Premalignant Pancreatic Cystic Lesions Management

Premalignant Pancreatic Cystic Lesions Management: Comparison

Please note this is a comparison between Version 1 by Margaret G Keane and Version 2 by Bruce Ren.

Pancreatic cystic lesions are an increasingly common clinical finding. They represent a heterogeneous group of lesions that include two of the three known precursors of pancreatic cancer, intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN). Given that approximately 8% of pancreatic cancers arise from these lesions, careful surveillance and timely surgery offers an opportunity for early curative resection in a disease with a dismal prognosis.

pancreatic cystic lesions
pancreatic cancer
intraductal papillary mucinous neoplasm
mucinous cystic neoplasm
endoscopic ultrasonography
magnetic resonance imaging
computer tomography
diagnosis
management
surveillance

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1. Introduction

Globally, pancreatic cancer is the twelfth most common cancer but the seventh most common cause of cancer-related death. In 2018, there were an estimated 459,600 new cases and 432,000 deaths from the disease ^[1]. The incidence in the Western population is increasing, with the highest being in Europe and North America ^[1][2][3][4]. It is estimated to become the second leading cause of cancer-related death by 2030 ^[5]. A study of 3.9 million cancer patients globally found pancreatic cancer to have the lowest five-year survival rates, ranging from 7.9% in the United Kingdom to 14.6% in Australia ^[6]. Due to the lack of overt symptoms in earlier stages of the disease, most patients are diagnosed at a stage when curative resection is no longer possible, leading to the low survival rate ^[7]. Patients diagnosed at an early stage have a substantially better prognosis and survival compared to those diagnosed with more advanced stages, as more patients diagnosed in earlier stages are likely to be candidates for surgical resection with improved survival ^[8]. Even if the tumor is not amendable to surgical resection, a lower tumor burden results in less chemoresistance, therefore making chemoradiotherapy treatments more effective ^[9][10]. Therefore, early diagnosis in pancreatic cancer has become a recognized healthcare priority ^[7][11].

Globally, pancreatic cancer is the twelfth most common cancer but the seventh most common cause of cancer-related death. In 2018, there were an estimated 459,600 new cases and 432,000 deaths from the disease [1]. The incidence in the Western population is increasing, with the highest being in Europe and North America [1,2,3,4]. It is estimated to become the second leading cause of cancer-related death by 2030 [5]. A study of 3.9 million cancer patients globally found pancreatic cancer to have the lowest five-year survival rates, ranging from 7.9% in the United Kingdom to 14.6% in Australia [6]. Due to the lack of overt symptoms in earlier stages of the disease, most patients are diagnosed at a stage when curative resection is no longer possible, leading to the low survival rate [7]. Patients diagnosed at an early stage have a substantially better prognosis and survival compared to those diagnosed with more advanced stages, as more patients diagnosed in earlier stages are likely to be candidates for surgical resection with improved survival [8]. Even if the tumor is not amendable to surgical resection, a lower tumor burden results in less chemoresistance, therefore making chemoradiotherapy treatments more effective [9,10]. Therefore, early diagnosis in pancreatic cancer has become a recognized healthcare priority [7,11].

Pancreatic cystic lesions (PCL) are an increasingly common incidental finding. They are present in 1.2–2.6% of patients undergoing abdominal computed tomography (CT) ^[12][13] and in up to 13.5% of patients undergoing abdominal magnetic resonance imaging (MRI) for non-pancreatic indications ^[14]. The incidence increases further with age, with approximately 10% of individuals over 70 years old undergoing a CT being found to have PCL ^[15]. PCL have a broad differential diagnosis ^[16].

Pancreatic cystic lesions (PCL) are an increasingly common incidental finding. They are present in 1.2–2.6% of patients undergoing abdominal computed tomography (CT) [12,13] and in up to 13.5% of patients undergoing abdominal magnetic resonance imaging (MRI) for non-pancreatic indications [14]. The incidence increases further with age, with approximately 10% of individuals over 70 years old undergoing a CT being found to have PCL [15]. PCL have a broad differential diagnosis [16].

Table 1 shows the characteristics of the common PCL. Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are of particular importance because these are considered precursor lesions to pancreatic cancer ^{[17][18][19][20][21][22]}. In contrast to the other precursors, such as pancreatic intraepithelial neoplasia (PanIN) which can only be identified on surgical histopathology, IPMNs and MCNs can be easily identified on cross-sectional imaging ^{[23][24][25][26][27]} Given that approximately 8% of all pancreatic cancers are believed to arise from these lesions, this offers an opportunity for early cancer detection ^[28].

shows the characteristics of the common PCL. Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are of particular importance because these are considered precursor lesions to pancreatic cancer [17,18,19,20,21,22]. In contrast to the other precursors, such as pancreatic intraepithelial neoplasia (PanIN) which can only be identified on surgical histopathology, IPMNs and MCNs can be easily identified on cross-sectional imaging [23,24,25,26,27] Given that approximately 8% of all pancreatic cancers are believed to arise from these lesions, this offers an opportunity for early cancer detection [28].

Table 1.

Key clinical and imaging features of common pancreatic cystic lesions.

	Intraductal Papillary Mucinous Neoplasm (IPMN)	Mucinous Cystic Neoplasm (MCN)	Serous Cystic Adenoma	Pseudocyst	Cystic Pancreatic Neuroendocrine Tumor	Solid Pseudopapillary Neoplasm
Sex	M or F	F	F	M or F	M or F	F
Age	65	40	60	-	50	30
Pancreatic localization

1.1. Classification of IPMNs and MCNs

An IPMN is a mucin producing tumor that arises from the pancreatic duct. They are equally common in men and women. There are three types of IPMNs, which are differentiated based on morphologic differences. Main duct IPMNs (MD-IPMN) are characterized by involvement with the main pancreatic duct (MPD), and identified by a dilated MPD (≥5 mm) without an associated cyst or other cause for ductal obstruction. Branch duct IPMNs (BD-IPMN) arise from a branch off the MPD, and are identified as unilocular or multilocular pancreatic cyst with communication with the MPD, which measures <5 mm. Mixed-type IPMNs (MT-IPMN) meet criteria for both MD and BD IPMNs (

Table 1). Furthermore, IPMNs can be histologically classified as gastric, intestinal, pancreaticobiliary or oncocytic based on cellular morphology and mucin (MUC) gene expression and tissue architecture ^[29]. Studies have suggested that knowing the epithelial subtypes may be of prognostic importance (

). Furthermore, IPMNs can be histologically classified as gastric, intestinal, pancreaticobiliary or oncocytic based on cellular morphology and mucin (MUC) gene expression and tissue architecture [33]. Studies have suggested that knowing the epithelial subtypes may be of prognostic importance (

Table 2) ^[30].

) [34].

Table 2.

Pathological subtypes of IPMN.

Subtype	Papillae	Mimicker	Typical Level of Atypia	MUC Staining
Gastric	Thick fingerlike or small tubules	Foveolar gland or pyloric gland	LGD	MUC5AC MUC6
Intestinal	Villous	Intestinal villous neoplasm	IGD / HGD	MUC2 MUC5AC
Head	Body/Tail	Throughout	Throughout	Throughout	Body/Tail
Pancreaticobiliary	Fern like	Cholangiopapillary neoplasm	HGD	MUC1 MUC5AC MUC6	Typical imaging features	MD-IPMN: Dilated MPD SB IPMN: Dilated side branch or cyst that connects to the MPD	Unilocular, macrocystic	Microcystic (honeycomb) appearance	Unilocular cyst, sometimes with necrotic debris	Solid cystic lesion, hypervascular	Solid cystic lesion
Oncocytic	Pylloid	Oncocytic tumor	HGD	MUC5AC MUC6 (+/− MUC1 or MUC2)	Communication with the MPD	+	−	−	+ or −	−	−
Solitary/multifocal	Solitary/multifocal	Solitary	Solitary	Solitary	Solitary	Solitary
Malignant potential (surgically resected lesions) *	MD/MT IPMN: 36–100% BD IPMN: 11–30%	10–39%	0%	0%	10%	10–15%

Gastric-type IPMNs have the best prognosis, as they are typically small BD-IPMNs with low-grade dysplasia (LGD), and have a 5-year survival of >90%. Prognosis following resection is good, with 5- and 10-year survival rates of over 90%. Intestinal-type IPMNs are often involving the MPD and are MT or MD-IPMNs with high-grade dysplasia (HGD). Prognosis of intestinal IPMNs are less favorable, with 5- and 10-year survival rates of 70% and 50%, respectively, when associated with pancreatic cancer. Pancreatobiliary-type IPMNs arise from BD, MT or MD-IPMNs but are exclusively high-grade neoplasms, and seen up to 80% of cases associated with invasive pancreatic cancer. Five- and 10-year survival rates are 50% and 0%, respectively. Oncocytic IPMNs are rare but tend to occur in younger patients. They arise in MD-IPMNs with HGD and around 50% are associated with invasive cancer. Patients with oncocytic-type IPMNs with associated cancer have a 5- and 10-year survival of 60% and 40%, respectively ^[31].

MCNs, on the other hand, are lined by tall columnar mucin producing epithelial cells and in contrast to IPMNs, are surrounded by ovarian-type stroma ^[16][32]. There is predominance for these lesions to be detected in middle-aged women ^[33] (

MCNs, on the other hand, are lined by tall columnar mucin producing epithelial cells and in contrast to IPMNs, are surrounded by ovarian-type stroma [16,36]. There is predominance for these lesions to be detected in middle-aged women [37] (

Table 1

1.2. IPMN/ MCN Progression to Invasive Cancer

The natural history and longitudinal risk of malignancy in IPMNs and MCNs are poorly understood. Although these lesions can progress from low-grade to high-grade dysplasia and ultimately pancreatic cancer, not all IPMNs or MCNs progress to cancer within a patient’s lifetime. Each type of IPMN is associated with different rates of malignant transformation. In surgically resected BD-IPMN, the risk of malignant transformation has been reported to be between 6 and 51%. MD and MT- IPMNs are recognized to have higher rates of malignant transformation, ranging between 35–100% ^{[23][24][25][26]}. The risk of malignant transformation in MCNs have been reported to be between 0–34% ^[34]. Regardless, the data on the natural history of IPMNs and MCNs have limitations. Natural history studies that rely on surgical specimens include a disproportionate number of high-risk lesions so may overestimate the true cancer risk whereas cohort studies without histologic proven IPMNs and MCNs ^[35] may underestimate cancer risk.

The natural history and longitudinal risk of malignancy in IPMNs and MCNs are poorly understood. Although these lesions can progress from low-grade to high-grade dysplasia and ultimately pancreatic cancer, not all IPMNs or MCNs progress to cancer within a patient’s lifetime. Each type of IPMN is associated with different rates of malignant transformation. In surgically resected BD-IPMN, the risk of malignant transformation has been reported to be between 6 and 51%. MD and MT- IPMNs are recognized to have higher rates of malignant transformation, ranging between 35–100% [23,24,25,26]. The risk of malignant transformation in MCNs have been reported to be between 0–34% [29]. Regardless, the data on the natural history of IPMNs and MCNs have limitations. Natural history studies that rely on surgical specimens include a disproportionate number of high-risk lesions so may overestimate the true cancer risk whereas cohort studies without histologic proven IPMNs and MCNs [38] may underestimate cancer risk.

Pancreatic cancer in IPMN can arise directly from the PCL (an associated cancer) or from the pancreatic parenchyma away from the IPMN (concomitant cancer), which occurs in between 9–44% of cases ^[36][37]. IPMN-associated and concomitant cancers have a better prognosis than non-IPMN pancreatic cancers. A recent systematic review revealed an improved 5-year survival for IPMN cancers (OR 0.23, 95% CI 0.09–0.56). Median survival ranged from 21 to 58 months in the IPMN cancers compared to 12–23 months in the non-IPMN related cancer group. It was noted that IPMN cancers were frequently found as stage 1 disease (OR 4.40, 95% CI 2.71–7.15) so it is possible that the improved survival is actually due to earlier detection ^[38].

Pancreatic cancer in IPMN can arise directly from the PCL (an associated cancer) or from the pancreatic parenchyma away from the IPMN (concomitant cancer), which occurs in between 9–44% of cases [39,40]. IPMN-associated and concomitant cancers have a better prognosis than non-IPMN pancreatic cancers. A recent systematic review revealed an improved 5-year survival for IPMN cancers (OR 0.23, 95% CI 0.09–0.56). Median survival ranged from 21 to 58 months in the IPMN cancers compared to 12–23 months in the non-IPMN related cancer group. It was noted that IPMN cancers were frequently found as stage 1 disease (OR 4.40, 95% CI 2.71–7.15) so it is possible that the improved survival is actually due to earlier detection [41].

Whole exome and targeted sequencing of small cohorts of IPMNs and MCNs have identified genetic alterations in oncogenes and tumor suppressor genes, which drive progression to dysplasia and ultimately cancer. Like in pancreatic cancer, one of the earliest genetic alterations in IPMNs are thought to be in KRAS and GNAS ^[39][40][41]. Over time, mutations in tumor suppressor genes such as RNF43, CDKN2A, TP53 and SMAD4 occur which drives the progression to invasive cancer ^[40][41]. A targeted analysis of larger cohorts has confirmed that these gene mutations correlate with the grade of dysplasia and histological subtype ^[42][43]. However, targeted next generation sequencing of IPMNs has suggested there is considerable intratumoral genetic heterogeneity in these lesions and several different molecular alterations are present in different parts of the cyst ^[44]. It is likely that this combination of genetic alterations drive the transition from a noninvasive precursor lesion to invasive cancer in IPMNs ^[45][46].

Whole exome and targeted sequencing of small cohorts of IPMNs and MCNs have identified genetic alterations in oncogenes and tumor suppressor genes, which drive progression to dysplasia and ultimately cancer. Like in pancreatic cancer, one of the earliest genetic alterations in IPMNs are thought to be in KRAS and GNAS [42,43,44]. Over time, mutations in tumor suppressor genes such as RNF43, CDKN2A, TP53 and SMAD4 occur which drives the progression to invasive cancer [43,44]. A targeted analysis of larger cohorts has confirmed that these gene mutations correlate with the grade of dysplasia and histological subtype [45,46]. However, targeted next generation sequencing of IPMNs has suggested there is considerable intratumoral genetic heterogeneity in these lesions and several different molecular alterations are present in different parts of the cyst [47]. It is likely that this combination of genetic alterations drive the transition from a noninvasive precursor lesion to invasive cancer in IPMNs [48,49].

MCNs are lined by columnar mucinous epithelium ^[16] and like IPMNs, are also now classified pathologically into a three-tiered system with associated LGD, HGD or pancreatic cancer ^[47]. Like IPMNs, MCNs also harbor genetic changes that lead to tumor progression and ultimately the development of invasive cancer. KRAS mutations are found in 3–100% of MCNs ^[39][40][48]. The frequency of KRAS alterations also seems to increase with grade of dysplasia ^[48][49]. GNAS mutations are commonly found in IPMNs but are not found in MCNs; however alterations in RNF43 have been found in 12% of low-grade MCNs and 25% of high-grade MCNs ^[39]. Loss of CDKN2A/p16 may also play a role in progression to cancer in IPMNs as it is a common finding in MCNs with HGD but is absent in MCNs with LGD. Similarly TP53 is present in 25–56% of MCNs with HGD or cancer, but not in MCNs with LGD ^[48]. Similar to IPMNs, loss of SMAD4 expression appears predominantly in MCNs with invasive cancer. In one study, which examined 36 MCNs, SMAD4 expression was retained MCNs with LGD or HGD but was lost in 86% of MCNs with invasive cancer ^[50].

MCNs are lined by columnar mucinous epithelium [16] and like IPMNs, are also now classified pathologically into a three-tiered system with associated LGD, HGD or pancreatic cancer [50]. Like IPMNs, MCNs also harbor genetic changes that lead to tumor progression and ultimately the development of invasive cancer. KRAS mutations are found in 3–100% of MCNs [42,43,51]. The frequency of KRAS alterations also seems to increase with grade of dysplasia [51,52]. GNAS mutations are commonly found in IPMNs but are not found in MCNs; however alterations in RNF43 have been found in 12% of low-grade MCNs and 25% of high-grade MCNs [42]. Loss of CDKN2A/p16 may also play a role in progression to cancer in IPMNs as it is a common finding in MCNs with HGD but is absent in MCNs with LGD. Similarly TP53 is present in 25–56% of MCNs with HGD or cancer, but not in MCNs with LGD [51]. Similar to IPMNs, loss of SMAD4 expression appears predominantly in MCNs with invasive cancer. In one study, which examined 36 MCNs, SMAD4 expression was retained MCNs with LGD or HGD but was lost in 86% of MCNs with invasive cancer [53].

The timeline for progression from IPMN/MCN with LGD to invasive cancer remains poorly understood. Mathematical modelling of the carcinogenesis of PanINs, suggests the progression from PanIN 1 to pancreatic cancer could take up to 35 years, of which 12 years includes the progression from PanIN-3 to pancreatic cancer ^[51]. Studies classify PCLs as low-risk or high-risk, with high risk having characteristics of high-risk stigmata, defined as presence of obstructive jaundice, enhancing mural nodule ≥5 mm, and main pancreatic duct ≥10 mm or worrisome features, defined as presence of pancreatitis, cyst ≥3 cm, enhancing mural nodule <5 mm, thickened cyst wall, main pancreatic duct of 5–9 mm, abrupt change in caliber of pancreatic duct, lymphadenopathy, increased serum level of carbohydrate antigen 19-9, and a cyst growth rate ≥5 mm/2 years ^[27]. A systematic review of retrospective surveillance cohorts found that low-risk IPMNs defined as BD-IPMNs without mural nodules, had an approximate 8% chance of progressing to invasive cancer within 10 years while BD-IPMN with worrisome features had 25% chance of progressing to cancer in 10 years ^[52]. A genetic analysis of the evolutionary timeline of the malignant transformation of IPMNs suggests a window of approximately 3 years to progress from HGD to invasive cancer ^[53]. These studies suggest progression to cancer occurs over at least several years in IPMNs/MCNs, which supports the utility of surveillance programs that enable the early detection of pancreatic cancer and high-risk lesions.

The timeline for progression from IPMN/MCN with LGD to invasive cancer remains poorly understood. Mathematical modelling of the carcinogenesis of PanINs, suggests the progression from PanIN 1 to pancreatic cancer could take up to 35 years, of which 12 years includes the progression from PanIN-3 to pancreatic cancer [54]. Studies classify PCLs as low-risk or high-risk, with high risk having characteristics of high-risk stigmata, defined as presence of obstructive jaundice, enhancing mural nodule ≥5 mm, and main pancreatic duct ≥10 mm or worrisome features, defined as presence of pancreatitis, cyst ≥3 cm, enhancing mural nodule <5 mm, thickened cyst wall, main pancreatic duct of 5–9 mm, abrupt change in caliber of pancreatic duct, lymphadenopathy, increased serum level of carbohydrate antigen 19-9, and a cyst growth rate ≥5 mm/2 years [27]. A systematic review of retrospective surveillance cohorts found that low-risk IPMNs defined as BD-IPMNs without mural nodules, had an approximate 8% chance of progressing to invasive cancer within 10 years while BD-IPMN with worrisome features had 25% chance of progressing to cancer in 10 years [55]. A genetic analysis of the evolutionary timeline of the malignant transformation of IPMNs suggests a window of approximately 3 years to progress from HGD to invasive cancer [56]. These studies suggest progression to cancer occurs over at least several years in IPMNs/MCNs, which supports the utility of surveillance programs that enable the early detection of pancreatic cancer and high-risk lesions.

1.3. Guidelines for the Management of IPMN and MCN

There are currently five major guidelines on the management of IPMN and MCN: the revised International Consensus guidelines ^[54], the European evidence based guidelines on the management of pancreatic cystic neoplasms ^[55], the American Gastroenterology Association (AGA) guidelines on the management of asymptomatic PCL ^[56], the American College of Gastroenterology (ACG) clinical guideline on the diagnosis and management of PCL ^[57] and the American College of Radiology (ACR) white paper on the management of incidental pancreatic cysts ^[58]. The similarities and differences between the recommendations are discussed below. The quality of the evidence on which management recommendations are based in IPMN and MCN is often low, so many of the guidelines are formed from expert and consensus opinion (

There are currently five major guidelines on the management of IPMN and MCN: the revised International Consensus guidelines [30], the European evidence based guidelines on the management of pancreatic cystic neoplasms [57], the American Gastroenterology Association (AGA) guidelines on the management of asymptomatic PCL [58], the American College of Gastroenterology (ACG) clinical guideline on the diagnosis and management of PCL [59] and the American College of Radiology (ACR) white paper on the management of incidental pancreatic cysts [60]. The similarities and differences between the recommendations are discussed below. The quality of the evidence on which management recommendations are based in IPMN and MCN is often low, so many of the guidelines are formed from expert and consensus opinion (

Table 3

and

Table 4

Table 3.

Indications for surgical resection in IPMN or MCN as outlined by current guidelines.

Guideline	Cyst Type	Absolute Indications for Surgery	Relative Indications for Surgery
American Gastroenterology Association (2015) ^[56][

Table 4. Comparison of the guideline recommendations for surveillance protocols and indications for EUS.

Guideline	Surveillance Protocol	Indication for EUS	Discharge from Surveillance
58]	MCN	All MCN	-
58]	American Gastroenterology Association (2015) ^[56][58]	Patients with pancreatic cysts <3 cm without a solid component or a dilated pancreatic duct should undergo MRI in 1 year, then every 2 years, for a total of 5 years if there is no change in size or characteristics.	Pancreatic cysts with at least 2 high-risk features, such as size >3 cm, a dilated (or increasingly dilated) main pancreatic duct, or the presence of an associated solid component	Discharge if there has been no significant change in the characteristics of the cyst after 5 years of surveillance or if the patient is no longer a surgical candidate	IPMN
International Consensus Guidelines (2017) ^[54][30]	MPD ≥5 mm (on MRI and EUS) and solid component	In cysts without worrisome features: <1 cm: CT / MRI in 6 months, then every 2 years if no change Cytology positive for malignancy		1–2 cm: CT / MRI 6 monthly for 1 year, yearly for 2 years, then every 2 years if no change	-
	2–3 cm: EUS in 3-6 months, then in 1 year if no change, alternating MRI with EUS. Consider surgery in young, fit patients with need for prolonged surveillance. >3 cm: Alternating MRI with EUS every 3–6 months. Strongly consider surgery in young, fit patients	If one or more of the following “worrisome features” are present: Acute Pancreatitis Cyst >3 cm∙ Enhancing mural nodule <5 mm Thickened/enhancing cyst walls Main duct size 5–9 mm Abrupt change in caliber of pancreatic duct with distal pancreatic atrophy Lymphadenopathy Increased serum level of CA19-9 Cyst growth rate > 5 mm/2 years	Continue as long as patients are fit to undergo surgical resection	International Consensus Guidelines (2017) ^[54][30]	MCN	All MCN	-
European (2018) ^[55][57]	1st year after diagnosis: Clinical evaluation, serum CA19-9, MRI or EUS every 6 months. After 1 year + no indications for surgery: Clinical evaluation, serum CA19-9 and MRI or EUS annually	EUS-FNA should only be performed when the results are expected to change clinical management. EUS-FNA should not be performed if the diagnosis is already established by cross-sectional imaging, or where there is a clear indication for surgery	Continue as long as patients are fit to undergo surgical resection	International Consensus Guidelines (2017) ^[54][30]	IPMN
American College Gastroenterology (2018) ^[57][59]	Cytology suspicious or positive for malignancy Jaundice (tumor-related) Enhancing mural nodule (≥5 mm) MPD dilatation ≥10 mm	In patients with a presumed IPMN/MCN without concerning features or indications for surgery: <1 cm MRI in 2 years 1–2cm MRI in 1 year 2–3 cm MRI or EUS in 6–12 months	Growth rate ≥5 mm over 2 years Increased levels of serum CA19-9 PD dilatation between 5 and 9 mm Cyst diameter ≥30 mm Acute pancreatitis (caused by IPMN) Enhancing mural nodule (<5 mm) Abrupt change in diameter of MPD with distal atrophy Lymphadenopathy Thickened or enhancing cyst walls
EUS-FNA can be considered if the diagnosis is unclear, and results will alter management. Cyst fluid CEA can differentiate IPMN/MCN from other cysts. Cytology can assess for the presence of HGD or pancreatic cancer. Molecular markers can help identify IPMNs / MCNs in cases where it will change management	Continue as long as patients are fit to undergo surgical resection	European (2018) ^[55][57]	MCN	Cyst diameter ≥40 mm Enhancing mural nodule Symptoms (jaundice, acute pancreatitis, new- onset diabetes mellitus)
		European (2018) ^[55][57]
Radiology White paper (2017) ^[58][60]	Pancreatic cyst without features of concern: <2 cm imaging every 1–2 years depending on age and length of size stability	IPMN	Positive cytology for malignancy or HGD Solid mass Jaundice (tumor- related) Enhancing mural nodule (≥5 mm) MPD dilatation ≥10 mm	Growth rate ≥5 mm per year Increased levels of serum CA19-9 (>37 U/mL) MPD dilatation between 5 and 9.9 mm Cyst diameter ≥40 mm New- onset diabetes mellitus Acute pancreatitis (caused by IPMN) Enhancing mural nodule (<5 mm)
American College Gastroenterology (2018) ^[57][59]			Significantly elevated serum CA19-9 Any of the following imaging findings: mural nodule, solid component, dilation of MPD >5 mm, focal dilation of the MPD, mucin-producing cysts ≥3 cm. The presence of HGD or pancreatic cancer on cytology
Radiology White paper (2017) ^[58][60]	IPMN or MCN	Jaundice Enhancing mural nodule MPD >10 mm	Indications for EUS-FNA: High risk features: mural nodules, wall thickening, MPD >7 mm, peripheral calcium, cyst >2.5 cm Interval growth (>20% in longitudinal axis)



>2 cm imaging every 6 months for 2 years, then annually for 2 years then every 2 years.

		Increasing cyst size, the presence of “worrisome features” or “high-risk stigmata,” should prompt EUS FNA	Continue as long as patients are fit to undergo surgical resection. Stop surveillance if cyst <1.5 cm and stable over 10 years of surveillance
IPMN or MCN
-	Indication for multidisciplinary review:		Jaundice secondary to the cyst Acute pancreatitis secondary to the cyst

2. Management of IPMN and MCN

2.1. Surveillance

Surveillance of IPMN and MCN provides the opportunity for early detection and potentially surgical curative surgery. Surveillance should therefore be offered to patients as long as they remain surgically fit enough and willing to undergo surgical resection ^{[54][55][56][57][58]}. However, differentiating IPMNs and MCNs correctly from all other PCL pre-operatively is a recognized clinical challenge, and as a result, a high number of patients are entering long-term surveillance annually ^[59][60].

Surveillance of IPMN and MCN provides the opportunity for early detection and potentially surgical curative surgery. Surveillance should therefore be offered to patients as long as they remain surgically fit enough and willing to undergo surgical resection [30,57,58,59,60]. However, differentiating IPMNs and MCNs correctly from all other PCL pre-operatively is a recognized clinical challenge, and as a result, a high number of patients are entering long-term surveillance annually [115,116].

The best modality for surveillance of IPMNs and MCNs has not been established, and therefore guidelines vary in their recommendations. For most patients, MRI is preferred method for surveillance as it avoids repeated exposure to ionizing radiation and provides improved delineation of the pancreatic duct and presence of an enhancing mural nodule or internal septations. However, there are ongoing concerns about possible gadolinium deposition in the brain, kidney and bone after repeated use of certain contrast agents in patients with normal renal function ^[61]. Some patients find MRI scans claustrophobic and they take considerably longer to perform than a CT scan, which only takes a few minutes. EUS or a pancreas protocol CT can therefore be considered as the primary surveillance tools in patients who cannot have or choose not to have MRI with MRCP ^{[54][55][56][57][58]}.

The best modality for surveillance of IPMNs and MCNs has not been established, and therefore guidelines vary in their recommendations. For most patients, MRI is preferred method for surveillance as it avoids repeated exposure to ionizing radiation and provides improved delineation of the pancreatic duct and presence of an enhancing mural nodule or internal septations. However, there are ongoing concerns about possible gadolinium deposition in the brain, kidney and bone after repeated use of certain contrast agents in patients with normal renal function [117]. Some patients find MRI scans claustrophobic and they take considerably longer to perform than a CT scan, which only takes a few minutes. EUS or a pancreas protocol CT can therefore be considered as the primary surveillance tools in patients who cannot have or choose not to have MRI with MRCP [30,57,58,59,60].

For IPMNs without high-risk or worrisome features, the cyst size guides the frequency of surveillance in the International Consensus guidelines. In multifocal IPMNs, surveillance intervals are based on the size of the largest IPMN ^[54]. Size alone correlates imperfectly with malignancy in IPMN as cancers have occasionally been observed in small IPMN (<2 cm) with other worrisome features. The AGA and revised European guidelines do not include size as a basis of their surveillance interval recommendations ^[55][56] (

For IPMNs without high-risk or worrisome features, the cyst size guides the frequency of surveillance in the International Consensus guidelines. In multifocal IPMNs, surveillance intervals are based on the size of the largest IPMN [30]. Size alone correlates imperfectly with malignancy in IPMN as cancers have occasionally been observed in small IPMN (<2 cm) with other worrisome features. The AGA and revised European guidelines do not include size as a basis of their surveillance interval recommendations [57,58] (

Table 4

). There is limited evidence to support the recommended surveillance intervals in the guidelines. It is likely that this schedule is overly intensive with associated healthcare costs for some patients. For others, this schedule may not be intensive enough and they may develop an interval cancer. All patients should be made aware when entering surveillance programs, that in rare cases, a cancer could develop between surveillance imaging. They should contact their medical team prior to their next imaging study if they develop any new symptoms in the interim period.

Recent studies on MCNs have shown that the risk of cancer in cysts less than 40 mm in size and without worrisome features is exceedingly rare ^[62][63]; therefore, in contrast to other guidelines, the revised European guidelines recommends surveillance of all MCNs <40 mm, following the same surveillance intervals as for a BD IPMN ^[55].

Recent studies on MCNs have shown that the risk of cancer in cysts less than 40 mm in size and without worrisome features is exceedingly rare [84,118]; therefore, in contrast to other guidelines, the revised European guidelines recommends surveillance of all MCNs <40 mm, following the same surveillance intervals as for a BD IPMN [57].

2.2. When Can Surveillance Be Stopped?

Although the potential of IPMNs to progress to invasive cancer is clearly recognized, there remains controversy over which guidelines should be followed. The AGA guidelines recommend for the discontinuation of surveillance at 5 years in cysts less 3 cm in the absence of MPD duct dilation and mural nodule. This recommendation was in contrast to the other guidelines ^[56] and based on a single study of patients with less than 2 cm cysts without worrisome features, in whom none were found to develop invasive cancer after a surveillance period beyond 5 years ^[64] [

Although the potential of IPMNs to progress to invasive cancer is clearly recognized, there remains controversy over which guidelines should be followed. The AGA guidelines recommend for the discontinuation of surveillance at 5 years in cysts less 3 cm in the absence of MPD duct dilation and mural nodule. This recommendation was in contrast to the other guidelines [58] and based on a single study of patients with less than 2 cm cysts without worrisome features, in whom none were found to develop invasive cancer after a surveillance period beyond 5 years [119] [

Table 4]. Recent studies have varied. Some larger studies of patients with well-characterized IPMNs have disputed this finding by demonstrating a risk of malignant transformation that persists beyond 5 years and which probably increases over time ^{[18][19][22][65][66][67][68]}. The largest retrospective study to date of 1404 patients with a clinically defined IPMN found an incidence of malignant transformation of 2.9%, 5.9% and 14% at 5, 10 and 15 years, respectively ^[36]. As part of secondary analyses, the authors also demonstrated that patients with low risk BD-IPMN <15 mm, had a cumulative incidence rates of pancreatic carcinoma 2.2%, 4.6%, and 7.4% at 5, 10, and 15 years, respectively ^[36]. In contrast, a recent multicenter study of 806 patients with BD-IPMN ≤15 mm at diagnosis who do not develop worrisome features had an overall risk of malignancy of 1.7% over a 5 year median follow-up, with a cumulative incidence of malignancy of 0.94% at 5 years and 3.37% at 10 years ^[69]. This is similar to other studies that have suggested cysts can be risk-stratified based on size ^[22][70][71]. Regardless, the International Consensus and European guidelines recommend continued surveillance in all patients with an IPMN/MCN, as long as they are fit to undergo surgical resection ^[54][55].

]. Recent studies have varied. Some larger studies of patients with well-characterized IPMNs have disputed this finding by demonstrating a risk of malignant transformation that persists beyond 5 years and which probably increases over time [18,19,22,120,121,122,123]. The largest retrospective study to date of 1404 patients with a clinically defined IPMN found an incidence of malignant transformation of 2.9%, 5.9% and 14% at 5, 10 and 15 years, respectively [39]. As part of secondary analyses, the authors also demonstrated that patients with low risk BD-IPMN <15 mm, had a cumulative incidence rates of pancreatic carcinoma 2.2%, 4.6%, and 7.4% at 5, 10, and 15 years, respectively [39]. In contrast, a recent multicenter study of 806 patients with BD-IPMN ≤15 mm at diagnosis who do not develop worrisome features had an overall risk of malignancy of 1.7% over a 5 year median follow-up, with a cumulative incidence of malignancy of 0.94% at 5 years and 3.37% at 10 years [124]. This is similar to other studies that have suggested cysts can be risk-stratified based on size [22,125,126]. Regardless, the International Consensus and European guidelines recommend continued surveillance in all patients with an IPMN/MCN, as long as they are fit to undergo surgical resection [30,57].

2.3. Surgical Resection in IPMN/MCN

2.3.1. Indications for Surgical Resection

The indications for surgery for patients with IPMN or MCN differ between guidelines but absolute and relative indications for surgery are summarized in

Table 3. The International Consensus guidelines define “high risk features” as obstructive jaundice, MPD as greater than 10 mm, positive cytology or an enhancing mural nodule ≥5 mm. If any of these high-risk features are present, they advocate direct surgical referral without further testing. An EUS is advised if any “worrisome features” are present, which includes; cyst growth rate ≥5 mm over 2 years, increased levels of serum CA19-9, MPD dilation between 5 and 9 mm, cyst diameter ≥30 mm, acute pancreatitis (attributable to the IPMN), enhancing mural nodule of <5 mm, an abrupt change in diameter of MPD with distal atrophy, lymphadenopathy or thickened or enhancing cyst walls ^[54]. The European guidelines, published in 2018, define absolute indications for surgery as positive cytology for malignancy, the presence of a solid mass, obstructive jaundice, an enhancing mural nodule (≥5 mm) or MPD dilatation ≥10 mm. Relative indications for surgery include a growth rate ≥5 mm per year, elevated serum CA19-9 (>37 U/mL), MPD dilatation between 5 and 9.9 mm, cyst diameter ≥40 mm, new-onset diabetes mellitus, acute pancreatitis caused by IPMN or an enhancing mural nodule (<5 mm). If patients have no comorbidity, a lower threshold for surgery is advocated of just one relative indication. In patients with significant comorbidity, more than one relative indication is required to proceed to surgery and if only one relative indication was present, then close surveillance is advised with CA19-9 and MRI with or without an endoscopic ultrasound (EUS) examination ^[55].

. The International Consensus guidelines define “high risk features” as obstructive jaundice, MPD as greater than 10 mm, positive cytology or an enhancing mural nodule ≥5 mm. If any of these high-risk features are present, they advocate direct surgical referral without further testing. An EUS is advised if any “worrisome features” are present, which includes; cyst growth rate ≥5 mm over 2 years, increased levels of serum CA19-9, MPD dilation between 5 and 9 mm, cyst diameter ≥30 mm, acute pancreatitis (attributable to the IPMN), enhancing mural nodule of <5 mm, an abrupt change in diameter of MPD with distal atrophy, lymphadenopathy or thickened or enhancing cyst walls [30]. The European guidelines, published in 2018, define absolute indications for surgery as positive cytology for malignancy, the presence of a solid mass, obstructive jaundice, an enhancing mural nodule (≥5 mm) or MPD dilatation ≥10 mm. Relative indications for surgery include a growth rate ≥5 mm per year, elevated serum CA19-9 (>37 U/mL), MPD dilatation between 5 and 9.9 mm, cyst diameter ≥40 mm, new-onset diabetes mellitus, acute pancreatitis caused by IPMN or an enhancing mural nodule (<5 mm). If patients have no comorbidity, a lower threshold for surgery is advocated of just one relative indication. In patients with significant comorbidity, more than one relative indication is required to proceed to surgery and if only one relative indication was present, then close surveillance is advised with CA19-9 and MRI with or without an endoscopic ultrasound (EUS) examination [57].

The ACR guidelines define absolute indications for surgery as obstructive jaundice, dilated MPD, positive cytology showing cancer, an enhancing nodule or solid mass. Relative indications included an elevated CA 19-9, new-onset diabetes, acute pancreatitis, cyst growth >5 mm per 2 years, MPD 5–9 mm, cyst >4 cm, or enhancing nodule <5 mm ^[58]. ACG has set recommendation for referral to surgery which includes obstructive jaundice, acute pancreatitis, solid mass, MPD >5 mm, cyst >3 cm, change in MPD with upstream atrophy, positive cytology showing cancer and presence of a mural nodule but strongly advocates patients are discussed in a multidisciplinary setting prior to surgery ^[57]. Lastly, the AGA guidelines recommends consideration of surgery if there are two or more of the following features present: dilated MPD, cyst >3 cm, and/or mural nodule. Unlike the other guidelines, the AGA are more conservative and do not recommend resection for MPD dilatation alone, and require the presence of a mural nodule or positive cytology as well ^[56]. Many of the differences in the recommendations between the guidelines arise because they are based on low or very low quality evidence due to a lack of well characterized prospectively followed cohorts of patients with PCL.

The ACR guidelines define absolute indications for surgery as obstructive jaundice, dilated MPD, positive cytology showing cancer, an enhancing nodule or solid mass. Relative indications included an elevated CA 19-9, new-onset diabetes, acute pancreatitis, cyst growth >5 mm per 2 years, MPD 5–9 mm, cyst >4 cm, or enhancing nodule <5 mm [60]. ACG has set recommendation for referral to surgery which includes obstructive jaundice, acute pancreatitis, solid mass, MPD >5 mm, cyst >3 cm, change in MPD with upstream atrophy, positive cytology showing cancer and presence of a mural nodule but strongly advocates patients are discussed in a multidisciplinary setting prior to surgery [59]. Lastly, the AGA guidelines recommends consideration of surgery if there are two or more of the following features present: dilated MPD, cyst >3 cm, and/or mural nodule. Unlike the other guidelines, the AGA are more conservative and do not recommend resection for MPD dilatation alone, and require the presence of a mural nodule or positive cytology as well [58]. Many of the differences in the recommendations between the guidelines arise because they are based on low or very low quality evidence due to a lack of well characterized prospectively followed cohorts of patients with PCL.

2.3.2. Surgery

High-risk cystic lesions in the head or in the uncinate process of the pancreas typically undergo a pancreatoduodenectomy, whereas a distal pancreatectomy with splenectomy is performed for cysts located in the body or tail of the pancreas. A conventional pancreatoduodenectomy involves removing the pancreatic head, duodenum, part of the jejunum, common bile duct, gallbladder as well as performing a partial gastrectomy, and can be performed open or by minimally invasive laparoscopic or robotic approaches. A distal pancreatectomy involves the removal of the body and tail of the pancreas to the left of the superior mesenteric artery and vein and can also be accomplished using open or minimally invasive approaches. Surgical resection of an IPMN or MCN is associated with a perioperative morbidity of 20–40% and mortality of 1–3% for pancreatoduodenectomy and <1% for distal pancreatectomy ^[72][73] in high volume centers. Less extensive resections, such as a central pancreatectomy or enucleation, can be performed as a parenchyma-sparing technique. This is a potentially attractive approach because of the potential for improved post-operative pancreatic function. Unfortunately, post-operative morbidity and mortality is similar or higher due to the significant risk of pancreatic fistula. Therefore, this procedure is only performed in select young patients ^[74].

High-risk cystic lesions in the head or in the uncinate process of the pancreas typically undergo a pancreatoduodenectomy, whereas a distal pancreatectomy with splenectomy is performed for cysts located in the body or tail of the pancreas. A conventional pancreatoduodenectomy involves removing the pancreatic head, duodenum, part of the jejunum, common bile duct, gallbladder as well as performing a partial gastrectomy, and can be performed open or by minimally invasive laparoscopic or robotic approaches. A distal pancreatectomy involves the removal of the body and tail of the pancreas to the left of the superior mesenteric artery and vein and can also be accomplished using open or minimally invasive approaches. Surgical resection of an IPMN or MCN is associated with a perioperative morbidity of 20–40% and mortality of 1–3% for pancreatoduodenectomy and <1% for distal pancreatectomy [127,128] in high volume centers. Less extensive resections, such as a central pancreatectomy or enucleation, can be performed as a parenchyma-sparing technique. This is a potentially attractive approach because of the potential for improved post-operative pancreatic function. Unfortunately, post-operative morbidity and mortality is similar or higher due to the significant risk of pancreatic fistula. Therefore, this procedure is only performed in select young patients [129].

Although IPMNs can extend along the MPD or be a multifocal disease, none of the current guidelines currently recommend a total pancreatectomy due to the morbidity associated with patient being rendered diabetic and having definite postoperative endocrine insufficiency ^[54][55]. Despite recommendations, in an international expert survey, around half of the respondents suggested that in certain situations, they would advise total pancreatectomy ^[75], mainly for IPMN with MPD involvement in order to reduce the risk of recurrence. Indications for surgery in BD-IPMN also differ between the guidelines and are summarized in

Although IPMNs can extend along the MPD or be a multifocal disease, none of the current guidelines currently recommend a total pancreatectomy due to the morbidity associated with patient being rendered diabetic and having definite postoperative endocrine insufficiency [30,57]. Despite recommendations, in an international expert survey, around half of the respondents suggested that in certain situations, they would advise total pancreatectomy [130], mainly for IPMN with MPD involvement in order to reduce the risk of recurrence. Indications for surgery in BD-IPMN also differ between the guidelines and are summarized in

Table 4

The International Consensus and AGA guidelines recommend resection of MCN regardless of size whereas the revised European guidelines support surveillance of MCN <40 mm without concerning features, following the same surveillance intervals as for a BD IPMN ^[54][56].

Several studies have evaluated the accuracy of the different guidelines at predicting advanced neoplasia based on the recommended indications for surgery in IPMN ^[76][77][78]. These studies recognized that all current guidelines lead to surgical overtreatment of IPMNs. In a comparative study, the AGA guidelines appears to have a significant risk of missing patients with advanced neoplasia (12–45%), although fewer patients would have undergone unnecessary surgery ^[76][77]. Our center, like many other large hepatopancreaticobiliary centers, broadly follows the International Consensus and European guidelines and discusses each patient with high-risk or worrisome features at a regular multidisciplinary meeting prior to surgical resection ^[79].

Several studies have evaluated the accuracy of the different guidelines at predicting advanced neoplasia based on the recommended indications for surgery in IPMN [131,132,133]. These studies recognized that all current guidelines lead to surgical overtreatment of IPMNs. In a comparative study, the AGA guidelines appears to have a significant risk of missing patients with advanced neoplasia (12–45%), although fewer patients would have undergone unnecessary surgery [131,132]. Our center, like many other large hepatopancreaticobiliary centers, broadly follows the International Consensus and European guidelines and discusses each patient with high-risk or worrisome features at a regular multidisciplinary meeting prior to surgical resection [134].

2.3.3. Follow Up after Surgery and Predictors of Recurrence

IPMNs without invasive cancer, recur even after surgery in contrast to MCNs, which do not recur. In a study of 130 patients followed for a median of 38 months, 17% developed imaging evidence of a new or progressive IPMN. Eight percent ultimately underwent a completion pancreatectomy and of those 27% (3 patients) had invasive cancer. In addition, two further patients developed metastatic pancreatic adenocarcinoma and did not undergo resection. All 5 patients (4%) that developed cancer had negative margins after the initial operation. The presence of a negative margin did not significantly affect whether patients developed a recurrence of IPMN. A family history of pancreatic cancer was predictive of developing a new IPMN (23% vs. 7% (

p < 0.05)). The chances of developing a new IPMN at 1, 5, and 10 years after the initial surgery was 4%, 25%, and 62%, respectively, and the estimated chances of developing invasive cancer at 1, 5, and 10 years after surgery was 0%, 7%, and 38%, respectively ^[80]. In a multicenter study of 126 patients undergoing resection for a non-invasive IPMN, followed for a median of 9.5 years, a family history of pancreatic cancer (hazard ratio 3.05) and high-grade IPMN (hazard ratio 1.88) were risk factors for recurrence. Again, a positive margin alone was not predictive of recurrence, but the extent and grade of dysplasia at the margin did significantly predict recurrence. Of note, 74% of recurrences occurred after 3 years and 32% after 5 years, supporting long-term surveillance post resection ^[81].

< 0.05)). The chances of developing a new IPMN at 1, 5, and 10 years after the initial surgery was 4%, 25%, and 62%, respectively, and the estimated chances of developing invasive cancer at 1, 5, and 10 years after surgery was 0%, 7%, and 38%, respectively [135]. In a multicenter study of 126 patients undergoing resection for a non-invasive IPMN, followed for a median of 9.5 years, a family history of pancreatic cancer (hazard ratio 3.05) and high-grade IPMN (hazard ratio 1.88) were risk factors for recurrence. Again, a positive margin alone was not predictive of recurrence, but the extent and grade of dysplasia at the margin did significantly predict recurrence. Of note, 74% of recurrences occurred after 3 years and 32% after 5 years, supporting long-term surveillance post resection [136].

The European guidelines advocate that patients undergoing a resection of a BD-IPMN with LGD or Intermediate grade dysplasia (IGD) be followed in the same way, as an unresected IPMN and surveillance should be continued as long as patients are fit to undergo a completion pancreatectomy. For patients with HGD, MT IPMN or MD IPMN, follow-up with cross-sectional imaging of the remnant pancreas every 6 months for the first 2 years is recommended, followed by yearly surveillance after that, as long as imaging findings are stable ^[55]. The International Consensus guidelines advocate enhanced follow- up with at least twice a year imaging in patients with a family history of pancreatic cancer, a surgical resection margin with HGD, and a resected IPMN of a no intestinal subtype. A follow-up every 6 to 12 months in all other patients with resected IPMNs is recommended ^[54] An IPMN-associated cancer should be followed up in the same way as follow-up for PDAC after pancreatectomy ^[55] which involves undertaking cross sectional imaging and measuring CA19-9 every 3–4 months ^[82].

The European guidelines advocate that patients undergoing a resection of a BD-IPMN with LGD or Intermediate grade dysplasia (IGD) be followed in the same way, as an unresected IPMN and surveillance should be continued as long as patients are fit to undergo a completion pancreatectomy. For patients with HGD, MT IPMN or MD IPMN, follow-up with cross-sectional imaging of the remnant pancreas every 6 months for the first 2 years is recommended, followed by yearly surveillance after that, as long as imaging findings are stable [57]. The International Consensus guidelines advocate enhanced follow- up with at least twice a year imaging in patients with a family history of pancreatic cancer, a surgical resection margin with HGD, and a resected IPMN of a no intestinal subtype. A follow-up every 6 to 12 months in all other patients with resected IPMNs is recommended [30] An IPMN-associated cancer should be followed up in the same way as follow-up for PDAC after pancreatectomy [57] which involves undertaking cross sectional imaging and measuring CA19-9 every 3–4 months [137].

A systematic review of 13 studies with 773 patients with a MCN, found no risk of recurrence after resection of MCN without pancreatic cancer ^[34]. Thus, patients with surgically resected MCN whether with LGD or HGD, do not require surveillance. Patients with invasive cancer arising from a surgically resected MCN have a 25% risk of cancer recurrence ^[62]. Therefore, the International Consensus and European guidelines advocate patients with an MCN- associated cancer should be followed in the same way as those with an IPMN-associated cancer or pancreatic cancer after a partial pancreatectomy ^[54][55].

A systematic review of 13 studies with 773 patients with a MCN, found no risk of recurrence after resection of MCN without pancreatic cancer [29]. Thus, patients with surgically resected MCN whether with LGD or HGD, do not require surveillance. Patients with invasive cancer arising from a surgically resected MCN have a 25% risk of cancer recurrence [84]. Therefore, the International Consensus and European guidelines advocate patients with an MCN- associated cancer should be followed in the same way as those with an IPMN-associated cancer or pancreatic cancer after a partial pancreatectomy [30,57].

2.4. Cyst Ablation

While surgery is the only curative treatment for resectable high-risk IPMNs or MCNs, it is associated with significant morbidity and mortality. In addition, despite current recommendations, approximately 25% of patients who have a presumed IPMN or MCN surgically resected are ultimately found to have a cyst with no malignant potential ^[83]. This is even more prevalent in resected BD IPMN where up to 78% do not have high-grade dysplasia or invasive cancer ^[84]. There has therefore been a growing interest in minimally invasive alternative approaches, especially for those patients who are elderly or have high-risk surgical candidates ^[85][86]. One such method is cystic ablation of the PCL.

While surgery is the only curative treatment for resectable high-risk IPMNs or MCNs, it is associated with significant morbidity and mortality. In addition, despite current recommendations, approximately 25% of patients who have a presumed IPMN or MCN surgically resected are ultimately found to have a cyst with no malignant potential [138]. This is even more prevalent in resected BD IPMN where up to 78% do not have high-grade dysplasia or invasive cancer [139]. There has therefore been a growing interest in minimally invasive alternative approaches, especially for those patients who are elderly or have high-risk surgical candidates [140,141]. One such method is cystic ablation of the PCL.

Cystic ablation has primarily been undertaken by injecting alcohol or a chemotherapy agent directly into the cyst under EUS-guidance, with the aim of disrupting the epithelial cyst lining leading to cyst resolution ^{[87][88][89][90][91][92][93][94][95]}. A recent meta-analysis found the pooled rate of complete resolution of cysts treated with alcohol and paclitaxel was 63.6%, but dropped to 32.8% if ethanol alone was used. Adverse events were reported in approximately 15%, mostly due to acute pancreatitis ^[96]. An important limitation of many of the single center studies is that follow up was relatively short ^{[87][88][89][90][91][92][93][94][95]}, but longer-term data is emerging. Choi and colleagues have reported the largest series to date of 164 patients. Patients were followed up for 71 months and complete radiological ablation was achieved in 99% ^[97]. The highest rate of successful ablation has been in MCNs ^[96]. This is likely because there are more septations in serous cystic neoplasms and IPMNs, which stop the fluid diffusing through the whole cyst and limiting the ablation of the epithelial lining. Radiofrequency ablation (RFA) causes tissue destruction by the application of a high frequency alternating current, which generates heat leading to a coagulative necrosis. RFA catheters that can be passed through the working channel of a linear echoendoscope have been developed to enable targeted RFA under EUS guidance. Two small prospective studies, with follow up of less than 12 months, evaluated the safety and efficacy of this technique in the management of PCL. Complete ablation was reported between 33–65%, with adverse events occurring in 0–10% ^[98][99].

Cystic ablation has primarily been undertaken by injecting alcohol or a chemotherapy agent directly into the cyst under EUS-guidance, with the aim of disrupting the epithelial cyst lining leading to cyst resolution [142,143,144,145,146,147,148,149,150]. A recent meta-analysis found the pooled rate of complete resolution of cysts treated with alcohol and paclitaxel was 63.6%, but dropped to 32.8% if ethanol alone was used. Adverse events were reported in approximately 15%, mostly due to acute pancreatitis [151]. An important limitation of many of the single center studies is that follow up was relatively short [142,143,144,145,146,147,148,149,150], but longer-term data is emerging. Choi and colleagues have reported the largest series to date of 164 patients. Patients were followed up for 71 months and complete radiological ablation was achieved in 99% [152]. The highest rate of successful ablation has been in MCNs [151]. This is likely because there are more septations in serous cystic neoplasms and IPMNs, which stop the fluid diffusing through the whole cyst and limiting the ablation of the epithelial lining. Radiofrequency ablation (RFA) causes tissue destruction by the application of a high frequency alternating current, which generates heat leading to a coagulative necrosis. RFA catheters that can be passed through the working channel of a linear echoendoscope have been developed to enable targeted RFA under EUS guidance. Two small prospective studies, with follow up of less than 12 months, evaluated the safety and efficacy of this technique in the management of PCL. Complete ablation was reported between 33–65%, with adverse events occurring in 0–10% [153,154].

Although these initial studies are promising, there continues to be a concern about partial treatment when ablating PCLs. In addition, changes in cyst shape after treatment make it challenging to define complete ablation radiographically. At present, these treatments are only recommended for use within research protocols and formal registries ^[100]. Further studies are required to determine the long-term efficacy and the clinical benefits of these treatments as well as their place in management protocols ^[100].

Although these initial studies are promising, there continues to be a concern about partial treatment when ablating PCLs. In addition, changes in cyst shape after treatment make it challenging to define complete ablation radiographically. At present, these treatments are only recommended for use within research protocols and formal registries [155]. Further studies are required to determine the long-term efficacy and the clinical benefits of these treatments as well as their place in management protocols [155].