Table 2:
Characteristics and Outcomes of Included Studies
| Author, yr, country | Study design and follow-up | Study population | Prognostic factors analyzed | Outcome measurement | Results: prognostic value |
|---|---|---|---|---|---|
| (Bartsch et al., 2005) Germany | Retrospective single center f/u 3.6 y (0.4–11.6) |
n=26 MEN1 + pancreatic surgery n=9 NF-pNET |
Tumor size | Metastatic potential | NF-pNET: No correlation between size and metastatic potential (P>0.5) |
| (Cejas et al., 2019) USA, The Netherlands | Retrospective multi center f/u median 2 y |
n=61 MEN1 + pancreatic surgery n=47 NF-pNET |
(1) ARX and PDX1 (2) ALT status |
Distant metastases | Liver relapses (n=9) only in ARX+ or ARX-/PDX1- cases HR for distant recurrence in MEN1 NF-pNET 7.1 for ARX+ (P=0.03) compared to PDX1+ cases For all cases (sporadic/MEN1) only ALT and ARX+/double negative were independently associated with occurrence of distant relapse |
| (Conemans et al., 2018b) The Netherlands | Retrospective multi center f/u median 5.8 y |
n=61 MEN1 + pancreatic surgery n=46 NF-pNET |
IHC expression of p27kip1 and p18ink4c | LM | No significant association between p27kip1 and p18ink4c IHC and clinical and pathological characteristics |
| (Conemans et al., 2018a) The Netherlands | Retrospective multi center f/u median 5.8 y |
n=61 MEN1 + pancreatic surgery n=47 NF-pNET |
CMI | LM | Higher CMI in NF-pNETs with LM (P=0.013) |
| (Conemans et al., 2017a) The Netherlands | Retrospective multi center f/u mean 6.6 y |
n=69 MEN1 + pancreatic surgery n=53 NF-pNET |
(1) Tumor size (2) Mitotic index (3) KI-67 (4) WHO grade |
LM | Tumor grade based on KI-67 or combination of KI-67 and mitotic index, not significantly associated with LM Based on mitotic index grade significantly associated with LM: KM survival data 5 y (P=0.000): ≤ 2 cm: 100% free of LM >2 cm Grade 1: 90% free of LM >2 cm Grade 2: 40% free of LM |
| (Davi et al., 2011) Italy | Prospective single center cohort, retrospective analysis f/u N/A1 |
n=31 MEN1 + dpNET n=16 NF-pNET n=8 ww n=8 surgery |
Tumor Size | Metastases | For patients with NF-pNET who underwent surgery: No correlation between tumor size and metastases (P=0.21). NF-pNET <2cm: 0% metastases For patients conservatively treated: n=8 stable, no metastases after median 2 y (1–10) |
| (D’Souza S et al., 2014) USA | Retrospective single center f/u mean 6.6 y |
n=11 MEN1 NF-PNET | Existing or new lesions | Tumor growth | Growth rate differs significantly between existing and new lesions (P=0.01) |
| (Nell et al., 2018) The Netherlands | Retrospective multi center median f/u ww: 7.2 y surgery: 4.5 y |
n=152 MEN1 NF-pNET n=99 ww n=53 surgery |
Surgery versus ww | Metastasis-free survival | Propensity Score-adjusted HR (ww=1): Surgery 0.73 (95% CI 0.25–2.11) Surgery <2 cm: 2.04 (95% CI 0.31–13.59) Surgery 2–3 cm: 1.38 (95% CI 0.09–20.31) Surgery >3 cm N/A >3 cm: 5/6 (83%) managed with ww developed LM vs. 6/16 (38%) who underwent surgery |
| (Partelli et al., 2016) Italy, Germany, UK | Retrospective multi center median f/u: ww: 9.1 y Surgery: 10.6 y |
n=60 MEN1 NF-pNET <2 cm n=33 ww n=27 surgery |
Surgery versus ww Decision at initial diagnosis |
Distant metastases PFS |
PFS not different between ww and surgery (P=0.2) Development of new metastases (P=1), pNET-related death (P=0.9), and tumor enlargement during f/u (P=0.2) not different between ww and surgery |
| (Pieterman et al., 2017) The Netherlands | Retrospective longitudinal multi center f/u median 5y |
n=99 MEN1 + NF-pNET <2cm (n=115 tumors) | Genotype Age Hypergastrinemia Existing/new tumor Baseline size Gender |
Growth rate (mm/y) | Overall (n=115) no association prognostic factors and growth rate No difference in age, gender, genotype, hypergastrinemia, new tumors and baseline size between progressive and stable tumors Stratified analysis of progressive tumors: tumors with germline missense mutations faster growth (P=0.09). Other factors not significant. |
| (Sakurai et al., 2007) Japan | Retrospective single center f/u mean 6.5y |
n=14 MEN1 and NF-pNET | Tumor size | Metastases | n=5/6 (83%) >35 mm newly developed tumors or metastases n=1/8 (13%) <35 mm newly developed tumors |
| (Triponez et al., 2006a) France and Belgium | Retrospective multi center f/u mean 4.3 y |
n=108 MEN1 NF-pNET | Tumor size Surgery |
OS Metastases |
Larger tumor size associated with metastases (p<0.01) 0–30 mm better survival compared to >30 mm (p<0.01) no difference between <10 mm and 10–30 mm (P=0.31) Survival worse in non-curative surgery (p<0.01) Survival not different between curative surgery vs ww (P=0.15) |
| (Triponez et al., 2006b) France and Belgium | Retrospective multi center mean f/u: ww: 3.3y mean 6.7 y |
n=65 MEN1 NF-pNET ≤ 2 cm n=50 ww n=15 surgery |
Surgery vs. ww | OS DFS |
No significant difference in progression and death between surgery and ww Overall life expectancy in patients with NF-pNET <2 cm not different than n=229 MEN1 patients without any dpNET (P=0.33) |
1
Not separately reported for NF-pNET
More detailed information on study characteristics and outcomes can be found in Supplemental Tables 1 and 2.
Abbreviations: ALT alternative lengthening of telomeres CMI cumulative methylation index DFS disease-free survival dpNET duodenopancreatic neuroendocrine tumor, f/u follow-up HR hazard ratio IHC immunohistochemistry LM liver metastases MEN1 multiple endocrine neoplasia type 1 n number N/A not available NF-pNET non-functional pancreatic neuroendocrine tumor OS overall survival PFS progression-free survival pNET pancreatic neuroendocrine tumor UK United Kingdom USA United States of America WHO world health organization ww watchful waiting y year