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

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.

Keywords: chromogranin A; chromogranin B; colorectal neoplasms; interleukin-6; neuroendocrine cells; survival analysis; thrombocytosis; thrombopoietin.

Figure A1

Serum level of carcinoembryonic antigen (A) and carbohydrate antigen 19-9 (B) within colorectal cancer patients with (CgA⁺) and without (CgA⁻) chromogranin A-positive neuroendocrine-cell differentiation within the tumor (median ± standard deviation). For a better view, tumor marker values were presented on a logarithmic scale, due to extreme outliers.

Figure A2

Personalized indicator thrombocytosis (PIT) values of colorectal cancer (CRC) patients. The value of every PIT variant: uncorrected (A), hemoglobin- (B), red blood cell count- (C) and mean corpuscular hemoglobin-corrected PIT (D) was more commonly higher within CRC patients with CgA-positive neuroendocrine-cell differentiation (CgA⁺). Median ± standard deviation.

Figure 1

Chromogranin A, chromogranin B, interleukin-6, and thrombopoietin levels within the study groups (median ± standard deviation). Serum chromogranin A level (A) was significantly higher in patients with chromogranin A-positive neuroendocrine-cell differentiation within the colorectal adenocarcinoma (CgA⁺), while serum chromogranin B level (B) was higher in patients without chromogranin A-positive neuroendocrine-cell differentiation (CgA⁻). Plasma interleukin-6 (C) was elevated in both cancer groups, compared to those of healthy controls. In the CgA⁻ group there were four additional interleukin-6 outliers over 40 pg/mL (55.58, 77.19, 82.37, and 127.60 pg/mL), which have been cut off from the top of the figure for better visibility. The plasma thrombopoietin level (D) was higher within CgA⁻ patients, compared to both the other cancer group and the healthy controls.

Figure 2

Survival analysis results of colorectal cancer (CRC) patients with (CgA⁺) and without (CgA⁻) chromogranin A-positive neuroendocrine-cell differentiation within the tumor. Three patients died due to postoperative complications (PC). Predictions based on the competing risk survival model (Aalen–Johansen estimator) suggest that patient survival was better within the CgA⁻ group (A), while patients within the CgA⁺ group (B) were much more exposed to tumor-related mortality (p = 0.0378). Combined curves (C) of the two study groups also suggested that CgA⁺ patients had a worse prognosis.

Figure 3

Chromogranin A-specific immunohistochemical staining of colorectal cancer samples (magnification: 20×). Two distinguishable pattern of the chromogranin A-positive neuroendocrine (CgA⁺) cells could have been observed within the samples. In the first, CgA⁺ cells were located individually in a scattered pattern (A), while in the remaining samples CgA⁺ cells formed small groups (B).