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Although it provides better imaging capability than CT and MRI scans, EUS alone is insufficient for
[32]
differentiating between benign and malignant IPMNs . The advantage of EUS is that it can be combined
with other techniques to improve diagnostic accuracy, for example, EUS fine-needle aspiration (EUS-FNA)
or other newly developed tools like through-the-needle micro-forceps biopsy (TTNB), or confocal laser
endomicroscopy (CLE).

EUS-FNA and cystic fluid analysis
EUS-FNA improves diagnostic accuracy by obtaining fluid samples for cytological, chemical, and molecular
[33]
assessments . EUS-FNA can differentiate mucinous from non-mucinous lesions and help to identify high-
risk features .
[34]

Cytology
The identification of malignancy during cytological assessment using EUS-FNA was reported to have a
[32]
sensitivity of 25%-88% and a specificity of 83%-99% . The occurrence of macrophages, histiocytes, and
neutrophils in a cytological assessment suggests a pseudocyst, while the presence of mucin indicates an
[32]
MCN. Although not commonly seen, glycogen-rich cuboidal cells are diagnostic of SCA . The reported
sensitivity in the literature in identifying MCNs was 54%-63% and the specificity was 88%-93% [35,36] .

Tumour markers
Various tumour markers have been used to differentiate between mucinous and non-mucinous PCLs and
between malignant and benign PCLs. Carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9,
CA 72-4, and CA72-4 have been reported to present in higher levels in mucinous cysts and can aid in
discriminating between mucinous and non-mucinous PCLs. With a CA 72-4 cut-off level of 3.32 ng/mL, the
sensitivity, specificity, and accuracy in differentiating mucinous cysts were 80%, 69.5%, and 73.6%,
respectively . Another study used a cut-off of 7 U/mL with a sensitivity of 80%, a specificity of 61%, and an
[37]
[38]
accuracy of 72% . A meta-analysis using a CA 19-9 cut-off of 35-45 U/mL in detecting mucinous PCLs
produced a sensitivity of 47% and specificity of 88% . Due to CA 19-9 being a constituent of normal
[39]
pancreatic digestive juices, its concentration might be similar in pseudocysts and mucinous lesions. This
limits the diagnostic potential of CA 19-9, particularly when the study population includes patients with
pseudocysts. However, a high level of CA 19-9 should always warrant the suspicion of malignant or
potentially malignant pancreatic cystic lesions.

A CEA cut-off of 192 ng/mL is used in clinical practice to diagnose mucinous pancreatic cysts . A recent
[40]
meta-analysis found that a cut-off of 192 ng/mL was highly specific (88.6%) for differentiating mucinous
from non-mucinous cysts and had a sensitivity of 60.4% .
[41]

Biochemical markers
Intra-cystic glucose measurement has yielded promising results in differentiating mucinous from non-
mucinous cysts. In a multicentre study, a glucose concentration of ≤ 25 mg/dL had a sensitivity of 88.1% and
a specificity of 91.2% in detecting mucinous pancreatic cysts .
[42]

Although amylase has been studied more widely than lipase, it has been noted that both have no useful
[33]
diagnostic potential for identifying cysts with a malignant tendency . If a pseudocyst has been excluded, a
high level of amylase may indicate an IPMN because it suggests a communication between the cyst and the
pancreatic duct.