**6. Evaluation for malignancy**

Several tests can be performed when confronted with a possible IPMN. Regarding this subject, some changes have occurred recently, most of them centering on the use of EUS-FNA (endoscopicultrasonography/fine-needle aspiration) andendoscopic retrograde cholangiopancreatography(ERCP)andanalysesoftheobtainedfluid(**Figure 3**).

#### **6.1. Cross-sectional imaging**

Magnetic resonance cholangiopancreatography (MRCP) and computerized axial tomography scan(CATscan)areusefulasthefirststep,andperhapstheonlyone,ifresultsareveryclear (see management) (**Figure 4**). It is useful to describe:


**Figure 3.** General sequence when diagnosing IPMNs.

**Figure 4.** MRCP images of MD-IPMN (left) and BD-IPMN (right).

#### **6.2. EUS-FNA**

(endoscopicultrasonography/fine-needle aspiration) andendoscopic retrograde cholangio-

Magnetic resonance cholangiopancreatography (MRCP) and computerized axial tomography scan(CATscan)areusefulasthefirststep,andperhapstheonlyone,ifresultsareveryclear

• Anatomical characteristics: lymph node involvement and main pancreatic duct

• Mural nodules: IPMN with >3 mm nodules is highly suggestive of malignancy.

pancreatography(ERCP)andanalysesoftheobtainedfluid(**Figure 3**).

(see management) (**Figure 4**). It is useful to describe:

**Figure 3.** General sequence when diagnosing IPMNs.

**Figure 4.** MRCP images of MD-IPMN (left) and BD-IPMN (right).

**6.1. Cross-sectional imaging**

76 Challenges in Pancreatic Pathology

involvement.

This technique has been evolving, and more hospitals are incorporating it into their routine diagnostic tests, helping to introduce its more general application and obtaining information by:


On the 2012 international consensus guidelines [28], certain recommendations were made as to when to use EUS-FNA:


Nonetheless, the more recent American Gastroenterological Association (AGA) guideline on the management of pancreatic cysts [29] issues a conditional recommendation: "pancreatic cysts with at least two high-risk features, such as size ≥3 cm, a dilated main pancreatic duct, or the presence of an associated solid component, should be examined with endoscopic ultrasonography with fine-needle aspiration (EUS-FNA)" (**Figure 5**).

Macroscopically, highly viscous fluid is the first clue that the cyst is mucinous cyst. Furthermore, high concentration of CEA reflects the presence of a mucinous epithelium, and it is elevated in both IPMNs and MCNs. Thus, it is quite beneficial to distinguish mucinous cysts from non-mucinous. A cut-off CEA level of 192 ng/mL has the sensitivity of 73%, specificity of 84%. Due to connectivity to the pancreatic ductal system, amylase level may be elevated in IPMNs.

In conclusion, the most recent papers encourage the use of EUS-FNA in the initial diagnostic tests [15, 30] to identify smaller cysts with high grade or invasive pathology [30] and to detect mural nodules otherwise missed on cross-sectional imaging or malignant cytology in lesions >3 cm. The high specificity and accuracy of EUS strongly position it as the optimum tool for diagnosing malignant BD-IPMNs, particularly in patients without worrisome features and with smaller cysts [31]. It is particularly important to consider that inherent risks can be derived from this test, including complications associated with these endoscopic procedures such as difficulty in cytological interpretation of samples and relatively low sensitivity [31].

#### *6.2.1. Biomarkers*

DNA analysis of pancreatic cyst fluid demonstrated that KRAS mutation is highly specific (96%) for mucinous cysts, but the sensitivity is only 45%. KRAS is an early oncogenic mutation in the adenoma-carcinoma sequence but cannot discriminate a benign from malignant mucinous cyst. A recent study [32] demonstrated that the "GNAS mutation

**Figure 5.** Use of EUS-FNA according to 2012 International Consensus Guidelines [28] and AGA Guidelines [29].

detected in cyst fluid can separate IPMN from MCN, but similar to KRAS mutations, it does not predict malignancy. The absence of a GNAS mutation also does not correlate with a diagnosis of MCN because not all IPMNs will demonstrate a GNAS mutation [33–35]. A GNAS mutation was present in 66% of IPMNs." But a recent mutations study in GNAS at codon 201 has been identified in duodenal fluid samples even before the IPMN lesion, which was identified on radiologic imaging [36]. Moreover, one study reports that 33% of incipient IPMNs analyzed have a GNAS mutation, suggesting that a large proportion of incipient IPMNs are part of the IPMN pathway, and these mutations occur early in this process [6, 37].

A recent study identified glucose and kynurenine to be differentially expressed between non-mucinous and mucinous pancreatic cysts [38]. Metabolic abundances for both were significantly lower in mucinous cysts compared with non-mucinous cysts. The clinical utility of these biomarkers will be addressed in future studies although it is clear that it will be of great utility when differentiating benign vs. malignant cysts.

#### **6.3. Other procedures**

#### *6.3.1. ERCP*

For sampling of fluid brushes in the 2012 International Consensus Guidelines for the management of IPMN, routine use of this test was not recommended and was left only for scientific purposes [28]. However, as professionals are becoming more familiarized with it and results are increasingly being more accurate, newer studies are encouraging cytology of the pancreatic juice and it is starting to be considered a reliable predictor of malignancy in IPMN [39]. Cytological examination alone is often non-diagnostic due to the low cellularity of the aspirated fluid. A positive or negative diagnosis can be obtained through a cytology analyses with a 100% specificity. Moreover, if a high-grade epithelial atypia is found in the cyst fluid, it is correlated with an 80% chance of malignancy [40].

#### *6.3.2. PET scan*

Positron emission tomography has been proposed as a useful technique for diagnosing and staging different malignancies. Several studies have investigated the outcomes in IPMN cases, concluding that dual-phase F-18 fluorodeoxyglucose positron emission tomography with computed tomography (FDG-PET/CT) has an overall specificity of 92–95% and a sensitivity of 88–94% when trying to differentiate malignant IPMNs vs. benign lesions. It has been proposed that PET scans should be performed in older patients, cases at increased surgical risk, or when the feasibility of parenchyma-sparing surgery demands a reliable preoperative exclusion of malignancy [41, 42].
