Table 2.
Overview of reviewed studies regarding the use of cyst fluid for risk stratification of branch duct IPMNs.
| Author | Molecular Marker(s) | Key Findings | Diagnostic Parameters | Conclusions |
|---|---|---|---|---|
| Singhi (2018) [16] | TP53, PIK3CA, PTEN, KRAS, GNAS | Combination of KRAS/GNAS and TP53/PTEN/CDKN2A indicates advanced neoplasia | Analysis of KRAS/GNAS and TP53/PTEN/CDKN2A was 100% specific and 89% sensitive for advanced neoplasia | The integration of molecular testing in pre-operative patients can be useful in predicting future risk of malignancy |
| Hata (2018) [17] | Telomere fusions | Branch duct IPMN cyst fluid aspirates revealed no telomere fusions in low grade lesions, however prevalence increased with advancing histologic grade | Prevalence of telomere fusions: Low grade 0% Intermediate 15.4% High 26.9% Cancer 42.9% p = 0.025 |
Telomere fusions can be readily detected in cyst fluid and are helpful in predicting the grade of dysplasia |
| Shirakami (2021) [18] | miR-711, miR-3679-5p, miR-6126, miR-6780b-5p, miR-6798-5p, and miR-6879-5p | Six miRNAs were significantly elevated in the cyst fluid of branch duct IPMN with carcinoma when compared to benign branch duct IPMNs | Differences in miRNA levels between low-grade and high-grade lesions were all statistically significant (p < 0.05) | Certain miRNAs are elevated in the cyst fluid of cancerous lesions thus offering the potential to predict high risk lesions requiring surgical resection |
| Hata (2017) [19] | SOX17, PTCHD2, BNIP3, FOXE1, SLIT2, EYA4, and SFRP1 | Gene methylation patterns can accurately distinguish between advanced neoplasia and low-grade lesions (all but BNIP3) | Single marker: SOX17 sensitivity 83%, specificity 82% Two gene: SOX17/FOXE1 or EYA4 accuracy 86% Four gene: FOXE1/SLIT2/EYA4/SFRP1 accuracy 88%, 84% sensitivity, and 89% specificity |
Cyst fluid analysis of gene methylation patterns, whether single gene or in combination, can accurately distinguish between advanced neoplasia and low-grade lesions |
| Majumder (2019) [20] | TBX15 and BMP3 | Two gene methylation analysis can discriminate between advanced neoplasia and low-grade lesions | Combination of methylated TBX15 and BMP3 had sensitivity 90% and specificity of 92% for detecting advanced neoplasia | Methylation analysis of this two gene combination can be useful in predicting grade of dysplasia |
| Singhi (2016) [26] | TP53, PIK3CA, PTEN | Molecular analysis of cyst fluid was able to detect advanced neoplasia via mutations in TP53, PIK3CA, and/or PTEN | Detected branch duct IPMN harboring advanced neoplasia with 91% sensitivity and 97% specificity | Integration of molecular analysis in PCLs can better detect cysts with advanced neoplasia than AGA guidelines |
| Khalid (2009) [29] | KRAS, allelic loss, DNA quantity | 10/40 malignant cysts had negative cytology, all of which could be diagnosed as malignant with high amplitude KRAS mutation in conjunction with high amplitude allelic loss | High amplitude KRAS mutation followed by allelic loss: 96% specific and 37% sensitive for malignancy in the cyst | Increased cyst fluid DNA quantity, high-amplitude mutations, and allelic loss can be used to predict malignancy, especially when cytology is negative |
| Springer (2015) [30] | SMAD4, LOH in RNF43 and TP53, Chromosomal aneuploidy | Analysis for SMAD4, TP53, LOH in chromosome 17, or aneuploidy of 5p, 8p, 13q, or 18q could correctly identify high-grade dysplasia or invasive cancer. This could reduce unnecessary operations by 91% | The panel could identify patients requiring surgery with 75% sensitivity and 92% specificity | Molecular analysis of cyst fluid can be used to risk-stratify cysts with malignant potential and can reduce the amount of unnecessary operations |
| Rosenbaum (2017) [32] | TP53, SMAD4, CDKN2A, NOTCH1 | NGS revealed mutations in TP53, SMAD4, CDKN2A, and NOTCH1 to only be present within malignant cysts. | These mutations had 100% specificity and 46% sensitivity for carcinoma | Variants in TP53, SMAD4, CDKN2A, and NOTCH1 favor the diagnosis of high-risk cyst and warrant surgery or further investigation |
| Fujikura (2021) [33] | KLF4 | KLF4 mutations detected in cyst fluid samples were significantly more prevalent in cysts with low grade dysplasia | KLF4 prevalence: Low grade 50% Intermediate 39% High 15% |
High and low grade IPMNs have distinct molecular pathways with KLF4 mutations being enriched in the low grade pathway |
| Simpson (2018) [35] | DNA quantity, LOH in tumor suppressor | High DNA quantity in conjunction with high clonality LOH in tumor suppressor genes could detect advanced neoplasia | High quantity DNA and LOH had specificity of 99%, PPV 60%, and diagnostic accuracy of 91% for advanced lesions | Increased DNA quantity along with LOH in tumor suppressors can be predictive of high-risk lesions |