur A, Gorden P, Libutti SK: Insulinoma. Surg Clin North Am. 2009, 89 (5): 1105-1121.View ArticlePubMedPubMed CentralGoogle Scholar
- O’Dorisio TM, Krutzik SR, Woltering EA, Lindholm E, Joseph S, Gandolfi AE, Wang YZ, Boudreaux JP, Vinik AI, Go VL, Howe JR, Halfdanarson T, O'Dorisio MS, Mamikunian G: Development of a highly sensitive and specific carboxy-terminal human pancreastatin assay to monitor neuroendocrine tumor behavior. Pancreas. 2010, 39 (5): 611-616.View ArticlePubMedGoogle Scholar
- Chen YJ, Vortmeyer A, Zhuang Z, Huang S, Jensen RT: Loss of heterozygosity of chromosome 1q in gastrinomas: occurrence and prognostic significance. Cancer Res. 2003, 63 (4): 817-823.PubMedGoogle Scholar
- Yang YM, Liu TH, Chen YJ, Jiang WJ, Qian JM, Lu X, Gao J, Wu SF, Sang XT, Chen J: Chromosome 1q loss of heterozygosity frequently occurs in sporadic insulinomas and is associated with tumor malignancy. Int J Cancer. 2005, 117 (2): 234-240.View ArticlePubMedGoogle Scholar
- de Herder WW, Niederle B, Scoazec JY, Pauwels S, Kloppel G, Falconi M, Kwekkeboom DJ, Oberg K, Eriksson B, Wiedenmann B, Rindi G, O'Toole D, Ferone D, Frascati Consensus Conference, European Neuroendocrine Tumor Society: Well-differentiated pancreatic tumor/carcinoma: insulinoma. Neuroendocrinology. 2006, 84 (3): 183-188.View ArticlePubMedGoogle Scholar
- Mei M, Deng D, Liu TH, Sang XT, Lu X, Xiang HD, Zhou J, Wu H, Yang Y, Chen J, Lu CM, Chen YJ: Clinical implications of microsatellite instability and MLH1 gene inactivation in sporadic insulinomas. J Clin Endocrinol Metab. 2009, 94 (9): 3448-3457.View ArticlePubMedGoogle Scholar
- Zhao YP, Zhan HX, Zhang TP, Cong L, Dai MH, Liao Q, Cai LX: Surgical management of patients with insulinomas: Result of 292 cases in a single institution. J Surg Oncol. 2011, 103 (2): 169-174.View ArticlePubMedGoogle Scholar
- Wang YH, Lin Y, Xue L, Wang JH, Chen MH, Chen J: Relationship between clinical characteristics and survival of gastroenteropancreatic neuroendocrine neoplasms: A single-institution analysis (1995–2012) in South China. BMC Endocr Disord. 2012, 12: 30-View ArticlePubMedPubMed CentralGoogle Scholar
- Liu B, Tang LH, Liu Z, Mei M, Yu R, Dhall D, Qiao XW, Zhang TP, Zhao YP, Liu TH, Xiao Y, Chen J, Xiang HD, Wu HY, Lu CM, Lv B, Zhou YR, Zhang Y, Deng DJ, Chen YJ: Alpha-Internexin: a novel biomarker for pancreatic neuroendocrine tumor aggressiveness. J Clin Endocrinol Metab. 2014, 99 (5): E786-E795.View ArticlePubMedGoogle Scholar
- Rindi G, Falconi M, Klersy C, Albarello L, Boninsegna L, Buchler MW, Capella C, Caplin M, Couvelard A, Doglioni C, Delle Fave G, Fischer L, Fusai G, de Herder WW, Jann H, Komminoth P, de Krijger RR, La Rosa S, Luong TV, Pape U, Perren A, Ruszniewski P, Scarpa A, Schmitt A, Solcia E, Wiedenmann B: TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. J Natl Cancer Inst. 2012, 104 (10): 764-777.View ArticlePubMedGoogle Scholar
- Tomassetti P, Migliori M, Simoni P, Casadei R, De Iasio R, Corinaldesi R, Gullo L: Diagnostic value of plasma chromogranin A in neuroendocrine tumours. Eur J Gastroenterol Hepatol. 2001, 13 (1): 55-58.View ArticlePubMedGoogle Scholar
- Paik WH, Ryu JK, Song BJ, Kim J, Park JK, Kim YT, Yoon YB: Clinical usefulness of plasma chromogranin a in pancreatic neuroendocrine neoplasm. J Korean Med Sci. 2013, 28 (5): 750-754.View ArticlePubMedPubMed CentralGoogle Scholar
- de Herder WW: Biochemistry of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab. 2007, 21 (1): 33-41.View ArticlePubMedGoogle Scholar
- Portela-Gomes GM, Grimelius L, Wilander E, Stridsberg M: Granins and granin-related peptides in neuroendocrine tumours. Regul Pept. 2010, 165 (1): 12-20.View ArticlePubMedGoogle Scholar
- Ramage JK, Ahmed A, Ardill J, Bax N, Breen DJ, Caplin ME, Corrie P, Davar J, Davies AH, Lewington V, Meyer T, Newell-Price J, Poston G, Reed N, Rockall A, Steward W, Thakker RV, Toubanakis C, Valle J, Verbeke C, Grossman AB, Uk Ireland Neuroendocrine Tumour Society: Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut. 2012, 61 (1): 6-32.View ArticlePubMedGoogle Scholar
- Crippa S, Zerbi A, Boninsegna L, Capitanio V, Partelli S, Balzano G, Pederzoli P, Di Carlo V, Falconi M: Surgical management of insulinomas: short- and long-term outcomes after enucleations and pancreatic resections. Arch Surg. 2012, 147 (3): 261-266.View ArticlePubMedGoogle Scholar
- Molina R, Alvarez E, Aniel-Quiroga A, Borque M, Candas B, Leon A, Poyatos RM, Gelabert M: Evaluation of chromogranin A determined by three different procedures in patients with benign diseases, neuroendocrine tumors and other malignancies. Tumour Biol. 2011, 32 (1): 13-22.View ArticlePubMedGoogle Scholar
- Ito T, Igarashi H, Jensen RT: Serum pancreastatin: the long sought universal, sensitive, specific tumor marker for neuroendocrine tumors?. Pancreas. 2012, 41 (4): 505-507.View ArticlePubMedPubMed CentralGoogle Scholar
- Nolting S, Kuttner A, Lauseker M, Vogeser M, Haug A, Herrmann KA, Hoffmann JN, Spitzweg C, Goke B, Auernhammer CJ: Chromogranin a as serum marker for gastroenteropancreatic neuroendocrine tumors: a single center experience and literature review. Cancers. 2012, 4 (1): 141-155.View ArticlePubMedPubMed CentralGoogle Scholar
- Tatemoto K, Efendic S, Mutt V, Makk G, Feistner GJ, Barchas JD: Pancreastatin, a novel pancreatic peptide that inhibits insulin secretion. Nature. 1986, 324 (6096): 476-478.View ArticlePubMedGoogle Scholar
- Hertelendy ZI, Patel DG, Knittel JJ: Pancreastatin inhibits insulin secretion in RINm5F cells through obstruction of G-protein mediated, calcium-directed exocytosis. Cell Calcium. 1996, 19 (2): 125-132.View ArticlePubMedGoogle Scholar
- Gayen JR, Saberi M, Schenk S, Biswas N, Vaingankar SM, Cheung WW, Najjar SM, O’Connor DT, Bandyopadhyay G, Mahata SK: A novel pathway of insulin sensitivity in chromogranin A null mice: a crucial role for pancreastatin in glucose homeostasis. J Biol Chem. 2009, 284 (42): 28498-28509.View ArticlePubMedPubMed CentralGoogle Scholar
- Wiesli P, Uthoff H, Perren A, Pfammatter T, Zwimpfer C, Seiler H, Kindhauser R, Spinas GA, Schmid C: Are biochemical markers of neuroendocrine tumors coreleased with insulin following local calcium stimulation in patients with insulinomas?. Pancreas. 2011, 40 (7): 995-999.View ArticlePubMedGoogle Scholar
- Hosaka M, Watanabe T, Sakai Y, Uchiyama Y, Takeuchi T: Identification of a chromogranin A domain that mediates binding to secretogranin III and targeting to secretory granules in pituitary cells and pancreatic beta-cells. Mol Biol Cell. 2002, 13 (10): 3388-3399.View ArticlePubMedPubMed CentralGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6823/14/64/prepub
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