Risk Stratification of Pancreatic Neuroendocrine Neoplasms Based on Clinical, Pathological, and Molecular Characteristics
Abstract
:1. Introduction
2. Main Body
2.1. Classification of pNEN
2.2. Prediction of Prognosis: Risk Stratification in pNEN
2.2.1. Clinicopathological Prognostic Factors
Clinical Prognostic Factors
- 1)
- Tumor-Node-Metastasis (TNM) Stage
- 2)
- Other Clinical Factors
- 3)
- 68Gallium Positron Emission Tomography/Computed Tomography (68Ga-DOTATOC PET/CT)
- 4)
- Serum Biomarkers
Pathological Prognostic Factors
- 1)
- WHO Grading System: Differentiation and Cell Proliferation
- 2)
- Other Pathological Prognostic Factors
Factors | Prognosis | References |
---|---|---|
Clinical Factors | ||
Tumor, lymph node, metastasis (TNM) related factors |
| [7,9,22,23,24,25,26,27,28,29,30,31,32,33] |
Age |
| [24,26,32,40] |
Functionality |
| [22,26,32] |
Surgical resection |
| [25,27,40,41] |
68Ga-DOTATATE PET/CT |
| [42,43,44,45] |
Serum CgA |
| [47,48,49,51] |
Serum NSE |
| [47,53,54] |
Serum pancreastatin |
| [57,58] |
Albumin-to-alkaline phosphatase ratio |
| [59] |
Pancreatic duct dilatation and neutrophil-to-lymphocyte ratio |
| [60] |
Pathological Factors | ||
WHO classification/Ki-67/mitotic rate/grade/differentiation |
| [3,10,21,22,23,25,27,28,29,30,31,32,33,41,69,70,71,72,76] |
Lymph node ratio |
| [72] |
Neuroinvasion or vascular invasion |
| [33] |
Peritumoral or stromal infiltrative patterns |
| [33] |
Tumor-associated macrophage infiltration, high CD68 score |
| [23,28] |
FAS ligand |
| [83] |
Nectin-3 |
| [84] |
Risk Stratification Model with Clinicopathological Factors
2.2.2. Molecular Prognostic Factors
Genetic Prognostic Factors for pNENs
- 1)
- Inherited Syndromes
- 2)
- Sporadic pNENs
- 3)
- MEN1
- 4)
- DAXX/ATRX
- 5)
- Genetic Alteration in AKT/mTOR Pathway
- 6)
- Genetic Alteration in Angiogenesis Pathway
- 7)
- Miscellaneous
Factors | Efficacy/Details | References |
---|---|---|
Germline mutations in inherited syndromes |
| [69,92] |
MEN1 |
| [16,93,94,95] |
DAXX/ATRX |
| [4,16,94,95,96,97,98,99,100,101] |
Akt/mTOR pathway |
| [16,94,102,103,104,105] |
Angiogenesis pathway |
| [94] |
CDKN2A |
| [106] |
SSTR2A |
| [107,108] |
MGMT |
| [109,110,111,112] |
ARID1A |
| [114] |
Epigenetic Prognostic Factors for pNENs
- 1)
- DNA Methylation
- 2)
- DAXX/ATRX
- 3)
- Aristaless-Related Homeobox (ARX) Gene and Pancreatic and Duodenal Homeobox 1 (PDX1)
- 4)
- Ras-Association Domain Family 1 (RASSF1) Gene
- 5)
- CDKN2A
- 6)
- Tissue Inhibitor of Metalloproteinase-3 (TIMP-3)
- 7)
- MGMT
- 8)
- Insulin Growth Factor-2 Gene (IGF2)
- 9)
- Promoter Methylation of MutL Homolog 1 (MLH1)
- 10)
- CIMP
- 11)
- MEN1
- 12)
- Long Interspersed Nucleotide Element 1 (LINE1) and Arthrobacter Luteus (ALU) Homolog
- 13)
- MicroRNA (miRNA)
Factors | Efficacy/Details | References |
---|---|---|
DNA methylation pattern |
| [115,116] |
DAXX/ATRX |
| [16,96,98,101,117] |
Aristaless-related homeobox gene (ARX), pancreatic and duodenal homeobox1 (PDX1) |
| [118,119] |
Ras-association domain gene family 1 (RASSF1) |
| [109,110,120,121,122,123,124,125,126,127,132] |
Cyclin-dependent kinase inhibitor 2a/P16INK4a (CDKN2A) |
| [122,124,125,128] |
Tissue inhibitor of metalloproteinase-3 (TIMP3) |
| [129,130] |
O-6-alkylguanine-DNA alkyltransferase (MGMT) |
| [110,111,115,122,131,132,133,134,135,136] |
Insulin growth factor-2 gene (IGF2) |
| [137,138,139] |
Promoter methylation of MLH1 |
| [122,140,141] |
CpG island methylator phenotype (CIMP) |
| [132] |
MEN1 |
| [143,144,145,146,147] |
Long interspersed nucleotide element 1 (LINE1) and Arthrobacter luteus (ALU) homolog |
| [130,149,150] |
MicroRNA (miRNA) |
| [152,153,154,155,156,157,158] |
2.2.3. Recent Advances in Multifactorial Prediction Models, including Molecular Biomarkers
Classification of pNENs based on Multiomics Sequencing
Classification of the Cell Origin of pNENs: α-Cell-Like or β-Cell-Like Tumors
Multiomics Profile and Histology Classification
Advances in Liquid Biopsy for pNENs
3. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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pNET Grade 1 | pNET Grade 2 | pNET Grade 3 | pNEC Grade 3 | |||||
---|---|---|---|---|---|---|---|---|
Mitoses/10 HPF | Ki-67 Index | Mitoses/10 HPF | Ki-67 Index | Mitoses/10 HPF | Ki-67 Index | Mitoses/10 HPF | Ki-67 Index | |
2010 | <2 | <3% | 2–20 | 3–20% | NA | NA | >20 | >20% |
2017 | <2 | <3% | 2–20 | 3–20% | >20 | >20% | >20 | >20% |
2019 | <2 | <3% | 2–20 | 3–20% | >20 | >20% | >20 | >20% |
AJCC 8th Edition and ENETS Staging for pNENs | |||
---|---|---|---|
Stage | T * | N ** | M |
I | T1 | N0 | M0 |
II(A) # | T2 | N0 | M0 |
II(B) # | T3 | N0 | M0 |
III(A) # | T4 | N0 | M0 |
III(B) # | Any T | N1 | M0 |
IV | Any T | Any N | M1 |
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Choi, J.H.; Paik, W.H. Risk Stratification of Pancreatic Neuroendocrine Neoplasms Based on Clinical, Pathological, and Molecular Characteristics. J. Clin. Med. 2022, 11, 7456. https://doi.org/10.3390/jcm11247456
Choi JH, Paik WH. Risk Stratification of Pancreatic Neuroendocrine Neoplasms Based on Clinical, Pathological, and Molecular Characteristics. Journal of Clinical Medicine. 2022; 11(24):7456. https://doi.org/10.3390/jcm11247456
Chicago/Turabian StyleChoi, Jin Ho, and Woo Hyun Paik. 2022. "Risk Stratification of Pancreatic Neuroendocrine Neoplasms Based on Clinical, Pathological, and Molecular Characteristics" Journal of Clinical Medicine 11, no. 24: 7456. https://doi.org/10.3390/jcm11247456