WGO Practice Guideline:
Juan Malagelada, Chair (Spain)
Nalini Guda, Co-chair (USA)
Khean-Lee Goh (Malaysia)
Thilo Hackert (Germany)
Peter Layer (Germany)
Xavier Molero (Spain)
Stephen Pandol (USA)
Masao Tanaka (Japan)
Muhammed Umar (Pakistan)
Anton LeMair (Netherlands)
(Click to expand section)
* FNA may not be performed if the lesion is in the pancreatic body or tail if there is any concern about malignancy, due to the risk of seeding along the FNA track that may not be addressed by subsequent surgery. In patients who have lesions in the body or tail, the stomach is not removed, whereas in those with lesions in the pancreatic head, the duodenum is removed at surgery.
WGO cascades: a hierarchical set of diagnostic, therapeutic, and management options to deal with risk and disease, ranked by the resources available.
WGO guidelines and cascades are intended to highlight appropriate, context-sensitive and resource-sensitive management options for all geographical areas, regardless of whether they are “developing,” “semi-developed,” or “developed.” WGO cascades provide options that are not necessarily defined solely by resource priorities and may, for example, also include cost–benefit factors, patient preferences, and the availability of equipment, skills, and expertise.
Most asymptomatic incidental cysts are diagnosed in resource-enabled countries when imaging is being carried out to evaluate symptoms not necessarily related to pancreatic disease. For the Asian–Pacific region, for instance, two recent papers from Korea and Japan—both affluent countries—report asymptomatic cyst incidence rates of 2.2% and 3.5% [1,2]. In low-resource countries, most diagnoses are established at surgery or autopsy.
The authors of this guideline have therefore chosen not to use the conventional “cascade” pattern, but rather to make recommendations based on the current evidence. We understand that all the resources are not available everywhere, and an informed decision should be made in discussion with the patient regarding the risk for malignancy, available resources, and cost.
This guideline aims to provide physicians worldwide with a reasonable, up-to-date approach to the management of pancreatic cystic lesions. Since pertinent diagnostic and therapeutic resources are not uniformly available in different areas of the world, these guidelines are meant to be used as appropriate, with local resources and patient preferences being kept in mind.
“Pancreatic cystic lesions” is a conventional term that refers to a well-defined lesion in the pancreas that contains fluid. Most small lesions are detected incidentally when scanning is performed for evaluation of non–pancreas-related indications or symptoms. The etiology of pancreatic cysts is variable; they may be inflammatory or posttraumatic, or may have no known etiology. While most small lesions are benign, some lesions can lead to malignancy and hence a need for further work-up, surveillance, and management decisions. It is therefore necessary to obtain a good patient history and assess the nature of the lesion through appropriate investigations as needed, in order to assess the risk for malignant progression. Since potentially malignant lesions cannot be distinguished reliably from benign lesions on the basis of the clinical and morphological features alone, further evaluation and/or surveillance may be necessary.
Premalignant cystic lesions of the pancreas include mucinous cystic neoplasms and intraductal papillary mucinous neoplasms. As indicated above, some pancreatic cystic lesions may evolve into adenocarcinoma of the pancreas .
Since pancreatic ductal adenocarcinoma (PDAC) and pseudopapillary tumors rarely present as cystic lesions, they are not covered in the present guideline.
Pancreatic pseudocysts, which lack a definite cyst wall, usually occur in patients who have a history of pancreatitis or trauma. Pseudocysts are benign and often resolve spontaneously without any need for intervention, unless they are symptomatic; they are not the subject of the current guideline. However, it is important to ensure that the lesion is in fact a pseudocyst and not a true pancreatic cyst. While the management of benign or obviously malignant lesions is less ambiguous, treatment for indeterminate-risk or intermediate-risk lesions is unclear, and these guidelines will hopefully provide guidance on the appropriate work-up and management.
Pancreatic cysts are often asymptomatic; they are often benign, but some have malignant potential.
Pancreatic cystic lesions may be classified as:
Pancreatic cystic neoplasms may have a malignant potential; these include MCNs and IPMNs. Alternatively, they may have no malignant potential; these include serous cystic neoplasms (SCNs). Benign cystic lesions may be managed conservatively, while those with a significant malignant potential need surgical intervention .
Table 2 presents the World Health Organization (WHO) histological classification of pancreatic cysts, which also includes solid pseudopapillary neoplasms.
Origin of lesions—relevant to management of precursor lesions:
Many would agree that the main difference between IPMN and PanIN is size: PanIN lesions are microscopic flat or papillary lesions that arise in the small intralobular pancreatic ducts, usually measure less than 5 mm in size, very rarely form cystic structures, and are commonly undetectable on cross-sectional imaging or EUS. Maire et al.  tried to correlate the EUS findings with histopathology in a selected population. When the lesion is larger than 10 mm, IPMN is the preferred term, while below 10 mm the term “dilated side branch” is appropriate. Doubts have been expressed regarding the histological characterization of lesions between 0.5 and 1 cm. Molecular, genetic, or epigenetic markers may be helpful for differentiating between PanINs and IPMNs [3,14].
The following list highlights particularly common potentially confusing appearances that need to be considered in the differential diagnosis:
Most pancreatic cysts are asymptomatic and are discovered incidentally on diagnostic imaging that is carried out for an unrelated symptom or reason. In a minority of cases, the initial presentation may be due to a symptomatic cyst manifesting as acute pancreatitis, bleeding, jaundice, or palpable mass. In areas of the world in which advanced diagnostic imaging technology is unavailable or is applied with more restricted criteria, pancreatic cystic lesions may be discovered at a later stage, but this usually implies a larger size or progression to neoplasia.
In patients with a symptomatic cyst, pain is the most common manifestation. Pain may alert the physician to a greater likelihood for malignancy, except in postpancreatitis pseudocysts, and the risk of malignancy may be related to the duration of symptoms [15,16]. Other symptoms include jaundice, nausea, and vomiting secondary to compression of the stomach, or gastric outlet obstruction secondary to extrinsic compression of the duodenal lumen.
Patients with MCNs may also present with pain, an abdominal mass, or weight loss that may have been present for years before the diagnosis . However, most MCNs are discovered on cross-sectional imaging in otherwise asymptomatic patients.
Patient interview: history and background
Potential clinical presentations related to specific types of cyst: it should be noted that most patients with pancreatic cysts are asymptomatic.
The increasing numbers of patients all over the world with incidentally discovered cysts require further refinement of the recommendations for which imaging should be carried out [6,8].
The approach to pancreatic cysts continues to be problematic, due to the lack of good natural history data, few published studies with long-term follow-up data, and possible bias, since most of the reports are from centers that specialize in the treatment of pancreaticobiliary disorders.
Evolving technologies, such as molecular analysis (molecular markers, genetic testing) with first-line test results (cytology, imaging, and fluid chemistry), may be more accurate in determining the malignant potential of pancreatic cysts than current diagnostic testing methods . To date, however, not all of the available techniques are routinely included in clinical practice.
Patients with pancreatic cystic lesions must be evaluated with sensitivity to:
Conventionally, small lesions (< 2 cm) with uncomplicated features require relatively limited diagnostic evaluation and can be managed with observation and follow-up. At the other end of the spectrum, large lesions with a significant solid component or ductal dilation features may be considered for prompt surgery, in order to avoid circuitous and expensive work-up procedures.
The intermediate group of lesions are those in which a careful, in-depth evaluation may be most appropriate, since surgery carries significant morbidity and mortality risks.
5.2.1 Laboratory Studies
There are no specific serological tests available for assessing cystic lesions of the pancreas; serum CA-19-9 may be elevated in malignant cystic lesions, whereas raised amylase and lipase levels are observed in symptomatic cysts with concomitant pancreatitis. See also Tables 4 and 5.
5.2.2 Imaging Studies
Imaging studies are undertaken to obtain better characterization of cysts. The methods used therefore depend on the initial imaging method that detected the lesion in question.
If resources are constrained, the best choice for assessing pancreatic cysts is CT.
Protocol for CT of the pancreas:
Protocol for magnetic resonance cholangiopancreatography (MRCP) :
Endoscopic ultrasonography (EUS) is highly accurate and:
Endoscopic retrograde cholangiopancreatography (ERCP):
5.2.3 Biopsies – Cyst Fluid Analysis
Fine-needle aspiration can be carried out with EUS guidance for cytological assessment and cyst fluid drainage, in order to distinguish between serous and mucinous lesions. Where available, EUS-guided FNA is the preferred method, in contrast to percutaneous aspiration with CT guidance or ultrasound guidance.
Cyst fluid analysis. When fluid is aspirated, the following tests are recommended in the sequence described, depending on the volume of the aspirate:
Assessing the following risk features is helpful in decision-making between the options of observation versus surgery. Patients with at least two of these risk factors have about a 15% chance of developing pancreatic malignancy:
Other factors may also be predictive of a higher risk of malignancy [31–38]:
In addition, malignancy may develop in the remnant pancreas after partial pancreatic resection for a prior neoplastic lesion, since premalignant changes may be multifocal. There is a 2.8% risk of invasive cancer elsewhere in the pancreas in patients with IPMN, according to Lafemina et al. .
The risks of surgery may be substantial, with a 2% risk of mortality and an up to 40% risk of morbidity, and these should be weighed against the malignancy risks assessed relative to the features listed above. Consideration should always be given to the patient’s age and comorbidities, as these are crucial risk modifiers.
6.1.1 Indications For Specialist Evaluation
Pancreatic cysts may often be incidentally detected on cross-sectional imaging studies ordered as part of the evaluation of nonspecific abdominal or nongastrointestinal symptoms. At this initial discovery stage, a general practitioner, internist, or surgeon may assume the primary responsibility for evaluating the condition.
Uncomplicated cysts that are small (< 2 cm) and do not have any obvious malignant stigmata may not require specialist referral, since observation at the intervals detailed earlier is appropriate.
Evaluation, management, and follow-up can be carried out with observation and surveillance if the diagnosis has been reliably established.
Serous cystadenomas are uniformly benign. Mucinous lesions, however, are considered premalignant. The risk of malignancy appears to be higher in lesions that are larger than 3 cm at the time of diagnosis, in which surgery is therefore recommended. Smaller lesions may be monitored.
Unfortunately, the ability to reliably differentiate between serous and mucinous lesions preoperatively is limited. Traditional radiologic studies such as CT or ultrasound accurately classify only 10–15% of these lesions in some studies. In addition, the cyst wall is often partly denuded, so that even intraoperative biopsy is unreliable. Table 7 lists high-risk stigmata and worrisome features.
The size and growth rate of cysts at follow-up examinations can be used as indicators for resection. If there are no worrisome features at MRI/MRCP , then MRI should initially be repeated after 1 year and subsequently at 2 years.
Some discrepancies have been noted regarding the way in which surveillance should be managed in patients with premalignant pancreatic cystic lesions. From a systematic review and meta-analysis by Choi et al. , it appears that the incidence of progression of low-risk IPMNs (with no main pancreatic duct involvement or mural nodules) to cancer is 1.4% at 3 years, 3.1% at 5 years, and 7.7% at 10 years. The values are higher for IPMNs that have some risk features: 5.7% at 3 years, 9.7% at 5 years, and 24.7% at 10 years. The authors recommend continued long-term surveillance for all types of IPMN .
Indications for surgery [5,48]:
7.3.1 International Guidelines
2018 Gut. European evidence-based guidelines on pancreatic cystic neoplasms . Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890653/
2018 Am J Gastroenterol. ACG clinical guideline: diagnosis and management of pancreatic cysts .
2017 J Am Coll Radiol. Management of incidental pancreatic cysts: a white paper of the ACR Incidental Findings Committee . Available from: https://www.jacr.org/article/S1546-1440(17)30318-6/fulltext
2017 Pancreatology. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas .
2015 Gastroenterology. AGA guidelines for the management of pancreatic cysts .
2015 World J Gastroenterol. International guidelines for the management of pancreatic intraductal papillary mucinous neoplasms . Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566378/
2015 Ann Transl Med [Internet]. International consensus on the management of intraductal papillary mucinous neoplasm of the pancreas . Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671873/
2013 Dig Liver Dis. European experts consensus statement on cystic tumours of the pancreas .
2012 Pancreatology. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas .
2006 Pancreatology. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas .
7.3.2 Regional and Other Guidelines
2015 J Hepatobiliary Pancreat Sci. Revised Japanese guidelines for the management of acute pancreatitis 2015: revised concepts and updated points .
2015 Gastroenterology. American Gastroenterological Association technical review on the diagnosis and management of asymptomatic neoplastic pancreatic cysts .
2015 Gastroenterology. AGA Institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts .
2015 Gastroenterology. AGA guidelines for the management of pancreatic cysts .
2015 Ann Oncol. Cancer of the pancreas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up .
2015 Am J Gastroenterol. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes .
2014 Saudi Med J. Saudi Oncology Society clinical management guideline series. Pancreatic cancer .
2014 RöFo. S3 guideline for chronic pancreatitis—diagnosis, classification and therapy for the radiologist .
2014 Pancreas. American Pancreatic Association practice guidelines in chronic pancreatitis: evidence-based report on diagnostic guidelines .
2014 Jpn J Clin Oncol. EBM-based clinical guidelines for pancreatic cancer (2013) issued by the Japan Pancreas Society: a synopsis .
2014 Dig Liver Dis. Italian consensus guidelines for the diagnostic work-up and follow-up of cystic pancreatic neoplasms .
2014 Diagn Cytopathol. Utilization of ancillary studies in the cytologic diagnosis of biliary and pancreatic lesions: the Papanicolaou Society of Cytopathology guidelines for pancreatobiliary cytology .
2014 Diagn Cytopathol. Postbrushing and fine-needle aspiration biopsy follow-up and treatment options for patients with pancreatobiliary lesions: the Papanicolaou Society of Cytopathology guidelines .
2014 Diagn Cytopathol. Standardized terminology and nomenclature for pancreatobiliary cytology: the Papanicolaou Society of Cytopathology guidelines .
2014 Cancer Cytopathol. Guidelines for pancreaticobiliary cytology from the Papanicolaou Society of Cytopathology: a review .
2013 Am J Gastroenterol. American College of Gastroenterology guideline: management of acute pancreatitis .
2012 J Natl Compr Canc Netw. Pancreatic adenocarcinoma, version 2.2012: featured updates to the NCCN Guidelines .
2012 Ann Oncol. Pancreatic adenocarcinoma: ESMO-ESDO clinical practice guidelines for diagnosis, treatment and follow-up .
2008 Ann Oncol. Neuroendocrine gastro-entero-pancreatic tumors: ESMO clinical practice guidelines for diagnosis, treatment and follow-up .
2005 Ann Surg Oncol. Treatment guidelines for branch duct type intraductal papillary mucinous neoplasms of the pancreas: when can we operate or observe? .
2004 Gastrointest Endosc. ASGE guideline: The role of endoscopy in the diagnosis and the management of cystic lesions and inflammatory fluid collections of the pancreas .
Am J Surg Pathol. An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms .
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