Table 1

Summary of the main features of all studies analysed in this systematic review

StudyCountryTumour type analysed in the cohortNumber of tumours analysed for MSINumber of MSI/dMMR (%)Pancreatic site of MSI/dMMR tumoursHistology of MSI/dMMR tumoursMolecular data of MSI/dMMR tumoursMethodology for MSI analysis
IHC PCR NGS
Lynch syndromeSurvival data of MSI/dMMR tumours
Han et al 11 Japan, KoreaPC96 (66.6%)NANANAPCR1 NANA
Seymour et al 12 USAPDAC70 (0%)NANANAPCR2 NANA
Brentnall et al 13 USAPC138 (62%)NANANAPCR3 NANA
Abe et al 14 JapanPC447 (15.9%)NANANAPCR4 NANA
Venkatasubbarao et al 15 USAPDAC144 (28.6%)NAPDAC G3NAPCR5 NANA
Ouyang et al 16 JapanPC609 (15%)NANANAPCR2 NANA
Goggins et al 17 USAPDAC823 (3.7%)3 head (100%)MED KRAS wtPCR6 NA2/3 AWD at 16 and 52 months, 1/3 DOD after 4 months
Ghimenti et al18 ItalyPC210 (0%)NANANAPCR7 NANA
Caligo et al 19 ItalyPC3113 (42%)NANANAPCR2 NANA
Wilentz et al 20 MED184 (22.2%)NAMED; 1/4 showed also microglandular features. No associated PanIN KRAS wtIHCa, PCR8 13/4 AWD at 13, 24 and 67 months, 1/4 DOD after 4 months
Ueki et al 21 USAPDAC364 (11.1%)*NAMED2/4 harboured promoter hypermethylation of hMLH1 PCR2 NANA
Yamamoto et al 22 JapanPDAC10316 (15.5%)NA10/13 PDAC G3, 2 G2, 1 G110/13 KRAS wt; 11/13 TP53 wtPCR9 3MSI associated with better survival
Moriyama et al 23 JapanPDAC182 (11.1%)NANANAPCR10 NANA
Nakata et al 24 JapanPC468 (17.4%)NA5/8 G1, 3 G2-G3-G4NAPCR11 NAMSI associated with better survival
Tomaszewska et al 25 PolandPDAC300 (0%)NANANAIHCb NANA
Lüttges et al 26 Germany11 M/C-C and 12 PDAC231 (4.3%)1 head (100%)M/C-C, pT4 (8 cm) N1NAIHCc, PCR9a NANA
Nakata et al 27 JapanPC554 (7.2%)2 head (50%), 1 body (25%), 1 tail (25%)2 head: G1; 1 body: G4; 1 tail: G3NAIHCb NALoss of MSH2 associated with initial better survival
Maple et al 28 USALS-PC353 (8.6%)NA1 MED†, 2 PDACGermline MLH1 mutation in 1 patientIHCc, PCR12 1NA
Fujii et al 29 JapanPDAC210 (0%)NANANAPCR13 NANA
Laghi et al 30 272 cases Italy, 66 GermanyPDAC3381 (0.3%)HeadG3, pT4N2 KRAS cod12 mutation, BRAF wtIHCd, PCR9b NoNA (died of postsurgical complication)
Ottenhof et al 31 The NetherlandsPDAC783 (3.9%)‡NANANAIHCd NANA
Mitsuhashi et al 32 JapanPDAC2830 (0%)NANANAPCR14 NANA
Riazy et al 33 CanadaPDAC26541 (15.4%)NANANAIHCd NAdMMR did not correlate with survival§
Grant et al 34CanadaPDAC2904 (1.38%)NANAGermline mutations in 4 patients: 1) MLH1 c.677+3A>G; 2, 3) MSH2 c.942+3A>T, c.1906g>c; 4) MSH6 c.1707delC NGSa 4NA
Connor et al 35 CanadaPDAC2554 (1.6%)NANANAIHCd, PCR9a, NGSb 3NA
Humphris et al 36 Australia (international cohort)PDAC3854 (1%)NA1 case G4, 2 cases G2, 1 signet ringAll high TMB (100%), 2 KRAS wt (50%)IHCd, NGSc NoNA
Salem et al 37 USAPDAC87012 (1.4%)NANANANGSd No
Lupinacci et al 38 FrancePDAC5138 (1.6%)NA3pT1, 3pT2, 3pT3; 1 case medullary, 1 colloid, 6 conventionalNAIHCd, PCR9 3dMMR did not correlate with survival
Wartenberg et al 39 GreecePDAC1105 (4.5%)NAStroma rich in immune cells with a very high stromal CD8/FOXP3 ratioHigh prevalence of JAK3 mutations (3/5 cases vs 4/105 MSS PDAC); all KRAS mutated, 2/5 TP53 wtIHCd NASurvival analysis not specific for MSI status
Hu et al 40 USAPDAC8337 (0.8%)NA2 conventional, 4 mucinous/colloid IPMN-associated, 1 medullary**All available for NGS (5 cases) had high TMBIHCd, PCR9b, NGSe 7dMMR did not correlate with survival
Mori et al 41 JapanPC400 (0%)NANANAPCR15 NANA
Latham et al 42††USAPDAC82434 (4.1%)NANA5 patients with germline mutations: 1) MLH1 c.1731G.A; p.Ser577Ser; 2) MSH2 c.1906G.C; p.Ala636Pro; 3) MSH2 c.2038C.T; p.Arg680*; 4) PMS2: deletion exon 11; 5) MSH6c .3268G.T; p.Glu1090* NGSe 5NA
Kato et al 43 JapanPC100 (0%)NANANANGSe NANA
Singhi et al 44 USAPDAC25633 (0.1%)NANA3 KRAS wt, 1 TP53 wt, 1 case showed the druggable FGFR2-POC1B fusion; 1/3 high TMB; 3 cases harboured KMT2 genes mutations (2 KMT2D and 1 KMT2C) and 2 a JAK1 mutationNGSf NANA
Total 8323 218 (2.61%) 7 head, 1 body, 1 tail 36 conventional PDAC, (3 G4, 16 G3, 5 G2, 8 G1, 4 NOS); 10 MED, 6 MC/C, 1 signet ring Significant association of MSI/dMMR with KRAS and TP53 wt status and with JAK and KMT2 mutations Not significant association with survival
  • Microsatellite instability analysis with PCR: 1 PCR with not recommended panel of markers (nor NCI neither MSI PCR): D2S123, D2SI36 and D3S1067; 2 PCR with not recommended panel of markers (nor NCI neither MSI PCR), not further specified; 3 PCR with not recommended panel of markers (nor NCI neither MSI PCR): D2S123, D2S136, D3S1067, D5S107, D6S87, D8S255, D10SI97, D11S904, D17S261, D17S361, D17S787, D18S34; 4 PCR with not recommended panel of markers (nor NCI neither MSI PCR): D1S199, D2S123, D3S1298, TP53, D22S284; 5 PCR with not recommended panel of markers (nor NCI neither MSI PCR): D2S123, D2S136, D3S1067, D5S107, D6S87, D18S34; 6 PCR with not recommended panel of markers (nor NCI neither MSI PCR): BAT26, D10S579, D1OS541, D9S272, D9S258, D9S1809; 7 PCR with not recommended panel of markers (nor NCI neither MSI PCR): D2S313, D2S123, D5S404, D8S255, D10S197, D11S904, D17S250, THRA1, D17S579, D17S396; 8 PCR with not recommended panel of markers (nor NCI neither MSI PCR): length analysis of BAT25 and BAT26 markers; and direct sequencing of the polythymidine tract of the TGFBR2 gene; 9 PCR with NCI / MSI PCR markers: 9a BAT25, BAT26, D2S123, D5S346, D17S250, or 9b BAT25, BAT26, NR-21, NR-24 and NR-27; 10 PCR with not recommended panel of markers (nor NCI neither MSI PCR): D2S123, D3S1067, D9S171, D9S1870, D18S58, D18S46, D18S474; 11 PCR with not recommended panel of markers (nor NCI neither MSI PCR): D2S123, D3S1611, D5S346, D7S501, NM23, TP53-Penta, TP53-Dint and D18S35; 12 PCR with not recommended panel of markers (nor NCI neither MSI PCR): Bat 26, Bat 25, Bat 40, Bat 34c4, D17s250, D5s346, ACTC, D18s55, D10s197 and mycL; 13 PCR with not recommended panel of markers (nor NCI neither MSI PCR): D2S123, D5S107, D10S197, D11S904, D13S175; 14 PCR with not recommended panel of markers (nor NCI neither MSI PCR): BAT25 and BAT26; 15 PCR with not recommended panel of markers (nor NCI neither MSI PCR): MYCL1, D9S242, D8S321, D20S82, D20S85, BAT-25, BAT-26, NR-21, NR-22, NR-25.

  • Microsatellite instability analysis with IHC: a IHC for MLH1 and MSH2: all MSI cases in this series showed MLH1 loss and MSH2 retained. This study first demonstrated the reliability of IHC in determining MSI in pancreatic cancer; b IHC for MLH1 and MSH2; c IHC for MLH1, MSH2 and MSH6; d IHC for MLH1, PMS2, MSH2 and MSH6.

  • Microsatellite instability analysis with NGS: a NGS using a custom panel targeting the exonic and splice site regions of 385 genes previously associated with cancer; b Whole-genome sequencing variant calls, RNA sequencing and microarray expression values available from the International Cancer Genome Consortium data portal; c NGS with ‘MSI sensor’ methodology; d MSI-NGS assessment with the reference genome hg19 from the University of California, Santa Cruz—‘Genome Browser database’; e MSK-IMPACT panel, ‘MSI sensor’ methodology; f Illumina HiSeq technology, MSI tested using 114 loci.

  • *In this study, 4 out of 36 cases were MSI, but these cases were specifically and deliberately added by authors to expand the spectrum of cases to be studied for hypermethylation; in addition, 3 of the 4 MSI tumours were previously reported by Goggins et al.

  • †First reported case of medullary phenotype associated with MSH2 loss (previously reported cases were all MLH1 negative).

  • ‡Data obtained from another manuscript (Lupinacci et al 48), two cases were MSH2-MSH6 negative, and one case was PMS2-MLH1 negative.

  • §dMMR had no survival advantage from gemcitabine or 5-fluorouracil adjuvant chemotherapy.

  • ¶This study investigated germline mutations.

  • **This case is probably a medullary PDAC (described as a poorly differentiated carcinoma with fused glands and some necrotic areas).

  • ††This study investigated >50 cancer types, with patients with PDAC representing 5.5% of the entire cohort.

  • AWD, alive without disease; dMMR, defective mismatch repair; DOD, died of disease; IHC, immunohistochemistry; LS-PC, long survivors-pancreatic cancer (>36 months after surgery); M/C-C, mucinous/colloid carcinoma of the pancreas; MED, medullary pancreatic cancer;MN, mononucleotide marker; MSI, microsatellite instability; NA, not assessed (or not reported); NGS, next-generation sequencing; PC, pancreatic cancer, not otherwise specified; PCR, polymerase chain reaction; PDAC, pancreatic ductal adenocarcinoma; TMB, tumour mutation burden; wt, wild type.