Chromogranin A as circulating marker for diagnosis and management of neuroendocrine neoplasms: more flaws than fame

Abstract

Owing to the heterogeneity of neuroendocrine neoplasms (NENs), the availability of reliable circulating markers is critical for improving diagnostics, prognostic stratification, follow-up and definition of treatment strategy. This review is focused on chromogranin A (CgA), a hydrophilic glycoprotein present in large dense core vesicles of neuroendocrine cells. Despite being long identified as the most useful NEN-related circulating marker, clinical application of CgA is controversial. CgA assays still lack standardization, thus hampering not only clinical management but also the comparison between different analyses. In the diagnostic setting, clinical utility of CgA is limited as hampered by (a) the variety of oncological and non-oncological conditions affecting marker levels, which impairs specificity; (b) the fact that 30-50% of NENs show normal CgA, which impairs sensitivity. Regarding the prognostic phase, there is prospective evidence which demonstrates that advanced NENs secreting CgA have poorer outcome, as compared with those showing non-elevated marker levels. Although the identification of cut-offs allowing a proper risk stratification of CgA-secreting patients has not been performed, this represents the most important clinical application of the marker. By contrast, based on prospective studies, the trend of elevated circulating CgA does not represent a valid indicator of morphological evolution and has therefore no utility for the follow-up phase. Ultimately, current knowledge about the role of the marker for the definition of treatment strategy is poor and is limited by the small number of available studies, their prevalent retrospective nature and the absence of control groups of untreated subjects.

Measurement of circulating transcript levels (NETest) to detect disease recurrence and improve follow‐up after curative surgical resection of well‐differentiated pancreatic neuroendocrine tumors

“…Levels were not significantly different in R0R compared with R1NR (39 ± 6%: [27%: [27][28][29][30][31][32][33][34][35][36][37][38][39][40], P = .08). All pNET cohorts, irrespective of recurrence, had higher levels (P < .05) than controls (19 ± 5%: [20%: [13][14][15][16][17][18][19][20]). CgA levels were not significantly different (P = .62-.94) between any of the 3 pNET cohorts (mean:…”

“…Chromogranin A (CgA) used to be considered as the most useful biomarker for detection of metastases after curative resection of pNET . However, its low sensitivity of 67% and specificity of 68%, as well as controversy regarding technical criteria of the assay, have led to a significant diminution in enthusiasm for its clinical utility . Overall, the general accuracy of CgA is moderate, given its poor metrics as a biomarker and the high false positives noted .…”

“…17 However, its low sensitivity of 67% and specificity of 68%, as well as controversy regarding technical criteria of the assay, have led to a significant diminution in enthusiasm for its clinical utility. 17,18 Overall, the general accuracy of CgA is moderate, given its poor metrics as a biomarker and the high false positives noted. [19][20][21] Although some reports describe an increased diagnostic accuracy with a high tumor load, this is of limited value in an early detection and treatment strategy.…”

Neuroendocrine neoplasms: current and potential diagnostic, predictive and prognostic markers

“…Importantly, the sensitivity of CgA depends further on the threshold cut-off (Zatelli et al 2007, Nolting et al 2012), NEN primary location (Baudin et al 2001, Tomassetti et al 2001, Nolting et al 2012, endocrine-associated syndrome (Modlin et al 2010a), disease spread, liver metastases (Zatelli et al 2007, Nikou et al 2008, Nolting et al 2012, Walter et al 2012 and the used assay (Ferrari et al 2004). Despite its use being described in some clinical guidelines, some recent publications suggest a limited applicability as follow-up marker (Marotta et al 2018). Importantly, different analytical properties of the CgA kits give different performances, a fact that must be taken into consideration when comparing results from different clinical studies.…”

MANAGEMENT OF ENDOCRINE DISEASE: Precision medicine in neuroendocrine neoplasms: an update on current management and future perspectives

“…CgA assays still lack standardization, thus limiting not only clinical management but also the comparison between different analyses. Moreover, the test specificity is hampered by non-oncological causes, such as benign diseases and iatrogenic conditions (proton pump inhibitors and histamine type-2 receptor antagonists), and by the fact that a variety of non-NEN malignancies are characterized by increased CgA levels (4,5,6). Another limitation of CgA assays is the sensitivity that ranges between 32 and 92% and is dependent on the type of NEN, the functional status and the size of the tumor (3).…”