C-reactive protein may be a prognostic factor for the whole gastroenteropancreatic neuroendocrine tumor group

ARTICLE HIGHLIGHTS

Research background

Neuroendocrine tumors develop as a result of the malignant transformation of neuroendocrine cells, they can be found in all areas of the body and their frequency is gradually increasing. They are most commonly seen in the gastrointestinal system (GIS), and may cause various clinical syndromes with different malignancy potentials. In general, these tumors are less malignant than epithelial tumors. The 5-year survival varies between 15% and 95% based on factors such as location of the primary tumor, changes in the tumor biology, extensiveness of the tumor at the time of diagnosis and treatment options. The determination of a high C-reactive protein (CRP) level, a marker of inflammation, in hematopoietic and some solid malignancies suggests a poor prognosis, and may have prognostic significance. It has been shown in several studies that the CRP level has prognostic importance in malignancies such as pancreatic adenocarcinoma, soft tissue sarcoma, and chronic lymphocytic leukemia.

Research motivation

The prognosis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is difficult to predict due to differences in tumor type, the diversity of molecular mechanisms responsible for pathology, a scarcity of large-scale and prospective randomized studies, and the possible development of various clinical syndromes. In general, the mean time to diagnosis of these tumors is 5 to 7 years as they have vague symptoms and may not be correctly managed. Therefore, the determination of prognostic factors affecting survival and achieving standardization of these tumors is important in terms of early identification due to their aggressive course, and treatment planning.

Research objectives

To specify the survival status and time of the patients included in this study, the relationship between tumor location, tumor extensiveness, size, pathological characteristics, sampling method and laboratory data were evaluated. The prognostic importance of certain variables were also assessed.

Research methods

Ninety-three patients aged 18 years and over, diagnosed with GEP-NETs who underwent surgical resection and/or non-surgical treatment in Dokuz Eylul University Hospital between January 2002 and June 2012 were included in this study. Patient data at the time of diagnosis was retrospectively reviewed. Independent variables such as demographic, radiological, surgical, pathological and specific laboratory data were assessed and recorded. Dependent variables were designated as the 1, 3 and 5-year survival and time (months) from diagnosis date to outcome date. In order to create a 5-year follow-up period, patients diagnosed after June 15, 2012, were not included in the study. The date of death in patients who died during the study was determined as the outcome date, and was June 15, 2017 for the other patients. As some tumor diameters were smaller than 1 cm and small quantities of material were obtained, the patients diagnosed by the endoscopic excisional biopsy, endoscopic incisional biopsy, fine-needle aspiration biopsy, and full layer biopsy were classified as the non-surgical group.

Research results

A significant negative relationship was observed between patient age at the time of diagnosis and 5-year survival (P = 0.019). 55% of patients were female. A significant relationship between female gender and 5-year survival was determined (P = 0.014). The mean primary tumor diameter was 3.1 ± 3.45 (SD) cm. A significant positive relationship between tumor diameter and 5-year survival was observed (P = 0.013). The mean CRP level was 22.5 mg/dL ± 33.8. There was a statistically significant relationship between CRP level and 5-year survival (P = 0.02). The mean survival (MS) time was (overall survival) 102.5 ± 6.3 mo. The 1, 3, and 5-year survival rates were 90%, 72%, and 61%, respectively. A strong negative relationship was observed between survival and both liver metastasis and and extrahepatic distant metastasis (P < 0.001, P < 0.001). When the mitotic count was taken as the basis for determining tumor grade, the MS was 111 ± 6.2 mo in the G1 group and was 35.1 ± 11.3 mo in the G3 group. When the Ki-67 level was taken as the basis for determining tumor grade, the MS was 124.6 ± 6.1 mo in the G1 group and was 54.4 ± 12.7 mo in the G3 group (P < 0.001). The MS was 118.1 ± 8.2 mo in those with a CRP level < 5 mg/L, was 118.6 ± 12.2 mo in those with a CRP between 5 and 20 mg/L, and was 72.3 ± 10.5 mo in those with a CRP level > 20 mg/L (P = 0.009). When pancreatic and stomach NETs were compared, the survival time in patients with pancreatic NETs was significantly lower (P = 0.016). When assessing mortality during the 5-year follow-up period, sensitivity and specificity were 80% and 45%, respectively, when the CRP “cut off” value was 3.85 mg/L; the sensitivity and specificity were 76% and 47%, respectively, when the CRP “cut off” value was 5 mg/L (the universal “cut off” value for CRP), and the sensitivity and specificity were 56% and 79% when the CRP “cut off” value was 20 mg/L. It was also observed that CRP levels greater than 20 mg/L with a 1 mg/dL increase, increased the risk of death 3.2-fold (95% CI: 14.5-7.1).

Research conclusions

CRP is an acute phase protein produced in the liver. The acute phase response is stimulated by IL-6 released from macrophages and T cells. Any acute or chronic inflammatory conditions may cause an increase in CRP due to the activation of IL-6. These conditions include infections, autoimmune diseases, and malignancies. As a result, CRP is a sensitive, but nonspecific marker[29]. For this reason, the CRP level in 21 patients whose elevation in CRP was determined to be due to non-tumor related causes was not taken into account in this study. In our study, a significant negative relationship between increased CRP level and survival was observed for the whole GEP-NET group (P = 0.009). Mean survival was 118.1 mo in patients with a CRP level < 5 mg/L, was 118.6 mo in those with a CRP level between 5 and 20 mg/L and was 72.3 mo in those with a CRP level > 20 mg/L. It was shown that each increase in the CRP value of 1 mg/L increased the risk of death by 1.5%. It was observed that the risk of death increased 3.2-fold when CRP level was greater than 20 mg/L, and when this value was taken as the cut off, the sensitivity was 56% and specificity was 79% for the occurrence of death. According to these results, the CRP level, especially when it is above 20 mg/L, is a prognostic factor for a poor outcome in the GEP-NET group. This was shown for the entire GEP-NET group for the first time. Wiese et al[30] performed a study on a PNET group and found a relationship between the CRP level at the time of diagnosis and survival, which indicated that a high CRP value may be an independent prognostic factor in the PNET group. Moreover, as a correlation between Ki-67 level and survival was not observed, the CRP level was shown to be an independent prognostic factor for the whole GEP-NET group.

Research prospective

Small-scale studies have been carried out in which patients were included according to the involved sites, the presence of metastasis, and stage or grade; however, only a few studies have analyzed the GEP-NET group holistically. It is known that all GEP-NETs can metastasize independent of tumor grade and stage; thus, follow-up parameters that can be used for the whole group, factors that affect clinical course and determination of confidence levels of available parameters are important. It was demonstrated in our study that CRP level negatively affected the disease course, especially in patients with a CRP level > 20 mg/dL as it was shown that CRP level was a prognostic factor for the GEP-NET group. We propose that CRP level is an independent prognostic factor for the whole GEP-NET group. However, further prospective and controlled studies are required to verify disease progression according to the CRP level at the time of diagnosis, and treatment can be planned accordingly. CRP level can also be monitored during the follow-up period.