Immunohistochemical analysis of chromogranin A and p53 expressions in ulcerative colitis–associated neoplasia: neuroendocrine differentiation as an early event in the colitis-neoplasia sequence

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 (χ219.1, 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.

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Immunohistochemical analysis of chromogranin A and multiple peptides in the mammalian merkel cell: Further evidence for its paraneuronal function?

Archives of Histology and Cytology ◽

10.1679/aohc.52.suppl_423 ◽

1989 ◽

Vol 52 (Suppl) ◽

pp. 423-431 ◽

Cited By ~ 43

Author(s):

W. HARTSCHUH ◽

E. WEIHE ◽

N. YANAIHARA

Keyword(s):

Chromogranin A ◽

Immunohistochemical Analysis ◽

Merkel Cell

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Plasma chromogranin A in incidental non-functioning, benign, solid adrenocortical tumors

Acta Endocrinologica ◽

10.1530/eje.0.1510215 ◽

2004 ◽

Vol 151 (2) ◽

pp. 215-222 ◽

Cited By ~ 2

Author(s):

G Bernini ◽

A Moretti ◽

V Fontana ◽

C Orlandini ◽

P Miccoli ◽

...

Keyword(s):

Malignant Transformation ◽

Chromogranin A ◽

Strong Association ◽

Neuroendocrine Differentiation ◽

Characteristic Analysis ◽

Adrenocortical Adenomas ◽

Adenoma Tissue ◽

Tissue Specimens ◽

The Masses

OBJECTIVE: To evaluate whether adenomas arising from the adrenal cortex, a tissue of epithelial origin, are associated with high chromogranin A (CgA) levels and whether such tumors may express and release this protein. In addition, to investigate whether high CgA levels imply a neuroendocrine differentiation of the adrenocortical adenomas and, therefore, represent a humoral marker of malignant transformation of these tumors. DESIGN: Plasma CgA of 80 patients with non-functioning, benign adrenocortical adenomas was compared with that of 137 tumor-free subjects. In 15 patients, the masses were surgically removed and CgA was measured 2 months later. The other 65 patients with adrenocortical adenomas underwent clinical and radiological follow-up (range 24-36 months). METHODS: CgA was evaluated by immunoradiometric assay in peripheral blood and by immunohistochemistry in adrenal tissue specimens. RESULTS: An increase in plasma CgA (P<0.001) was observed in patients with adrenocortical adenomas (83.4+/-7.5 ng/ml) in comparison with tumor-free subjects (43.1+/-1.5 ng/ml). The prevalence of high CgA levels was 25% in the former and 0.7% in the latter. By multiple regression analysis, an increase (49%) in the expected median CgA value was estimated for adrenocortical adenomas (P<0.001). Receiver operating characteristic analysis showed a good diagnostic performance of CgA in identifying patients with adrenocortical adenomas (pure accuracy=0.78, 95% CI=0.71-0.84). In the operated patients, CgA levels did not change before (80.6+/-16.5 ng/ml) and after (74.3+/-16.3 ng/ml) surgery and in no case was CgA immunoreactivity found in adenoma tissues. The non-operated patients did not develop signs or symptoms of disease and showed no features of malignant transformation of the masses. CONCLUSIONS: Our data showed a strong association between adrenocortical adenomas and high CgA levels. CgA hypersecretion was not due to adenoma tissue, which did not show immunoreactivity for CgA. Finally, elevated CgA levels did not represent a humoral marker of malignant transformation of cortical adenomas.

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Neuroendocrine differentiation in head and neck squamous cell carcinoma

The Journal of Laryngology & Otology ◽

10.1017/s0022215112002265 ◽

2012 ◽

Vol 126 (12) ◽

pp. 1261-1270 ◽

Cited By ~ 16

Author(s):

V H Schartinger ◽

C Falkeis ◽

K Laimer ◽

G M Sprinzl ◽

H Riechelmann ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Chromogranin A ◽

Somatostatin Receptor ◽

Somatostatin Receptors ◽

Neuroendocrine Differentiation ◽

Receptor Expression ◽

Neck Squamous Cell Carcinoma

AbstractObjective:Tumours with neuroendocrine differentiation frequently express chromogranin A, synaptophysin and somatostatin receptors. The role of neuroendocrine differentiation in head and neck squamous cell carcinoma is not yet clear.Method:The presence of chromogranin A, synaptophysin and somatostatin receptors was studied immunohistochemically in 78 head and neck squamous cell carcinoma specimens.Results:Sparse chromogranin A expression was found in 41 per cent, associated with high chromogranin A messenger RNA expression and the presence of dense core granules. Low synaptophysin expression was found in 18 per cent. The highest staining scores were found for somatostatin receptor 5 (82 per cent), followed by somatostatin receptor 1 (69 per cent) and somatostatin receptor 2 (54 per cent), whereas somatostatin receptors 3 and 4 expression was low. Expression was not correlated with tumour stage or survival.Conclusion:Cells with neuroendocrine differentiation are sparsely scattered in some head and neck squamous cell carcinomas. Their pathophysiological role is elusive. In contrast, somatostatin receptor and particularly somatostatin receptor 5 expression is frequent in head and neck squamous cell carcinoma. Somatostatin receptor expression is not considered to indicate neuroendocrine differentiation in head and neck squamous cell carcinoma.

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Neuroendocrine differentiation of prostatic adenocarcinoma – an important cause for castration-resistant disease recurrence

Journal of Laboratory Medicine ◽

10.1515/labmed-2018-0190 ◽

2019 ◽

Vol 43 (2) ◽

pp. 123-126

Author(s):

Cátia Iracema Morais ◽

João Lobo ◽

João P. Barreto ◽

Cláudia Lobo ◽

Nuno D. Gonçalves

Keyword(s):

Chromogranin A ◽

Specific Antigen ◽

Neuron Specific Enolase ◽

Neuroendocrine Differentiation ◽

Disease Recurrence ◽

Prostatic Adenocarcinoma ◽

Resistant Disease ◽

Castration Resistant ◽

Total Prostate Specific Antigen ◽

Total Psa

Abstract Background Neuroendocrine differentiation of prostatic carcinoma is a rare entity associated with metastatic castration-resistant disease. Among useful biomarkers of neuroendocrine differentiation, chromogranin A, serotonin, synaptophysin and neuron-specific enolase stand out, while total prostate-specific antigen (PSA) levels are often low or undetectable. Case presentation We report a case of prostatic adenocarcinoma recurrence after a 6-year disease-free follow-up, in which increased serum chromogranin A levels and undetectable total PSA provided a prompt indication of neuroendocrine transformation, confirmed through immunohistochemical evaluation. Conclusions Neuroendocrine differentiation is a relevant cause of prostatic adenocarcinoma recurrence, and awareness of this entity is crucial due to its underdiagnosis and adverse prognosis.

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Evaluation of CisBio ELISA for Chromogranin A Measurement

The Journal of Applied Laboratory Medicine ◽

10.1373/jalm.2018.028027 ◽

2019 ◽

Vol 4 (1) ◽

pp. 11-18 ◽

Cited By ~ 2

Author(s):

Maili Lim ◽

Patrick Erdman ◽

Sun Cho ◽

Anu Mathew ◽

Martin Fleisher ◽

...

Keyword(s):

Chromogranin A ◽

Reference Range ◽

Clinical Laboratory ◽

Neuroendocrine Differentiation ◽

Cancer Center ◽

Reference Laboratory ◽

Plasma Samples ◽

Serum Samples ◽

Significant Bias ◽

Range Study

AbstractBackgroundChromogranin A (CgA) is a nonspecific marker for the presence of neuroendocrine tumors and neuroendocrine differentiation. The objective of this study was to evaluate the performance of the CisBio CgA ELISA.MethodsPrecision, linearity, limit of blank, and recovery of the CisBio CgA ELISA were evaluated. Seventy waste serum samples obtained from the clinical laboratory at Memorial Sloan Kettering Cancer Center were analyzed by the CisBio CgA ELISA. Results were compared to those obtained from a reference laboratory that used a proprietary ELISA for serum CgA measurement. Paired waste plasma samples were also collected from 24 of these patients to assess possible differences between CgA in serum and plasma. Finally, a preliminary reference range study was performed with samples from healthy volunteers in serum (n = 60) and plasma (n = 60).ResultsWithin-run and between-run precision ranged from 3.0% to 5.1% and 4.8% to 12.9%, respectively. The limit of blank was 2.4 ng/mL. Recovery ranged from 88% to 102%. A statistically significant bias was observed when the CisBio CgA assay results were compared to those of a reference laboratory. Comparison of the 2 assays yielded a slope of 9.05, intercept of −18.0, and a correlation coefficient of 0.955. CgA values in serum correlated well to values measured in plasma.ConclusionsThe analytical performance of the CisBio CgA ELISA was acceptable. However, CgA results are method-specific owing to lack of standardization and use of different antibodies. This lack of standardization results in several challenges for the clinical laboratory when evaluating a CgA assay.

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Neuroendocrine Differentiation in Colorectal Carcinomas Assessing its Prognostic Significance

Tumori Journal ◽

10.1177/030089160308900111 ◽

2003 ◽

Vol 89 (1) ◽

pp. 49-53 ◽

Cited By ~ 15

Author(s):

Pinar Atasoy ◽

Arzu Ensari ◽

Salim Demirci ◽

Nazmiye Kurşun

Keyword(s):

Chromogranin A ◽

Poor Prognosis ◽

Prognostic Significance ◽

Neuron Specific Enolase ◽

Neuroendocrine Differentiation ◽

Colorectal Cancers ◽

Histologic Type ◽

Colorectal Carcinomas ◽

Neuroendocrine Marker ◽

Worse Prognosis

Aims and Background There is evidence that colorectal carcinomas with extensive neuroendocrine features have a substantially worse prognosis than those without, but the frequency and clinical significance of neuroendocrine features in conventional carcinomas has not been settled since few studies have been performed, with conflicting results. The aim of the study was to investigate neuroendocrine differentiation in colorectal carcinomas in relation to its prognostic significance. Methods In 50 patients with colorectal carcinoma, the extent and intensity of staining with each of the three antibodies (chromogranin A, neuron-specific enolase and synaptophysin) were determined and correlated with the histologic type, grade, stage of the tumor and survival time of the patients. Results We observed chromogranin A expression in 38%, neuron-specific enolase expression in 26%, and synaptophysin expression in 6% of the tumors. Chromogranin A was the most frequently and strongly expressed marker in our study. Of the three antibodies studied, only chromogranin A positivity was correlated with grade and stage of the tumors and was associated with a decreased effect on survival. Conclusions Our results show that chromogranin A is the most sensitive and specific neuroendocrine marker. Chromogranin A positivity appears to bear a poor prognosis in patients with colorectal cancers.

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Notch1-Hes1 signalling axis in the tumourigenesis of biliary neuroendocrine tumours

Journal of Clinical Pathology ◽

10.1136/jclinpath-2012-201273 ◽

2013 ◽

Vol 66 (5) ◽

pp. 386-391 ◽

Cited By ~ 17

Author(s):

Kenichi Harada ◽

Yasunori Sato ◽

Hiroko Ikeda ◽

Maylee Hsu ◽

Saya Igarashi ◽

...

Keyword(s):

Mrna Expression ◽

Cell Line ◽

Chromogranin A ◽

Neuroendocrine Tumours ◽

Neuroendocrine Differentiation ◽

Biliary Tree ◽

Neuroendocrine Marker ◽

Cholangiocarcinoma Cell ◽

Neoplastic Epithelium

AimsBiliary neuroendocrine tumours (NETs) are rare and mostly exist as a component of mixed adenoneuroendocrine carcinomas (MANECs). Although the NET component in biliary MANECs is generally more malignant and clinically more important to the prognosis than the ordinary adenocarcinomatous component, the histogenesis of biliary NET has not been clarified. In this study, the role of the Notch1-Hes1 signalling axis in the histogenesis of biliary NETs was examined.MethodsImmunohistochemistry for Notch1, its ligand Jagged1 and Hes1 was performed using surgical specimens from 11 patients with biliary MANEC. Moreover, after the knock-down of Notch1 mRNA expression in a cholangiocarcinoma cell line, the expression of chromogranin A (a neuroendocrine marker) and Ascl1 (a neuroendocrine-inducing molecule inhibited by activated Hes1) was examined by quantitative PCR.ResultsHistological examination revealed that the adenocarcinomatous components were predominately located at the luminal surface of the MANEC and the majority of stromal invasion involved NET components. Ordinary adenocarcinomas and non-neoplastic biliary epithelium constantly expressed Notch1, Jagged1 and Hes1, but the expression of Notch1 and Hes1 was decreased or absent in NET components, suggesting interference with the Notch1-Hes1 signalling axis in biliary NET. Moreover, in the cholangiocarcinoma cell line in which the expression of Notch1 mRNA was knocked down, the mRNA expression of Ascl1 and chromogranin A was increased.ConclusionsThe Notch1-Hes1 signalling axis suppresses neuroendocrine differentiation and maintains tubular/acinar features in adenocarcinoma and non-neoplastic epithelium in the biliary tree. Moreover, a disruption of this signalling axis may be associated with the tumourigenesis of NETs in biliary MANEC.

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Does Valproic Acid Induce Neuroendocrine Differentiation in Prostate Cancer?

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/607480 ◽

2011 ◽

Vol 2011 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Abhinav Sidana ◽

Muwen Wang ◽

Wasim H. Chowdhury ◽

Antoun Toubaji ◽

Shabana Shabbeer ◽

...

Keyword(s):

Prostate Cancer ◽

Valproic Acid ◽

Western Blot ◽

Blot Analysis ◽

Western Blot Analysis ◽

Neuroendocrine Differentiation ◽

Immunohistochemical Analysis ◽

Dependent Manner

Valproic Acid (VPA) is a histone deacetylase inhibitor that holds promise for cancer therapy. Here, we investigate whether VPA treatment induces neuroendocrine differentiation of Prostate Cancer (PCa). A tissue microarray of VPA-treated and untreated tumor xenografts and cell lines of human PCa (LNCaP, C4-2, DU145, and PC-3) were generated and were analyzed by immunohistochemical analysis (IHC) for NE markers chromogranin A (CgA), synaptophysin, and NCAM (neural cell adhesion molecule). Western blot analysis for CgA was performed to confirm the results of the TMA. IHC analysis did not reveal any induction of CgA, synaptophysin, or NCAM in any xenograft after VPA treatmentin vivo.In vitro, VPA treatment induced little synaptophysin expression in C4-2 and PC-3 cells and NCAM expression in LNCaP and PC-3 cells. In the case of CgA, VPA treatment decreased its expressionin vitroin a dose-dependent manner, as determined by western blot analysis. Thus our data demonstrates that VPA does not induce NE differentiation of PCa cells in the physiologically relevantin vivosetting.

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