Pancreatic cystic neoplasms and how to avoid them

Investigations to determine the specific type of undefined pancreatic cystic lesion are only indicated if the results will actually change clinical management. Computed tomography (CT), magnetic resonance imaging and cholangiopancreatography (MRI/MRCP) are effective techniques for the identification of PCNs, with MRI and MRCP being the most frequently utilizedutilised.⁴ However, the accuracy of these methods remains relatively low for identifying the specific type of PCN. In the absence of a specific diagnosis established by cross-sectional imaging, further investigations are not indicated if the results will not change clinical management. This may be the case if there is a clear indication or contraindication for surgery or follow-up, or in cases where there are extremely small and undetermined cysts with no indication for surgery.^2,3

While the analysis of cyst fluid carcinoembryonic antigen (CEA), glucose levels and cyst fluid amylase or lipase can enhance the accuracy of endoscopic ultrasonography (EUS) for differentiating mucinous from non-mucinous PCNs, the diagnostic accuracy of these biomarkers yet is insufficient to establish the specific PCN type and the likelihood of these cysts being malignant (low vs. high grade vs. invasive tumours).^6–10 In particular, cyst fluid CEA and glucose levels are unable to differentiate between mucinous cystic neoplasms (MCN) and intraductal papillary mucinous neoplasms (IPMN), nor between benign mucinous cysts and those with high-grade dysplasia or cancer.^6–9 New tools utilising DNA, miRNA, proteins, and cytokines in the cyst fluid are currently being evaluated as potential replacements or integrations for the existing biomarkers.^11–13 Nevertheless, despite demonstrating considerable promise, these tests have yet to demonstrate an acceptable level of cost-effectiveness for routine clinical use.

EUS-guided fine needle aspiration (FNA) and biopsy (FNB) are only indicated when there are unclear CT and MRI findings and their result is expected to alter clinical management.^2,3 Compared to EUS alone, the utilisation of cyst fluid cytology after EUS-FNA has been demonstrated to enhance the accuracy of differentiating between mucinous and non-mucinous PCN, as well as benign and malignant PCN.^14,15 However, it is important to note that the sensitivity of cytology is markedly reduced in this context.¹⁶ It is, therefore, imperative that clinicians always explicitly delineate the rationale for performing EUS-FNA-FNB and engage in a multidisciplinary discussion when there are any uncertainties regarding the appropriateness of the procedure.

The surveillance of PCNs is determined by the risk of progression to cancer in comparison to the general population. Patients with a definitive diagnosis of serous PCN do not require surveillance, given the benign nature of these lesions.¹⁷ In contrast, the risk of progression of mucinous PCNs, including MCN and IPMN, to high-grade dysplasia and invasive cancer justifies the initiation of surveillance in all patients who are medically suitable for surgery. In the absence of an indication for surgery, patients with MCN or IPMN should be subjected to long-term follow-up for a minimum of five years. If the lesions remain stable and do not exhibit any malignant characteristics, and the patient is aged 75 or above or has a limited life expectancy, surveillance can be discontinued, as it offers no advantage in cancer prevention compared to healthy controls.^18–20

In the absence of definitive indications for surgical intervention, it is recommended that patients with PCN be offered appropriate surveillance tailored to their age, comorbidities, and the specific characteristics of their PCN.^2,3 The majority of PCNs will manifest their biological behaviour through the dynamic evaluation over time. Once PCN stability is warranted, the risk of malignancy decreases significantly, reaching a level that is less than that of a major pancreatic resection (mortality of 3% at high-volume institutions).^18,21 Liberal policies for surgical resections at baseline are at high risk of diagnostic errors and can be harmful, as they are frequently not necessary.

In patients with IPMN who are suitable for surgical intervention, there are several indications for surgery that are considered absolute (Table 2, Figure 1).²² In the presence of one relative indication for surgery (Table 2), surveillance is an acceptable option for patients with significant comorbidities or a short life expectancy. However, this approach is less appropriate for those with no significant comorbidities or two or more relative indications for surgery.^2,3 It is also important to highlight that the greater the number of relative indications for surgery, particularly if developed during surveillance, the higher the probability of malignancy.^23,24

Table 2 | Indications for surgery in patients with IPMN.

Figure 1. Pancreatic cystic neoplasm (yellow arrow) with contrast-enhancing mural nodule (white arrow) at contrast-enhanced endoscopic ultrasound. Image courtesy of J.E. Domínguez-Muñoz.

Given the potential for IPMN or MCN to evolve into high-grade dysplasia or invasive cancer over time, the possibility of developing clinical or morphological indications for surgery may arise even after the initial control, which is typically conducted after six months. It is therefore recommended that surveillance of patients with IPMN or MCN who do not require surgery should not be interrupted following the initial followup.^2,3,25 Particular attention should be paid to lesions that have evolved after six months, as well as to MCN in young female patients who are planning to give birth, as MCN can significantly grow under hormonal stimulation during pregnancy.²⁵

High-grade dysplasia should represent the optimal surgical target for IPMN under surveillance. Given the relevance of the risk of cancer associated with IPMN for patients who have absolute or relative indications for surgery, resection of IPMN in those patients should not be delayed once they are under regular surveillance.^2,3 In contrast, although malignancy cannot be definitively excluded before histological examination of a surgical specimen, the risk of high-grade dysplasia or cancer in patients with IPMN is low in the absence of risk factors.²⁰ The advent of novel techniques such as cyst fluid molecular analysis and radiomics is poised to revolutionise this field in the near future.^{11,13,26–30} The accurate identification of lesions at an increased risk of malignant transformation will allow the performance of surgery in a more timely manner and on a smaller number of patients; in addition, it will permit the avoidance of surveillance in those at minimal risk of malignant progression.

A parenchyma-sparing pancreatectomy is a non-oncological procedure, with a morbidity rate comparable to, or even higher than, that of an oncological pancreatic resection.^31,32 It is, therefore, contraindicated in patients who have a surgical indication for IPMN, given their increased risk of cancer or high-grade dysplasia. The recommended surgical approach for IPMN is an oncological resection with standard lymphadenectomy. In this context, intraoperative frozen section analysis at the resection surface of the pancreas is imperative for the accurate delineation of the extent of the resection. The utilisation of intraoperative pancreatoscopy following the surgical resection of an MD-IPMN is an effective method for reducing the risk of leaving behind "skip lesions" within the remaining pancreas.^33,34

It is recommended that every PCN be evaluated at centres with high expertise in pancreatic disorders and the availability of a multidisciplinary evaluation of cases.^2,3 Following an appropriate diagnostic work-up, small cysts may remain unclassified in terms of their specific type. Despite that, an undefined cyst may be mucinous, and the risk of malignant transformation may be significant. For this reason, the criteria for surgical resection or surveillance of undefined cysts may be based on the same general rules that are defined for branch duct IPMN (BD-IPMN).^2,3 Nevertheless, undefined small pancreatic cysts are common and frequently have no impact on patient survival in the absence of any risk factor for malignancy. Therefore, it is recommended that each cyst undergo a preliminary follow-up after six months to detect even minimal change. Subsequently, the surveillance strategy should be tailored according to the presumptive diagnosis, the size of the cyst, and the patient’s clinical condition.