Endoscopic ultrasound for pancreatic cystic lesions: a narrative review

Abstract

The incidence of incidental pancreatic cystic lesions (PCLs) has risen in recent years, largely due to advances in and increased use of imaging techniques. Endoscopic ultrasound (EUS) has become a crucial tool for evaluating and characterising PCLs, allowing for detailed morphological assessment and aiding in the identification of lesions with a higher risk of progression to high-grade dysplasia or invasive pancreatic carcinoma. This review aims to outline the key aspects of EUS in the evaluation of PCLs, covering a range of modalities from morphological assessment and contrast-enhanced imaging to elastography, fine-needle aspiration for biomarker analysis, cytology, DNA sequencing, histological evaluation and the emerging role of confocal laser endomicroscopy or artificial intelligence. Additionally, we address therapeutic EUS modalities for PCLs, the current limitations of EUS, anticipated technological advancements and the diverse management strategies recommended by leading scientific societies for the clinical handling of PCLs.

Summary box.

• Endoscopic ultrasound (EUS) enhances morphological assessment of pancreatic cystic lesions (PCLs). It allows a detailed evaluation of cyst features, such as locularity, mural nodules, ductal communication and wall thickening, while contrast-enhanced (CE)-EUS and elastography give additional information.

• Cyst fluid biomarkers and genetic analysis improve diagnostic precision. Overall, intracystic glucose <50 mg/dL and carcinoembryonic antigen >192 ng/mL are reliable indicators of mucinous cysts. Moreover, genetic mutations identified through next-generation sequencing (NGS) show promise for detecting high-grade dysplasia (HGD) and guiding surgical decision-making, although their use remains limited by cost and availability.

• Microforceps biopsy and EUS-guided needle-based confocal laser endomicroscopy (nCLE) increase diagnostic yield. Through-the-needle biopsy increases diagnostic accuracy, with strong histologic concordance. EUS-nCLE enables real-time microscopic imaging of cyst walls, aiding in the detection of mucinous features and dysplasia.

• Guideline variability affects management strategies. The 2024 International Association of Pancreatology guidelines introduce updated worrisome features (eg, ≥2.5 mm/year growth and new-onset diabetes) and show improved predictive accuracy for malignancy compared with earlier versions and European guidelines.

• Artificial intelligence (AI) integration is an emerging frontier. The integration of new tools, such as AI or NGS, will improve physicians’ ability to predict which lesions exhibit HGD and, consequently, carry a higher risk of developing intramucosal carcinoma in the near future.

Introduction

The incidence of pancreatic cystic lesions (PCLs) incidentally diagnosed during cross-sectional imaging for unrelated conditions is as high as 49%–71%, while the prevalence in abdominal ultrasound ranges from 3% to 15%.¹ Although the vast amount of PCLs will never degenerate into pancreatic cancer,² there exists an overall risk of progression of around 0.24% per year.³ Different imaging examinations, including CT scans, MRIs and endoscopic ultrasound (EUS), have been performed to identify and characterise PCLs, increasing their capacity over time. Specifically, EUS is a technique that provides comprehensive information, such as morphology, tissue stiffness on elastography and contrast enhancement behaviour. It also allows fluid aspiration of the cystic content for biochemical, cytological and mutational analysis, and/or tissue acquisition (TA) for histological evaluation. Novel techniques, such as cyst fluid next-generation sequencing (NGS) analysis, EUS-guided needle-based confocal laser endomicroscopy (EUS-nCLE) and EUS-guided through-the-needle biopsy, have a very high accuracy (>90%) in the classification of PCLs,^{1 4} although these latter methods are not widely available. In addition, EUS permits to perform therapeutic interventions in specific cases. Many attempts have been made in the evaluation of PCLs to reduce misdiagnosis, identify EUS-related factors associated with malignancy and better select patients who would benefit from surgery. In this narrative review, we focus on the role of EUS in the management of PCLs, gathering new evidence and examining recent advancements as well as potential future developments.

PCL classification

PCLs can be classified based on their appearance, their mucinous versus non-mucinous secretion or according to their malignant potential. Non-neoplastic cysts do not have malignant potential and include pseudocysts, duplication cysts, retention cysts or lymphoepithelial cysts. However, pancreatic neoplastic cysts (PNCs) can potentially progress to malignancy or be malignant at diagnosis. PNCs are further classified as serous cystic neoplasm (SCN), mucinous cystic neoplasm (MCN), intraductal papillary mucinous neoplasm (IPMN), solid-pseudopapillary neoplasm (SPN) and some solid tumours with cystic components, such as the cystic neuroendocrine tumour (cNET). Overall, PNCs combined with pancreatic pseudocysts comprise about 90% of all PCLs.⁵ The malignant or premalignant behaviour of these PNCs varies among cyst types. Thus, identifying them correctly helps to properly manage them. Differentiating PNCs requires a combination of medical history, morphological features and sometimes contrast enhancement behaviour or cystic fluid analysis. The main characteristics of the above-mentioned PNCs to distinguish the different subtypes are shown in table 1.

Table 1. Pancreatic neoplastic cysts characteristics.

	Mucinous cystic lesions			Non-mucinous cystic lesions
	Mucinous cystic neoplasm	BD-IPMN	MD-IPMN or MT-IPMN	Serous cystic neoplasm	Cystic neuroendocrine tumour	Solid pseudopapillary neoplasm
Age	40–50 years	50–70 years	50–70 years	50–60 years	50–70 years	20–30 years
Gender	F (almost exclusively–90%)	F=M	F=M	F (60%)>M	M>F	F (almost exclusively–90%)
History of pancreatitis	Possible	Possible	Possible	Rare	No	No
Symptoms	50% asymptomatic; might associate compressive symptoms	Mostly asymptomatic; possible pancreatitis	Mostly asymptomatic; possible pancreatitis	50% asymptomatic; might associate compressive symptoms	90% asymptomatic/non-functional. Functional symptoms (depend on secreted hormone) 10% are associated with MEN 1	Mostly asymptomatic. Abdominal pain or discomfort (37%)
Most common location	Body–tail	Variable	Variable	Variable	Variable	Body–tail
Malignant potential	10%–36%	15%–25%	35%–75%	Rare (<0.01%) (exceptional cases in literature)	5%–20% (less than solid forms)	10%–15%
EUS and endoscopic morphological features	Single well- defined round shape with visible wall (pseudocapsule) and clear contours ‘orange-like’ or ‘cyst-in-cyst’	Anechoic multiloculated lesion 'cyst-by-cyst’ pattern, similar to a ‘bunch of grapes‘ ‘finger-like’ 'clubber-like’ Only 7% completely round	MD-IPMN: dilation of MPD (segmental or diffuse) MT-IPMN: dilation of MPD and BD-IPMN	Multiloculated lesions with irregular thin capsule. Four subtypes. Microcystic-honeycomb type: cysts of less than 1 cm (the most typical aspect-85%) Macrocystic type: larger than 1 cm Mixed type Solid variant: cysts of 1–2 mm which gives a pseudonodular aspect	Round and well-demarcated hypoechoic solid lesions with an anechoic area of cystic degeneration	Single well- defined encapsulated with regular margins, hypoechoic solid or mixed (solid and cystic in around 70% of cases)
Extra EUS/endoscopic characteristics	Debris or intracyst haemorrhage; hyperenhancement of septa with CE-EUS	Dilation of secondary branches (>5 mm)	Fish-eye of major papilla sign in 30% (pathognomonic)	Hypervascular internal septa with slow wash out	Hypervascular in arterial phase at CE-EUS with rapid washout
Communication with MPD	Infrequent (in around 20% might be found)	Yes	Yes (in MT-IPMN)	No	No	No
Dilation of MPD	No	Possible	Yes	No	No	No
Multifocality	No	Typical (20%–40%)	Might be found in MT	No	No	No
Calcification	Rare, usually cystic wall (eggshell) predictive of malignancy	No	No	30% central scar (pathognomonic)	No	20% (irregular)
Biomarkers or immunohistochemistry	Elevated CEA*, low glucose and KRAS+	Elevated CEA*, low glucose, high amylase, KRAS+ and GNAS+	Elevated CEA*, low glucose, high amylase, KRAS+ and GNAS+	Low CEA*, normal glucose, low amylase and Von Hippel-Lindau+	Low CEA*, cromogranin+ and sinaptophysin+	E-cadherin loss and beta-catenin+

^*Cut-off value for CEA is 192 ng/mL.

BD-IPMN, branch duct-IPMN; CEA, carcinoembryonic antigen; CE-EUS, contrast-enhanced endoscopic ultrasound; F, female; IPMN, intraductal papillary mucinous neoplasm; M, male; MD-IPMN, main duct-IPMN; MEN, Multiple Endocrine Neoplasia; MPD, main pancreatic duct; MT-IPMN, mixed type IPMN.

EUS examination of the morphology of different PNCs

EUS B-mode morphological evaluation alone has a varying accuracy (with an interobserver agreement that ranges from around 50% to 93%) in differentiating PCLs.^{6 7} However, there are specific morphological aspects and some complementary techniques that can help distinguish both categories. A precise location of the cyst, size (although it may be underestimated in larger cysts based on the scope window), locularity (unilocular or multilocular), microcystic or macrocystic component, internal structural features, mural nodules, contour, cystic wall, calcifications, relation with pancreatic duct, pancreatic duct diameter and content of the cyst can be described by EUS.^{5 8} Based on all these morphological characteristics, a diagnostic approach can be made (table 1).

Mucinous lesions

Intraductal papillary mucinous neoplasm

IPMNs are the most common type of mucinous cysts.⁹ They are pancreatic duct epithelial tumours characterised by a tall columnar epithelium with papillary projections producing mucin.⁸ IPMNs can be classified into main duct-IPMNs (MD-IPMNs), branch duct-IPMNs (BD-IPMNs) and mixed type IPMN (MT-IPMN), which combines features of both (figure 1, table 1).¹⁰ Multifocality is one of the characteristics of these cystic lesions,⁹ but this does not mean a higher risk of high-grade dysplasia (HGD)/intramucosal carcinoma (IC) compared with a single cystic lesion, so the surveillance depends on the cyst with a higher risk.¹¹ In these PCLs, it is quite common to see mucus inside the cyst, but differentiating it from a mural nodule can sometimes become very challenging on simple morphology, so the use of a needle for the ‘spearfishing sign’¹² or contrast enhancement with dedicated contrast-harmonic (CH) mode during EUS significantly improves sensitivity and specificity in differentiating mucus (without enhancement after contrast administration) from nodules (with enhancement after contrast administration; 100% and 80%, respectively; figure 2A and B)¹³ and in identifying nodules with dysplasia¹⁴ or invasive carcinoma (97% and 90.4%, respectively).¹⁵ Although it is considered a key aspect to decide a surgical indication for IPMNs, the evaluation of nodule size is still confusing and not standardised, as it is usually measured by ‘height’ in EUS and not ‘width’ or ‘maximal diameter’, which is usually used in CT/MRI (figure 2C). No comparisons among these dimensions have been evaluated so far, but in the last IPMN guidelines,¹⁰ they referenced the study by Shimzu et al,¹⁶ where the size of the nodule was evaluated by EUS (using height) to establish the cut-off nodule size to predict malignancy and surgical indication. The same occurs with thickened/enhanced walls, which are also an ambiguous aspect, with measurement methods and cut-off values to predict HGD or IC not well established. However, a similar OR for HGD/IC to mural nodule of ≥5 mm has been observed when the septal thickness, as measured by EUS, is 2.5 mm or more.¹⁷

Figure 1. EUS view of IPMNs : (A) EUS view of main duct-IPMN (red arrow) from the second duodenum, showing mesenteric vein (purple arrow) through the use of colour Doppler. (B) EUS view of branch duct-IPMN in the body of the pancreas from the been reported in the lit gastric station, including MPD (yellow arrow), communication with MPD (purple arrow) and IPMN (red arrow). (C) ‘Fish-eye’ sign, pathognomonic of main duct-IPMN. EUS, endoscopic ultrasound; IPMN, intraductal papillary mucinous neoplasm; MPD, main pancreatic duct.

Figure 2. (A) EUS in B-mode and after contrast enhancement in IPMN showing a nodule (red arrow) without contrast enhancement (green arrow) compatible with mucin clot. (B) EUS view of a mural nodule (red arrow) with contrast enhancement (green arrow) in an IPMN compatible with a hyperenhancing nodule. (C) CT examination showing an IPMN with a mural nodule (red arrow). EUS, endoscopic ultrasound; IPMN, intraductal papillary mucinous neoplasms.

Mucinous cystic neoplasm

MCNs are also mucin-producing cysts that can be found in middle-aged women and are mainly located in the body or tail of the pancreas.^{18 19} Samples from MCN epithelium show specific and typical histological characteristics, such as the presence of mucin-secreting columnar cells and ovarian-type stroma.²⁰

Non-mucinous lesions

Serous cystic neoplasm

SCNs are cysts with cuboidal or flattened glycogen-rich cells that produce a serous content (periodic acid–Schiff-positive, diastase-sensitive).^{8 21} They are considered benign lesions without malignant potential, and only some exceptional cases of malignant forms of cystadenocarcinoma have been reported in the literature (<0.01%), so conservative management is recommended.²² Generally, SCNs have a typical morphology on EUS that allows their differentiation and confident diagnosis, but when there is diagnostic uncertainty, mainly in solid forms, a combination of B-mode with CE-EUS, elastography (with a soft pattern)²³ and fine needle aspiration (FNA) with cystic fluid analysis could give the final diagnosis. On some occasions, mainly in microcystic forms that may appear as solid lesions, immunohistochemistry is helpful for the differential diagnosis. Neuron-specific enolase, α-inhibin and mucin-related glycoprotein (MUC1 and MUC6) are specific immunoprofiles for SCNs.²⁴

Solid-pseudopapillary neoplasm

SPNs are infrequent PCLs, accounting for 1% of pancreatic neoplasms. SPNs are considered low-grade malignant lesions with low metastatic potential (15%), but surgery is indicated.^{25 26}

Cystic NET

cNETs represent 10%–17% of all resected pancreatic NETs (pNETs).²⁷ They can be larger than solid pNETs, more symptomatic and more frequently associated with MEN-1, despite seeming to be less aggressive than solid forms. CH-EUS shows a typical behaviour, meaning rapid and intense enhancement in the early arterial phase,²⁸ which is different from other solid pancreatic lesions. Recent studies have also evaluated the role of CE-EUS behaviour in predicting aggressiveness and prognosis of pNETs, although it still cannot guide clinical decisions, and further validation is still needed.29,31

EUS and PCL sampling: FNA, through-the-needle biopsy and new advances

Apart from the morphological evaluation, Doppler or contrast enhancement behaviour of PCLs, EUS allows getting fluid from the PCLs with FNA, which allows better characterisation and diagnosis. According to all the latest guidelines,¹⁰ EUS-FNA should only be performed when the results are expected to change clinical management, avoiding unnecessary risks of adverse events (AEs), even if the rate is low (3.4%). When feasible, a complete drainage of the cyst should be performed with a single puncture. Antibiotic prophylaxis is still commonly used, although recent evidence indicates that it may not be necessary.^{32 33}

The obtained fluid can provide much information about the type of PCL through the identification of specific biomarkers. Therefore, mucinous cysts are characterised by cystic fluid carcinoembryonic antigen (CEA) >192 ng/mL (58% (45%–71%) sensitivity, 87% (82%–92%) specificity)^{34 35} or glucose <50 mg/dL (93% (89%–97%) sensitivity, 89% (83%–95%) specificity).35,37 One of the advantages of intracystic glucose measurement, beyond its superior sensitivity and specificity compared with CEA, is its ability to be assessed on-site using a glucometer. This method offers high accuracy, cost-effectiveness, broad availability and immediate results.38,40 Other useful cystic fluid marker is amylase: levels of <250 U/L have high specificity to rule out pseudocysts (although low sensitivity 44%)⁴¹ or CEA <5 ng/mL to identify serous cysts, pseudocysts or cNETs (sensitivity 50% and specificity 95%) (figure 3). In addition, the ‘string sign’, well defined by Bick et al,⁴² can differentiate mucinous from non-mucinous cysts with a 95% specificity and 94% positive predictive value if properly performed. Interobserver agreement was good (k=0.6) among experts, confirming its role in the identification of mucinous cysts, even if no agreement for a specific length as a cut-off for positivity was identified.⁴³ FNA can also be performed targeting a mural nodule or a mass. ‘Mucin balls’ can be easily differentiated from nodules because they are movable during the needle passage and can be grasped with the needle, showing the ‘spearfishing sign’.⁴⁴ Cystic fluid cytology is also recommended by guidelines, but its accuracy is less than 50%.

Figure 3. Values of specific targets in the pancreatic cystic fluid according to the suspected pancreatic cyst. BD, branch duct; CEA, carcinogenic embryonic antigen; IPMN, intraductal papillary mucinous neoplasm; MD, main duct; VHL, Von Hippel-Lindau.

In challenging cases, the use of microbiopsy forceps through a 19-gauge needle (figure 4) can be useful, increasing the diagnostic yield from 29% with FNA and cystic fluid analysis to 70% according to a recent meta-analysis and with excellent concordance with surgical specimens (87%).⁴⁵ However, the use of the forceps slightly increases the AEs rate (8.6%), although they are not frequently severe (mainly intracystic self-limited bleeding (6%) with similar rates of pancreatitis compared with FNA (1.1%)), and their use is limited by the location of the area to sample.⁴³ Therefore, although there is still no clear evidence of the best scenario to use it, it should probably be considered when a cystic fluid sample fails to give a definite diagnosis, and histology might change management.

Figure 4. Microbiopsy forceps (red arrow) through a 19-gauge needle of a cystic lesion with wall thickening (green arrow).

PCLs could also be studied using EUS-nCLE, which provides real-time high-resolution histologic in vivo imaging by using a confocal probe through a 19-gauge FNA needle, allowing microscopic visualisation of the cellular features of the cyst wall after intravenous injection of fluorescein.⁴ Unfortunately, a major limitation of EUS-nCLE is the difficulty in achieving widespread adoption, likely due to high upfront costs and a lack of standardised training. The two main goals of this technique are differentiating mucinous and non-mucinous cysts and excluding HGD or IC.¹⁰

Nowadays, DNA mutations of cystic fluid cells have also been used as biomarkers to distinguish PCLs and might be useful when other findings are not conclusive (figure 3)⁴⁶ or the amount of liquid obtained is small. KRAS mutations have been associated with mucinous cysts and are present in around 69% of IPMNs⁴⁷ with high specificity (80%–97%) but limited sensitivity (around 60%) to distinguish them from non-mucinous PCLs.^{34 48} GNAS mutations are reported in around 40% of the IPMNs (31% sensitivity and 100% specificity),³⁴ but they are not present in MCN. Instead, the presence of a Von Hippel-Lindau (VHL) mutation identifies SCN with a specificity of around 100%.³⁵ On the other hand, the absence of VHL with the combinations of KRAS and GNAS results in a specificity for mucinous cyst diagnosis of almost 100%.³⁵ The presence of CTTNB1 is associated with SPN and MEN1 mutations and can be found in NETs.⁴⁶ Furthermore, genetic analysis can be applied to detect the presence of HGD or progression to IC. According to Pflüger et al,³⁵ mutations in CDKN2A, PIK3CA, SMAD4 or TP53 each have very high specificity (95%–98%) for HGD or pancreatic ductal adenocarcinoma, although sensitivity is low (9%–42%). In recent years, NGS has also been implemented to study these genetic alterations. According to a recent study,⁴⁹ the use of a specific 22-gene NGS panel (PancreaSeq) in EUS-FNA pancreatic cyst fluid specimens reached a very high sensitivity and specificity for various pancreatic cyst types and advanced neoplasia arising from mucinous cysts. Furthermore, authors demonstrated that the presence in mucinous cysts of MAPK/GNAS mutations with TP53, SMAD4, CTNNB1 and/or mTOR gene alterations had 88% sensitivity and 95% specificity for advanced neoplasia.⁵⁰ Unfortunately, the main issue with NGS is the associated cost and, consequently, its low availability.

Cyst algorithm diagnosis and management according to the main guidelines

EUS is a minimally invasive procedure, having the advantage of avoiding radiation exposure but with the disadvantage of exposing the patient to both procedure-related and sedation-related AEs. Generally, EUS for PCLs is indicated when elements of suspicion are found on cross-sectional imaging, and further information is required. Multiple guidelines are proposed for the PCL diagnosis and management, such as those of the American Gastroenterology Association (AGA),⁵¹ American College of Gastroenterology (ACG),⁵² American College of Radiology (ACR),⁵³ European Study Group of Cystic Tumours of the Pancreas (ESGCTP)⁵⁴ and International Association of Pancreatology (IAP)/Fukuoka guidelines,¹⁴ recently updated with the Kyoto version,¹⁰ where EUS has its role. The main aim of all of them is to define the group of patients at higher risk of developing IC and therefore undergoing surgery. More details on the differences are shown in table 2.

Table 2. Guidelines summary of PCLs.

	2015 AGA guidelines51	2017 IAP guidelines14	2017 ACR guidelines53	2018 ESGTCP54	2018 ACG guidelines52	2024 IAP10
PCL to evaluate	Asymptomatic PNCs (without cystic neuroendocrine tumours, MD-IPMN or SPN)	IPMNs	PNCs	PCLs	PCLs	IPMNs
Target lesion	HGD or IC	HGD or IC	HGD or IC	HGD or IC	HGD or IC	HGD or IC
Indications for EUS	At least two high-risk features in MRI (cyst size ≥30 mm, main PD >3 mm, mural nodule or solid component) (should undergo EUS-FNA)	Diagnostic uncertainty of PCLs (±FNA) WF2017*	Diagnostic uncertainty of PCLs (±FNA) WF2017 (but in ACR guideline the MPD dilation is considered a WF if ≥7 mm). Consider it with FNA at diagnosis if PCLs are >1.5 cm or growth (defined by the ACR guideline) in PCLs ≤2.5 cm and indicated if there is growth >2.5 cm.	Diagnostic uncertainty of PCLs Radiological features of concern with FNA if results would change clinical practice	Diagnostic uncertainty of PCLs (±FNA) WF or high-risk features (with the only change of cyst growth of ≥3 mm/year with respect to IAP 2017WF)	Diagnostic uncertainty of PCLs (±FNA) WF2024†
Growth rate considered a WF or RI.	N/A	≥5 mm/2 years	Based on % increase depending on cyst size 0.5 cm: 100% growth 0.5–1.5 cm: 50% growth in long axis >1.5 cm: 20% growth long axis	≥5 mm/year	≥3 mm/year	≥2.5 mm/year
Surgical indication consideration	Presence of: Positive cytology Two RF (cyst size ≥30 mm; main PD >3 mm; mural nodule; solid component) or positive cytology	IPMN with HRS2017§ IPMN with WF2017* and confirmed nodule≥5 mm in EUS, +cytology or MD features suspicious for involvement	WF2017* or HRS2017§. If the only WF is ≥3 cm, these patients could be followed. (EUS always previous to surgery)	IPMN with one or more AI‡ IPMN with two RI¶ with significant comorbidities (but still fit for surgery) IPMN with one or more RI‡ without significant comorbidities	Patients with WF or HRS (with the only change of cyst growth of ≥3 mm/year with respect to IAP 2024 WF and without new onset diabetes as WF) should be evaluated in an MDT for surgery	IPMN with one or more HRS2024** IPMN with multiple WF2024¶ IPMN with WF2024‡ and repeated pancreatitis or young age
	Same indication as for IPMN	All MCN (according to 2012 IAP guidelines; not updated)	WF or HRS	>40 mm or smaller with RF (mural nodules; symptoms)	WF or high-risk features (with the only change of cyst growth of ≥3 mm/year with respect to IAP 2017 WF) should be evaluated in an MDT for surgery	All MCN (according to 2012 IAP guidelines; not updated)
				Compressive symptoms	Compressive symptoms
					All of them
Follow-up of resected PCL	MRI every 2 years if HGD or IC	IPMN with no RF→follow-up 6–12 months IPMNs with high RF (HGD in surgical margin, FH of PDAC or non-intestinal subtype)→cross-sectional image two times a year IPMN with IC→as PDAC		IPMN-LGD→regular IPMN follow-up IPMN-HGD→ every 6 months 2 years and then every year with MRI or EUS IPMN-IC→as PDAC	IPMN-LGD or intermediate→if no IPMN in remanent pancreas MRI every 24 months. If IPMN, follow-up according to the biggest one. IPMN-HGD→EUS or MRI every 6 months. MCN →follow-up only if IC (as PDAC) SCN→no follow-up SPN→yearly basis 5 years	IPMN with no RF→follow-up every 12 months IPMN with RF (HGD or FH of PDAC)→every 6 months IPMN with IC→as PDAC
Consider stop surveillance	Five consecutive years without change or unfit for surgery	Unfit for surgery	Unfit for surgery or 10 years of stability without WF	Unfit for surgery	Unfit for surgery. Individualised approach at 76–85 years	Unfit for surgery patients or <10 years life expectancy. Consider in cysts <2 cm with 5 years of stability

^*WF2017: acute pancreatitis; cyst ≥30 mm; enhancing mural nodule <5 mm; thickened/enhancing cyst walls; main pancreatic duct ≥5 and <10 mm; abrupt change in caliber of pancreatic duct with distal pancreatic atrophy; lymphadenopathy; increased serum level of CA 19.9; cystic growth rate >5 mm/2 year.

^†WF2024: acute pancreatitis; new onset or acute exacerbation of diabetes (new); cyst ≥30 mm; enhancing mural nodule <5 mm; thickened/enhancing cyst walls; main pancreatic duct ≥5 and <10 mm; abrupt change in calibre of pancreatic duct with distal pancreatic atrophy; lymphadenopathy; increased serum level of CA 19.9; cystic growth rate ≥2.5 mm/year (changed).

^‡AI: main PD ≥10 mm; enhancing mural nodule ≥5 mm or solid component; positive cytology.

^§HRS2017: jaundice; PD ≥10 mm; enhancing mural nodule ≥5 mm or solid component.

^¶RI: MPD dilatation ≥5 and <9.9 mm; cystic growth rate ≥ 5 mm/year; CA 19.9 >37 U/mL; symptoms; enhancing mural nodules <5 mm; cyst diameter ≥40 mm.

^**HRS2024: jaundice; PD ≥10 mm; enhancing mural nodule ≥5 mm or solid component; suspicious or positive cytology.

ACG, American College of Gastroenterology; ACR, American College of Radiology; AGA, American Gastroenterology Association; AI, absolute indication; ESGCTP, European Study Group on Cystic Tumours of the Pancreas; EUS, endoscopic ultrasound; FH, family history; HGD, high-grade dysplasia; HRS, high-risk stigmata; IAP, International Association of Pancreatology; IC, invasive carcinoma; IPMN, intraductal papillary mucinous neoplasm; LGD, low-grade dysplasia; MCN, mucinous cystic neoplasia; MD, main duct; MDT, multidisciplinary team; PCL, pancreatic cystic lesion; PD, pancreatic duct; PDAC, pancreatic adenocarcinoma; PNC, pancreatic neoplastic cyst; RF, risk factor; RI, relative indication; SCN, serous cystic neoplasia; SPN, solid pseudopapillary neoplasm; WF, worrisome feature.

Intraductal papillary mucinous neoplasm

Most guidelines are focused on this type of PCL due to their high prevalence and their relatively low incidence of malignant progression, especially for BD-IPMN, where the mean rate of HGD/IC in surgical series of resected lesions is about 31%.¹⁰ This means that all the efforts are addressed for the early identification of those cysts likely to have a malignant progression, keeping also in mind that a progression of the disease is expected in about 10%–15% of patients during 3–5 years of follow-up with a cumulative rate of malignant transformation of 8% at 10 years in low-risk IPMN but up to 25% in high-risk IPMN.^{54 55} The AGA guidelines⁵¹ stipulated that MRI should demonstrate at least two high-risk features (cyst size ≥ 30 mm, main PD >3 mm, mural nodule or solid component) for referral to EUS. On the other hand, to undergo surgery, one of the following should be present: (1) positive cytology for HGD/IC on EUS-FNA or (2) at least two high-risk features on MRI and/or EUS (cyst size ≥30 mm, main PD >3 mm, mural nodule or solid component). According to IAP, assessment of IPMN should be conducted by MRI/magnetic resonance cholangiopancreatography or multidetector CT. EUS can be performed as a secondary assessment tool when further features are required. In this case, cyst fluid evaluation can be useful to confirm the diagnosis and to identify HGD/IC presence. Since the 2012 guidelines, IAP has used the terms ‘worrisome features’ (WF) and ‘high-risk stigmata’ (HRS) instead of ‘relative’ or ‘absolute indication’, respectively, for surgery. WFs in the last updated version¹⁰ are (1) acute pancreatitis, (2) increased serum level of CA 19.9, (3) new onset or acute exacerbation of diabetes mellitus within the past year, (4) cyst ≥30 mm, (5) enhancing mural nodule <5 mm, (6) thickened/enhancing cyst walls, (7) MPD ≥5 mm and <10 mm, (8) abrupt change in calibre of pancreatic duct with distal pancreatic atrophy, (9) lymphadenopathy and (10) cystic growth rate ≥2.5 mm/year. The first three are ‘clinical’, and the last seven are ‘imaging based’. HRS are (1) obstructive jaundice in a patient with a cystic lesion of the head of the pancreas, (2) an enhancing mural nodule ≥5 mm or solid component, (3) MPD ≥10 mm and (4) suspicious or positive results of cytology. When HRS are present, surgery should be considered, taking into account the patient’s condition, preferences and life expectancy. If WFs are found, follow-up should be performed according to cystic size. Surgery should be considered anyway if the patient is suffering from multiple episodes of pancreatitis or if there are multiple WFs and the patient is fit enough due to the additive effect on the HGD/IC risk.¹⁰ Indeed, having 1, 2 or 3 WFs leads to the risk of HGD being 22%, 34% and 59%, respectively, reaching nearly 100% with four or more WFs.⁵⁶ No recommendations are given about EUS-nCLE use, while for the first time, IAP guidelines suggest genetic evaluation in unclear diagnoses. ESGCTP guidelines⁵⁴ state MRI as the gold standard for IPMN follow-up, while EUS should be used only in selected cases. According to these guidelines, all patients with MD- and MT-IPMN should be considered for surgery, whereas in BD-IPMN, the absolute indications for surgery are substantially equivalent to the ‘HRS’ of IAP guidelines. Regarding relative indications for surgery, the difference between WF of IAP guidelines and ESGCTP is the growth rate of ≥5 mm/2 years compared with 2.5 mm/year and cystic lesions of ≥40 mm compared with 30 mm, while other features remain similar.

A comparison between AGA,⁵¹ IAP (2017 version)¹⁴ and European guidelines⁵⁴ on diagnostic accuracy for IPMN has been reported in a recent study,⁵⁷ finding a lower sensitivity in predicting advanced neoplasia for the AGA guidelines as compared with the IAP and European guidelines (27% vs 94% and 96%). More recently, a new publication compared both the IAP from the 2017¹⁴ and 2024¹⁰ guidelines and the ESGTCP,⁵⁴ showing higher specificity, positive predictive value and accuracy for malignant IPMN with the newest guidelines compared with the 2017 version and the ESGTCP. This study also showed a better area under the curve (AUC) for surgical indication (AUC=0.623) when comparing with IAP guidelines from 2017 (AUC=0.524) and ESGTCP (AUC=0.582); these differences were statistically significant (p=0.008 and p<0.001, respectively).⁵⁸

Mucinous cystic neoplasm

In the 2012 edition of the IAP guidelines,⁵⁹ surgery was recommended for all MCNs. Unfortunately, these recommendations have not been updated in the subsequent version of the guidelines. According to the ESGCTP,⁵⁴ only MCN larger than 40 mm or smaller with risk features (such as mural nodules or symptoms) should undergo a standard oncologic resection. Then, for cysts measuring <40 mm without mural nodules or symptoms, follow-up with MRI or EUS is advised, starting every 6 months for the first year and then annually. EUS-FNA is indicated when the diagnosis is not already established. The same indications for both IPMN and MCN are suggested by AGA guidelines.⁵¹

Serous cystic neoplasm

According to the ESGCTP,⁵⁴ asymptomatic patients with radiological evidence of an SCN should be followed up for 1 year and then only symptom-based or in cases of uncertainty. When follow-up is required, the same recommendations of BD-IPMN should be followed. Surgery is recommended only for patients with compression-related symptoms. On the other hand, no recommendations for SCN are given by AGA or IAP.^{10 51}

Solid-pseudopapillary neoplasm

Only the ACG guidelines⁵² mention SPN management. All of them have a surgical indication. There is little evidence, but the ACG guideline recommends follow-up imaging on a yearly basis for 5 years after surgery.

Therapeutic role of EUS for pancreatic cysts

Besides the EUS-guided drainage of pancreatic collections (pseudocyst and walled-off pancreatic necrosis),^{60 61} EUS has other therapeutic roles in the field of PCLs: it can be used as a guide for fine needle injection (EUS-FNI) or ablation. Both represent innovative and minimally invasive approaches in the management of both PCLs and solid tumours, even if they have no clear application in daily practice. Indeed, few data are available on its use for cystic lesions.62,64

EUS-FNI facilitates the localised delivery of therapeutic agents, such as chemotherapeutic drugs, immunotherapies and gene therapies, directly into pancreatic cysts or tumours, enhancing intratumoral drug concentration and reducing systemic adverse effects.⁶⁵ Agents like gemcitabine, delivered through EUS-FNI, have shown promise in targeting pancreatic adenocarcinoma, with advanced drug delivery systems such as hydrogels and nanoparticles offering sustained release and improved therapeutic outcomes.^{62 65} Immunotherapy using EUS-FNI has been demonstrated to activate tumour-specific immune responses, while experimental gene therapy approaches targeting oncogenic mutations also hold potential.⁶⁵ However, EUS-FNI is still under investigation, so it is not routinely performed in clinical practice.

EUS-guided ablation techniques include ethanol ablation (EUS-EA), radiofrequency ablation (EUS-RFA) and laser ablation, each tailored to specific PCNs and solid tumours.^{62 65} EUS-EA, employing agents such as ethanol and paclitaxel, has been shown to induce a significant reduction in cystic volume and prevent progression to malignancy in selected PCNs.⁶² For instance, ethanol combined with paclitaxel has been effective in treating BD-IPMNs with minimal AEs.^{62 65}

Similarly, EUS-RFA uses thermal energy to induce coagulative necrosis within pancreatic lesions, achieving high technical and clinical success rates. Nowadays, EUS-RFA is recommended in clinical guidelines only for insulinomas smaller than 2 cm in patients unfit for surgery.⁶⁶ However, new research in pNETs and unresectable adenocarcinomas is ongoing.^{62 65} While both modalities offer promising results, challenges such as the risk of AEs, including pancreatitis and cyst infection, as well as variability in outcomes depending on tumour type and patient factors, necessitate careful patient selection.^{62 67} Ongoing studies aim to refine these techniques and evaluate their synergistic potential with systemic therapies, further enhancing their efficacy in pancreatic disease management.

EUS and artificial intelligence (AI)

AI is emerging as a valuable tool in the field of EUS for the evaluation of PCLs, particularly in enhancing diagnostic accuracy and aiding differentiation among lesion types. A retrospective study conducted in 2019 by Kuwahara et al⁶⁸ demonstrated that a deep learning algorithm trained on 3970 EUS images could diagnose malignancy in IPMNs with an accuracy of 94%, significantly outperforming human preoperative diagnosis, which had an accuracy of 56%. Similarly, Nguon et al⁶⁹ applied a convolutional neural network (CNN) to differentiate between MCNs and SCNs using EUS images, achieving an accuracy of 82.75% and an AUC score of 0.88. Further supporting the integration of advanced technologies, Machicado et al⁷⁰ explored EUS-nCLE for evaluating IPMNs, developing a CNN model that analysed EUS-nCLE images to differentiate HGD from low-grade lesions, achieving higher sensitivity (83.3%) and accuracy (85.7%) compared with international guideline-based evaluations, underscoring AI’s potential to enhance precision in real-time diagnostics. These findings highlight AI’s potential to complement and enhance EUS in the management of PCLs, though further research and clinical validation are required. In this setting, CNNs are highly suitable for real-time applications due to their ability to process images almost instantaneously, enabling rapid decision-making.

Conclusion

EUS is a fundamental technique with a key role in the diagnostic and therapeutic management of PCLs, with significant potential for expanding and refining its applications. Novel guidelines started focusing on the leading role of EUS in the management of PCLs, from morphological evaluation, which is already enhanced by complementary techniques such as CE-EUS and elastography, to advancements in TA and fluid analysis. Therefore, EUS has become increasingly important in decision-making for PCLs. In the near future, the integration of new tools, such as AI or NGS, will improve physicians’ ability to predict which lesions exhibit HGD and, consequently, carry a higher risk of developing IC. This will improve the identification of patients who would truly benefit from surgery and refine follow-up strategies. Furthermore, new evidence will continue to emerge regarding therapeutic EUS techniques.

Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study.