Cystic and neuroendocrine neoplasms of the pancreas

Acknowledgement

We would like to acknowledge Saxon Connor who authored the previous version of this chapter.

Introduction

Although pancreatic ductal adenocarcinoma accounts for the majority of pancreatic neoplasms, over the last three decades there has been increasing recognition of cystic and neuroendocrine pancreatic neoplasms. The aim of this chapter is to examine these tumours in more detail, with particular emphasis on intraductal papillary mucinous neoplasms (IPMN) and pancreatic neuroendocrine neoplasms (PanNEN). Where possible, evidence-based recommendations for the investigation and management of these tumours will be provided.

Pancreatic cystic neoplasms

The prevalence of pancreatic cystic neoplasms (PCNs) in the general population ranges from 2.6–18% and 37% in those >80 years old. ^, PCNs represent different biological entities with variable potential for malignant transformation. The quality of modern cross-sectional imaging means that many are diagnosed incidentally (i.e., in asymptomatic patients). The reported prevalence of PCNs in computed tomography (CT) is 2.1–2.6% and for magnetic resonance imaging (MRI) this is 13.5–45%. Table 18.1 shows the World Health Organisation (WHO) Histological Classification of Pancreatic Cystic Tumours, (2010, revised 2020).

Table 18.1

The WHO version 4 (2010) classification of pancreatic cystic neoplasms

Type	Histological classification
Benign	Acinar cell cystadenoma Serous cystadenoma
Premalignant	Intraductal papillary mucinous neoplasms (IPMN) Intraductal tubulopapillary neoplasms Mucinous cystic neoplasms (MCN)
Malignant	Acinar cell cystadenocarcinoma IPMN with an associated invasive carcinoma MCN with an associated invasive carcinoma Serous cystadenocarcinoma Solid pseudopapillary neoplasms

The challenge facing all pancreatic specialists is in establishing the histological diagnosis of the cyst without exposing the patient to unnecessary surgical intervention, whilst ensuring close surveillance of correctly identified pre-malignant lesions and appropriate timing of treatment thereafter.

Diagnosis

Radiology

The reporting accuracy for identifying specific types of PCNs is 40–95% for magnetic resonance cholangiopancreatography (MRCP)/MRI and 40–81% for CT. ^, Although CT and MR have comparable ability to characterise PCNs, MRI is superior in determining whether a cyst communicates with the pancreatic ductal system and internal structure: specifically the presence of nodularity and/or septations. ^, Furthermore, in patients who may require extensive surveillance, there is no associated ionising radiation exposure. CT is however, superior in patients in whom pancreatic parenchymal calcification is suspected, detailed vascular anatomy mapping is required, or in whom staging of suspected malignancy is required.

Endoscopy

Endoscopic ultrasound (EUS) is an important diagnostic adjunct to cross-sectional imaging in the assessment of PCNs. It is recommended in patients in whom imaging has identified worrisome features and surgical resection is being considered. Evidence for EUS-based differentiation between benign and malignant cysts remains mixed, but there is good evidence that the use of contrast-enhanced EUS helps identify hyper-enhancing mural nodules within cysts and that this is reproducible with increased inter-observer agreement. ^,

Cyst sampling

Fine needle aspiration (FNA) of cyst fluid for carcinoembryonic antigen (CEA) can help in differentiating between mucinous and non-mucinous PCNs. Gillis et al. performed a meta-analysis demonstrating a 42% sensitivity but 99% specificity in differentiating between mucinous and non-mucinous cysts in 1115 patients. These results have been replicated elsewhere using a cut off level of CEA level of >192 ng/L. More specific cyst identification (i.e., mucinous cystic neoplasms [MCN] versus IPMN) has not yet been possible with fluid sampling alone for CEA, but there are promising data regarding when fluid is assessed for KRAS/GNAS mutation analysis. In the same meta-analysis, Gillis et al. demonstrated that the combined sensitivity and specificity of cytology and KRAS was 0.71 and 0.88, respectively.

Intraductal papillary mucinous neoplasms

IPMN are defined as grossly visible, mucin-producing epithelial neoplasms of the pancreas. There are three types: main duct (MD-IPMN), branch duct (BD-IPMN) and mixed type. Main duct IPMN is characterised by segmental or diffuse dilation of the main pancreatic duct (MPD) of >5 mm without other causes of obstruction. BD-IPMN are pancreatic cysts >5 mm in diameter that communicate with the main duct. Mixed type meet the criteria for both, and a pancreatic pseudocyst is among the differential diagnoses for those patients with BD-IPMN in whom there is a history of pancreatitis. They are distinguished from MCNs by the absence of ovarian-type stroma.

The incidence is estimated at 2.04 (95% confidence interval [CI], 1.28–2.80) per 100 000 population; however, this increases significantly after the sixth decade of life. The precise aetiology remains unknown, although an association with extra-pancreatic primary cancers (10%), most commonly colorectal, breast and prostate, has been reported, but this is not significantly different to that seen with primary pancreatic adenocarcinoma. IPMN have also been shown to be a predictor of pancreatic cancer as compared to other intra-abdominal pathologies, with an odds ratio of 7.18.

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