Guidelines for the Diagnosis and Management of Pancreatic Cystic Neoplasms

Based on the latest developments in diagnostic modalities and a review of current guidelines, including the AGA, The IAP, and the European Study Group on Cystic Tumors of the Pancreas (European), this report discussed recommendations for the diagnosis and management of pancreatic cystic neoplasms (PCN).

Based on the latest developments in diagnostic modalities and a review of current guidelines, including the American Gastroenterological Association (AGA), The International Association of Pancreatology (IAP), and the European Study Group on Cystic Tumors of the Pancreas (European), this report discussed recommendations for the diagnosis and management of pancreatic cystic neoplasms (PCN). This review was published in Nature Reviews Gastroenterology & Hepatology.

The investigators summarized existing diagnostic and follow-up strategies and indications for surgery, highlighting important differences in the existing guidelines, and addressed new developments in the management of patients with PCN. The primary goal of these guidelines is to prevent malignancy and alleviate symptoms; recommendations of surveillance and surgical resection are made on the basis of symptoms and perceived risk of malignancy.

Recommendations for Classification of PCN

PCN are classified as either mucinous or nonmucinous cystic neoplasms. While the World Health Organization (WHO) recommends a 3-tiered system for grading dysplasia (low-grade, borderline-grade, and high-grade), the investigators suggest a 2-tiered grading system may improve concordance in reporting and alignment with clinical consequences in which PCN should be graded as either low-grade or high-grade dysplasia.

Intraductal papillary mucinous neoplasms (IPMN) are further classified as gastric, intestinal, pancreato-biliary, oncocytic, or mixed based on mucin gene expression, tissue morphology, and cytology. Classification of IPMN is important as each subtype represents a particular risk of malignancy.

Recommendations for Symptoms of PCN

Most PCN are asymptomatic and are incidentally discovered in cross-sectional imaging. In patients that present symptoms, abdominal pain is typical as is acute pancreatitis, which occurs when increased mucin production blocks the main pancreatic duct. Jaundice is another symptom associated with occlusion of the common bile duct from PCN. Atrophy or inflammation resulting in structural damage to the pancreas may lead to endocrine and exocrine dysfunction, which in many cases presents as new-onset diabetes.

Recommendations for Diagnosis of PCN

Diagnostic modalities

The investigators suggest that MRI with MRCP is the preferred method of follow-up for newly diagnosed PCN, as repeated radiation exposure following CT may increase the risk of malignancy. Endoscopic ultrasonography is indicated as an adjunctive modality when concerning clinical features are suspected (nodules, dilation of the pancreatic duct, thickening of the enhancing wall) or to obtain cyst fluid for cytology/biochemical analysis. 

Imaging characteristics

IPMN are typically characterized by morphology and location in which they extend into the main duct, side branch, or both; these types of neoplasms most commonly occur in the head of the pancreas. Mucinous cystic neoplasms, on the other hand, typically arise in the body and tail of the pancreas and appear as unilocular or septated macrocystic cysts.

Serous cystic neoplasms include morphological varieties such as microcystic, macrocystic, mixed, or solid cysts; microcystic neoplasms have a honeycomb-like appearance whereas macrocystic neoplasms are more difficult to distinguish from other PCN. A central calcification or scar is often present in serous cystic neoplasms. Both solid pseudopapillary neoplasms and cystic neuroendocrine tumors most commonly appear as a mixed cystic and solid mass in the pancreas; however, these can both appear as a completely cystic or calcified cystic mass.

New developments in imaging techniques

New secretin-enhanced MRCP used with MRI techniques may improve visualization of pancreatic duct pathology by stimulating the release of pancreatic juices into the ducts to increase size and visibility.

Contrast-enhanced endoscopic ultrasonography can most accurately discriminate between mural nodules and mucin clots with lower false-positive rates than other imaging modalities. Endoscopic ultrasonography is indicated for certain features of concern (cyst diameter ≥30 mm, cyst growth rate ≥5 mm over 2 years, nodule presence, pancreatic duct dilation, thickening of cyst walls, acute pancreatitis) and should be performed by a specialist.

Confocal laser endomicroscopy enables real-time visualization of PCN in which the ability to differentiate between neoplasms is highly specific: findings of serous cystic neoplasms are characterized by a superficial vascular network, IPMN by finger-like papillae, and mucinous cystic neoplasms by single or multiple epithelial layers without papillary configurations. 

Cystic fluid analysis

To differentiate between mucinous and nonmucinous PCN, endoscopic ultrasonography using fine-needle aspiration is a low-risk procedure that enables the identification of extracellular mucin and biomarker analysis. A novel approach for endoscopic ultrasound tissue acquisition involves a through-the-needle forceps device that can obtain samples of the cyst wall or mural nodule, which may improve diagnostic accuracy in the future.

The string sign is the macroscopic technique used to differentiate between mucinous and nonmucinous PCN, in which a string length >3.5 mm of cyst fluid aspirate stretched between the thumb and index finger indicates a mucinous neoplasm. This method is limited by the subjective assessment of results.

Biochemical analysis of the carcinoembryonic antigen (CEA) is thought to be the most useful tumor marker in differentiating between mucinous and nonmucinous pancreatic cystic neoplasms; while the international cut-off value of CEA is 192 ng/ml, the investigators suggest an optimal cut-off value of 20 ng/ml (with 91% sensitivity and 93% specificity). Amylase and glucose levels measured in the pancreatic cyst fluid are additional biomarkers used to identify mucinous PCN and differentiate subtypes. Both of these biomarkers should be further investigated.

DNA testing of pancreatic cyst fluid can identify mutated genes released into the pancreatic cyst fluid following cell death. The mutated genes KRAS and GNAS are highly sensitive and specific for IPMN but not mucinous cystic neoplasms; prevalence of mutations are associated with severity of dysplasia. While DNA testing to differentiate between neoplasm subtypes is promising, further studies are needed to explore how it may be integrated into current management practices.

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Recommendations for Predicting Advanced Neoplasia in IPMN

Enhancing mural nodules in IPMN

The presence of an enhancing mural nodule ≥5 mm has been used as a positive predictor of advanced pancreatic neoplasia in IPMN; however, the investigators suggest a more reliable cut-off size should be obtained using standardized methodology.

Main duct involvement in IPMN

Dilation of the main pancreatic duct is highly predictive for advanced pancreatic neoplasia in IPMN. While current guidelines suggest a dilated pancreatic duct between 5 and 9.9 mm is a positive predictor, the investigators recommend a cut-off diameter of 5 to 7 mm as useful to discern between low- and high-grade dysplasia or invasive cancer; cut-off values should be validated in large prospective studies.

Other characteristics in IPMN

According to current international guidelines, additional characteristics used to predict advanced pancreatic neoplasia in IPMN include the presence of acute pancreatitis, increased levels of serum carbohydrate antigen 19-9 without jaundice, thickened cyst wall, lymphadenopathy, abrupt change in pancreatic duct diameter with distal atrophy, cyst growth ≥5 mm in 2 years or cyst diameter ≥30 mm. In European guidelines, cyst growth ≥5 mm in 1 year or a cyst diameter ≥40 mm, along with new-onset diabetes were predictors of advanced pancreatic neoplasia in IPMN.