1. Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
2. Department of Biomarkers for Early Detection of Cancer, National Cancer Center Research Institute, Tokyo, Japan
3. Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
4. Surgery Division, Eiju General Hospital, Taito-ku, Tokyo, Japan
5. Institute of Pathology, University Medical Center Mainz, Mainz, Germany
6. Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany
Introduction: For pathological diagnosis of pancreatic neuroendocrine neoplasms (pNENs) the routinely used immunohistochemical markers are chromogranin A (CgA) and synaptophysin (Syn). Their ability as prognostic markers is not well established. A splice variant of actinin-4 (Actn-4sv) was recently found to be an excellent biomarker of neuroendocrine neoplasms of the lung. We aimed to investigate the expression of Actn-4sv in pNENs and evaluate its quality as a biomarker of pNENs.
Methods: Paraffin-embedded and frozen tissues specimens from 122 pNENs were analyzed. Western blots were performed to prove and compare the relative amount of Actn-4sv expression in pNENs tissue homogenates. For comparison pancreatic ductal adenocarcinoma (PDAC) and normal pancreatic tissues were analyzed in parallel. Immunohistochemistry (IHC) of paraffin sections of pNENs for Actn-4sv were performed and compared to the classic neuroendocrine markers CgA and Syn. Correlations were calculated between the staining intensity and distribution of Actn-4sv and staging, grading and afflicted lymph nodes respectively.
Results: Actn-4sv was expressed in 88.5% (108/122) of pNENs, but not in normal pancreatic tissues (0/14) or PDAC (0/14). Compared to CgA and Syn, Actn-4sv was not detectable in islet cells of the normal pancreas. Staining intensity of Actn-4sv on pNENs negatively correlated to the histological grading (Spearman r=-0.4990, p<0.0001) and staging (r = -0.2581, p = 0.0041) but no correlation to afflicted lymph nodes was found. A significantly better overall survival was observed for pNEN patients with higher expression of Actn-4sv (hazard ratio 2.7; log-rank test p= 0.0349).
Conclusions: The expression of Actn-4sv may be an important prognostic factor for patients with pNENs. Its expression correlates with the grading and staging of the tumors.
Keywords: actinin-4, actinin-4 splice variant, pNEN, survival