Table 1.
Characteristics of the included studies on IHC biomarkers for pancreatic cancer diagnosis.
| IHC biomarker | Sample size | Assay(s) used | Staining pattern(s) | IHC score/threshold for positivity | Sensitivity (%) | Specificity (%) | Other IHC expression indicators | Authors and publication year |
|---|---|---|---|---|---|---|---|---|
| Pentraxin 3 (pentraxin family member with inflammatory properties) | 140 PDAC, 86 benign pancreatic conditions, 19 gallstone disease, and 22 normal healthy | Immunohistochemistry, ELISA, and Western blotting | Cytoplasmic | Not mentioned | 86 | 86 | PPV = 97% | Goulart et al., 2021 (16) |
| Galectin-9 (β-galactoside-binding lectin family member with immunomodulatory attributes) | 70 PDAC, 36 benign pancreatic disease, and 28 healthy | Immunofluorescence and immunohistochemistry, and ELISA | Not mentioned | c-statistic of 0.776 | Seifert et al., 2020 (17) | |||
| Enolase 1 (ENO1) (pyruvate synthesis-related metabolic enzyme) | 73 pancreatic cancer patients without jaundice and 50 healthy | Immunohistochemistry | Cytoplasmic and nuclear | IHC score = 12.34 ± 2.79 (PDAC) vs. 7.26 ± 3.31 (normal) | 75.8 | 88.2 | Yin et al., 2018 (18) | |
| REG4 (regenerating islet-derived family member) | 154 PDAC, 34 CP, and 74 healthy | Immunohistochemistry and ELISA | 28.1% of the tumor cases: positive (positive when staining was visible) |
82 | 79 | Saukkonen et al., 2018 (19) | ||
| Periostin (POSTN) (matricellular protein) | 213 PDAC, 49 CP, 26 other benign pancreatic diseases, and 74 healthy | Immunohistochemical staining and ELISA | Combining intensity and percentage of positivity (1 = weak, 2 = moderate, 3 = strong) | 85.7 (PDAC CA19.9‐negative) | 71.6 | Dong et al., 2018 (20) | ||
| CA242 (sialic acid-containing carbohydrate antigen bound to core lipids/proteins found in serum or on the cell surface) | Same as above | Electrochemiluminescence immunoassays | 69.6 (PDAC CA19.9‐negative) | 68.9 | Dong et al., 2018 (20) | |||
| Galectin-1 (β-galactoside-binding lectin family member with immunomodulatory attributes) | Cohort 1: 31 PDAC, 23 CP, 7 normal; Cohort 2: 28 PDAC, 27 CP, 14 normal Cohort 3: 31 PDAC, 2 CP, 7 normal |
Immunohistochemistry and ELISA | Multiplying H-scores and stroma percentage | 82.8 | 100 | Martinez-Bosch et al., 2018 (21) | ||
| Maspin (B serine protease inhibitor family member) |
33 PDAC and 34 control cases (3 mucinous cystic neoplasm, 8 CP, and 23 nontumoral pancreatic tissues) | Immunohistochemistry | Mainly 2+ and 3+ (Staining intensity = negative (< 5% of tumor cells stained), 1+ (5%–25%), 2+ (26%–50%), 3+ (51%–75%), and 4+ (> 75%)) |
87.5 | 100 | Aksoy-Altinboga et al., 2018 (22) | ||
| on Hippel-Lindau gene product (pVHL) (hypoxia‐inducible factor family member) | Same as above | Immunohistochemistry | 100 | 81.8 | Aksoy-Altinboga et al., 2018 (22) | |||
| CA125 (sialic acid-containing carbohydrate antigen bound to core lipids/proteins found in serum or on the cell surface) | 97 PDAC and 115 benign pancreatic tissue cases | Immunohistochemistry | Basolateral membrane and cytoplasmic staining | IHC ≥ 4 (43.3%), IHC < 4 (24.7%), IHC = 0 (32.0%) (IHC score = intensity × percent) |
68 | 96.5 | Jiang et al., 2017 (23) | |
| MUC5AC (membrane-bound mucin glycoprotein) | the University of Pittsburgh Medical Center (n =321) and the Mayo Clinic (n =94) | Immunohistochemistry and ELISA | Average H-score = 1.3 ± 0.15 [H-score = percentage of cells positive × staining intensity (0–3)] |
83 | 80 | PPV = 84% | Kaur et al., 2017 (24) | |
| Thrombospondin-2 (THBS2) (member of the matricellular Ca2+-binding glycoproteins family) | 197 PDAC, 140 healthy, 115 patients with intraductal papillary mucinous neoplasm without PDAC | Immunohistochemistry, ELISA, and Western blot analysis | Membranous and nuclear | Cutoff of 2.47 for the original and cross-validation THBS2 assays | 87 | 98 | Kim et al., 2017 (25) | |
| LTBP2 (Latent transforming growth factor b binding protein 2) | 141 PDAC, 20 with benign diseases of the pancreas, and 20 normal | Immunohistochemistry and ELISA | Staining density: 0 = no staining, < 1% of cells; 1 = weak, 1-30%; 2 = moderate, 30%-70%; 3 = strong, > 70% | Significant elevation of LTBP2 levels in the PDAC tissues versus the adjacent nontumor tissues (p < 0.05) | Wang et al., 2017 (26) | |||
| CPA4 (metallocarboxypeptidase family member) | 150 PDAC, 50 healthy | Immunohistochemistry and ELISA | Epithelial cells staining | 86.7% of cases showed positive staining (Staining intensity: 0 = no staining; 1 = faint, < 20% of cells; 2 = moderate, 20%-40%; 3 = strong, > 40%. Negative expression: 0 or 1; positive expression: 2 or 3) |
61 | 90 | Sun et al., 2016 (27) | |
| Insulin-like growth factor II mRNA binding protein 3 (IMP3) (RNA-binding protein needed for the processing of ribosomal RNA) |
40 PDAC, 20 chronic pancreatitis, and 10 normal | Immunohistochemistry staining | Membranous or cytoplasmic | Moderate to strong immunostaining (score 2+ and score 3+) was observed in 75% of the PDAC cases Staining intensity: 1 = weak; 2 = moderate; 3 = strong |
85 | 90 | PPV = 94.4% | Ibrahim and Abouhashem 2016 (28) |
| Aminopeptidase N (CD13) (transmembrane metalloproteinase for epithelial polarity orientation) | 204 pancreatic cancer, 48 benign pancreatic tumors, 43 CP, and 87 healthy | Immunohistochemistry staining | The total immunoreactive score (IRS) = the staining intensity × distribution (score 0-3 = negative expression, score 4-12 = positive expression) | 84.3 | 88.2 | Pang et al., 2016 (29) | ||
| Dickkopf-1 (Dkk1) (secreted Wnt pathway inhibitor) | 140 PDAC, 92 control patients without PDAC | Immunohistochemistry and ELISA | Staining intensity: 0 = no staining; 1 = weak positive (< 20% of tumor cells); 2 = moderate positive (20-50%); 3 = strong positive (> 50%) | 89.3 | 79.4 | Han et al., 2015 (30) | ||
| KOC (homology domain–containing protein) | Tissue microarrays containing tumor and normal cores in 3:2 ratio, from 99 surgically resected pancreatico-biliary adenocarcinomas patients |
Immunohistochemistry | Cytoplasmic | Cut-offs for positivity: 5%, 10% or 20% positive cells; IHC score: 20; moderate-strong staining intensity | 84 | 100 | Ali et al., 2014 (31) | |
| S100P (member of the matricellular Ca2+-binding glycoproteins family) | Same as above | Immunohistochemistry | Cytoplasmic and nuclear | 83 | 100 | Ali et al., 2014 (31) | ||
| Mesothelin (glycoprotein detected on the cell surface) | Same as above | Immunohistochemistry | Cytoplasmic and membranous | 88 | 92 | Ali et al., 2014 (31) | ||
| MUC1 (membrane-bound mucin glycoprotein) | Same as above | Immunohistochemistry | Cytoplasmic and membranous | 89 | 63 | Ali et al., 2014 (31) | ||
| PAM4 (murine monoclonal antibody) | 298 PDAC, 120 CP, 79 healthy | Immunoassay | Positive cutoff value of 2.4 units/mL (calculated by ROC curve statistics) Tissue labelling: 0 = negative, <1% of the labelled tissue; 1 = weak, focal labeling of 1-25%; 2 = strong, focal labeling of 1-25%; 3 = weak, diffuse labeling > 25%; 4 = strong, diffuse labeling > 25% |
76 | 85 | Gold et al., 2013 (32) |
ELISA, enzyme-linked immunosorbent assays; CP, chronic pancreatitis; PPV, positive predictive value.