Histopathological Chromogranin A-Positivity Is Associated with Right-Sided Colorectal Cancers and Worse Prognosis

SIMPLE SUMMARY: Several factors are known to affect colorectal cancer (CRC) patient survival, including elevated platelet counts (thrombocytosis) and chromogranin A-positive neuroendocrine-cell differentiation (CgA(+)). Thrombocytosis can occur due to biochemical changes caused by the tumor itself (known as paraneoplastic thrombocytosis) or due to the bleeding of the tumor (reactive thrombocytosis). Our effort was primarily focused on (1) determining if CgA(+) and paraneoplastic thrombocytosis combined can affect CRC and (2) finding out if there is a possible connection between the two. With the help of chromogranin A immunohistochemical staining, the measurement of circulating biochemical markers of paraneoplastic thrombocytosis (interleukin-6 and thrombopoietin) and chromogranins A and -B, indication was found that CRC combined with CgA(+) has a well-distinguishable pathophysiology, compared to CRCs without CgA(+). A possible, new subtype of CRC is proposed, which can be identified easily with chromogranin A immunohistochemical staining. However, its impact should be further studied. ABSTRACT: Background: Colorectal cancer (CRC) is known to be affected by paraneoplastic thrombocytosis and chromogranin A-positive neuroendocrine-cell differentiation (CgA(+)). Their combined effect has never been previously investigated. Methods: A prospective cohort pilot study of 42 CRC patients and 42 age- and sex-matched controls was carried out. Plasma interleukin-6, thrombopoietin, and serum chromogranin A and -B were measured; furthermore, tumor tissue was immunohistochemically stained for CgA(+). Results: Twenty-seven and 15 patients were assigned to the chromogranin A-negative (CgA(−)) and CgA(+) groups, respectively. Within the CgA(+) group, right-sided tumors were more frequent (18.5% vs. 53.3%), no stage I cancer was found, and patients of this group were in worse general condition. Compared to control subjects, chromogranin A level was higher in the CgA(+) group (p = 0.0086), thrombopoietin (p = 0.0040) and chromogranin B (p = 0.0070) in the CgA(−) group, while interleukin-6 was high in both tumor groups (p ≤ 0.0090). Survival was significantly worse in the CgA(+) group (hazard ratio: 5.73; p = 0.0378). Conclusions: Different thrombopoietin levels indicated distinct thrombocytosis types. Within the two CRC groups, serum levels of chromogranins changed in different directions suggesting two well-distinguishable pathophysiologies. Based on these observations we propose a new subtype of CRC, which can be characterized by chromogranin A-positive neuroendocrine-cell differentiation.