A Preoperative Clinical Risk Score Including C-Reactive Protein Predicts Histological Tumor Characteristics and Patient Survival after Surgery for Sporadic Non-Functional Pancreatic Neuroendocrine Neoplasms: An International Multicenter Cohort Study

Abstract

Background: Oncological survival after resection of pancreatic neuroendocrine neoplasms (panNEN) is highly variable depending on various factors. Risk stratification with preoperatively available parameters could guide decision-making in multidisciplinary treatment concepts. C-reactive Protein (CRP) is linked to inferior survival in several malignancies. This study assesses CRP within a novel risk score predicting histology and outcome after surgery for sporadic non-functional panNENs. Methods: A retrospective multicenter study with national exploration and international validation. CRP and other factors associated with overall survival (OS) were evaluated by multivariable cox-regression to create a clinical risk score (CRS). Predictive values regarding OS, disease-specific survival (DSS), and recurrence-free survival (RFS) were assessed by time-dependent receiver-operating characteristics. Results: Overall, 364 patients were included. Median CRP was significantly higher in patients >60 years, G3, and large tumors. In multivariable analysis, CRP was the strongest preoperative factor for OS in both cohorts. In the combined cohort, CRP (cut-off ≥0.2 mg/dL; hazard-ratio (HR):3.87), metastases (HR:2.80), and primary tumor size ≥3.0 cm (HR:1.83) showed a significant association with OS. A CRS incorporating these variables was associated with postoperative histological grading, T category, nodal positivity, and 90-day morbidity/mortality. Time-dependent area-under-the-curve at 60 months for OS, DSS, and RFS was 69%, 77%, and 67%, respectively (all p < 0.001), and the inclusion of grading further improved the predictive potential (75%, 84%, and 78%, respectively). Conclusions: CRP is a significant marker of unfavorable oncological characteristics in panNENs. The proposed internationally validated CRS predicts histological features and patient survival.

Prognostic Value of C-Reactive Protein, Glasgow Prognostic Score, and C-Reactive Protein-to-Albumin Ratio in Colorectal Cancer

“…The prognostic scores of GPS and CAR are based on the CRP and albumin levels, and they may be related to inflammation and poor survival. In the past few years, CRP, GPS, and CAR have been shown to have prognostic value in patients with hepatocellular carcinoma ( Kinoshita et al, 2015 ) and gallbladder ( Utsumi et al, 2020 ), pancreatic ( Primavesi et al, 2020 ), ovarian ( Liu et al, 2017 ), esophageal ( Sakai et al, 2020 ), and gastric ( Okugawa et al, 2020 ) cancers.…”

C-reactive protein independently predicts survival in pancreatic neuroendocrine neoplasms

“…1 a) 50 , 51 , which is the main variable for the WHO-classification of neuroendocrine disease 39 , 40 and implemented in the European Neuroendocrine Tumour Society (ENETS) guidelines 5 . From the data by Primavesi et al 38 , one might argue that the same biological effect is measured. Importantly, however, serum CRP is shown to be a risk factor independent of grading in this analysis, thereby disproving this hypothesis.…”

“…Similarly, Primavesi et al 38 analysed 364 surgically resected patients in a retrospective multicentre study. The authors report significantly higher serum CRP levels in older patients (≥ 60 years), tumours ≥ 3 cm and G3 differentiated patients.…”

“…Preoperatively elevated serum C-reactive protein (CRP) level was identified as a risk factor for poor survival in several tumour entities 25 – 30 including surgically resected pancreatic cancer patients 31 – 34 and was consequently shown to affect progression in gastroenteropancreatic (GEP-) NEN in general 35 as well as in pNEN 36 . Only 2 studies have thus far examined the relationship between outcome of surgically resected pNEN and preoperative serum CRP levels 37 , 38 . However, both studies only analysed the simple presence or absence of elevated serum CRP and did not include grading as one of the most important prognostic parameters in pNEN in the analyses.…”

Hot Spot TERT Promoter Mutations Are Rare in Sporadic Pancreatic Neuroendocrine Neoplasms and Associated with Telomere Length and Epigenetic Expression Patterns

“…Known risk factors for poor survival after resection of pNETs include increased tumor size, presence of metastasis, vascular and lymphogenic invasion, positive lymph nodes of the primary tumor, T-Stage and non-functioning tumors [ 9 , 27 ]. The five identified TPM cases were not found significantly related to any of the clinicopathological and epigenetic parameters in this small sample of pNEN patients.…”