Table 3:
Overview of Prognostic Factors with Evidence in both MEN1-related and Sporadic NF-pNET
| Prognostic factor | Evidence in MEN1-related NF-pNETs | Evidence in sporadic NF-pNETs |
|---|---|---|
| Tumor size | Tumor size correlates with risk of metastases, (Sakurai et al., 2007, Triponez et al., 2006a) with low risk for tumors < 2cm (Nell et al., 2018, Partelli et al., 2016, Triponez et al., 2006b, Conemans et al., 2017)a. | Increased tumor size associated with reduced DFS, with < 2 cm a good cutoff for observation (Lee et al., 2019). Low risk of metastases when observing tumors < 2cm (Partelli et al., 2017, Partelli et al., 2019), especially when no bile duct involvement (Sallinen et al., 2018). |
| WHO grade / Ki-67 | In tumors > 2cm, higher WHO grade as defined by mitotic index associated with a higher risk of LM (Conemans et al., 2017)a. Tumor grade based on Ki-67 or combination of Ki-67 and mitotic index not associated with development of LM (Conemans et al., 2017)a. |
Higher WHO grade/ Ki-67 labeling index is one of the most prominent factors associated with worse DFS, DSS and OS (Lee et al., 2019). |
| DAXX/ATRX and/or ALT | ALT positivity associated with distant relapses (Cejas et al., 2019). | ALT and loss of DAXX/ATRX are associated with decreased DFS (Chou et al., 2018, Cives et al., 2019, Kim et al., 2017, Marinoni et al., 2014, Pipinikas et al., 2015, Roy et al., 2018, Singhi et al., 2017), ATRX loss is associated with poorer OS (Chou et al., 2018) and DAXX/ATRX loss is associated with shorted DSS (Marinoni et al., 2014). ALT associated with distant metastases in NF-pNETs <3cm (Pea et al., 2018). In metastatic pNETs, ALT and DAXX/ATRX loss associated with improved OS (Dogeas et al., 2014, Jiao et al., 2011, Kim et al., 2017). |
| PDX1 / ARX | Distant metastases only seen in ARX positive or ARX and PDX1 negative tumors (Cejas et al., 2019). | Distant metastases almost exclusively seen in ARX positive or ARX and PDX1 negative tumors (Cejas et al., 2019). |
| Tumor growth | Growth rate of NF-pNETs <2 cm 0.4–3 mm/year (D’Souza S et al., 2014, Pieterman et al., 2017). No clinical factor distinguishes between progressive and stable tumors. In progressive tumors, tumors with germline missense mutation grow faster (Pieterman et al., 2017). |
Most sporadic NF-pNETs <2cm do not exhibit meaningful growth during observation (Choi et al., 2018, Sallinen et al., 2017). Hypervascularity was found to be associated with less growth (Choi et al., 2018). Growth was found to be associated with grade 2 or grade 3 tumors (Jung et al., 2015). |
| Imaging-related characteristics | Lower SUVmax on 68Gallium-dotatate PET associated with decreased PFS in pNET (Lastoria et al., 2016). FDG-avidity of pNET associated with more aggressive disease (Ki-67 ≥ 5%) (Kornaczewski Jackson et al., 2017). |
Imaging factors associated with worse DFS/OS include: tumoral hypo-enhancement/vascularity, presence of main pancreatic duct involvement, presence of irregular tumor margins (Lee et al., 2019). Higher uptake on 18F-FDG PET correlates with poorer OS and with advancing classification/grade (Rinzivillo et al., 2018). |
Abbreviations: ALT alternative lengthening of telomeres DFS disease-free survival DSS disease-specific survival FDG fluorodeoxyglucose LM Liver metastases NF non-functioning OS overall survival PD-1 programmed cell death protein 1 PET positron emission tomography PFS progression-free survival pNET pancreatic neuroendocrine tumors SUV standardized uptake value TAM tumor-associated macrophages WHO World Health Organization