Pancreatic cystic neoplasm (PCN), representing 15% to 20% of all pancreatic cysts, is an increasing common clinical entity over these decades, due to the widely use of cross-section imaging. Computed tomography and magnetic resonance imaging (MRI) studies have shown that the prevalence of asymptomatic pancreatic cysts is about 2.5% to 5.0%,[2,3] and increases with age. Approximately 10% of persons with 70 years old or older are now diagnosed with pancreatic cysts.
PCNs are a heterogeneous group of tumors with a broad histologically differential, including benign, premalignant, or malignant lesions.[5,6] The most common entities are serous cystic neoplasms (SCNs), mucinous cystic neoplasms (MCNs), intraductal papillary mucinous neoplasms (IPMNs), and solid pseudopapillary neoplasms (SPN). Previous studies showed that the former 3 subtypes comprised 87% of all cystic lesions of pancreas.
The general risks of PCNs
Patients with PCNs are comprised of a wide range of disease entities from benign to potentially malignant and even to malignant lesions. The general malignant rate of resected PCNs was 12.8% according to a largest cohort containing 2251 cases in China. Understanding the natural history of PCNs and the features of malignant transformation is helpful in identifying patients at risk.
SCNs are normally benign, indolent neoplasms predominating in women, and they may occur anywhere in the pancreas.[9,10] There are essentially no deaths that are attributable to dissemination/malignant behavior of an SCN. Specific mortality due to an SCN is nearly zero. For patients diagnosed as SCNs, follow-up is recommended. Surgical indications for SCNs are still on debate since surgery for SCNs does not have survival benefits but leads to the highest postoperative morbidity among all types of PCNs. The 2018 European guideline proposed that surgery is recommended only in patients with symptoms related to the compression of adjacent organs (i.e., bile duct, stomach, duodenum, portal vein). Previous studies also suggested surgery when the lesion has a large tumor size, locates in the head of the pancreas, or grows quickly. Malignancy in SCNs is limited to approximately 30 case reports in the worldwide literature, representing <1% of all SCNs. However, some cases reported as “malignant”[14,15] do not fulfill the WHO criteria for an SCN. Thus, whether malignant SCNs are truly SCNs is doubted. This argument supports the fact that SCNs are low-risk PCNs once they are clearly diagnosed (Table 1).
IPMNs are mucin-producing cystic tumors, classified as premalignant lesions. They might be the most heterogeneous group of PCNs. The behavior of IPMNs can be considered benign, “borderline” or malignant according to the different grade of dysplasia of the involved cells. On the basis of the relationship between the lesion and the pancreatic duct, IPMNs can be divided into 3 subgroups: branch duct (BD)-IPMNs, main duct (MD)-IPMNs, and mixed type (MT)-IPMNs. The malignancy rate of BD-IPMNs was 3% to 25%, while that of MD/MT-IPMNs reached 33% to 60%. Therefore, IPMNs always have to be considered as potential precursors of pancreatic ductal adenocarcinoma (PDAC). There are several guidelines discussed the various methods to identify the potential patients at risk. Since pancreatic surgeries often involved multiple organs and have more postoperative complications, strict surgical indications should be selected. The International Association of Pancreatology International Consensus Guidelines (2017 Revised Fukuoka consensus) proposed the “worrisome features” (including (i) cyst >3 cm, (ii) enhancing mural nodule <5 mm, (iii) thickened/enhancing cyst walls, (iv) MD size 5–9 mm, (v) abrupt change in caliber of pancreatic duct with distal pancreatic atrophy, (vi) lymphadenopathy, (vii) increased serum level of CA19-9, (viii) cyst growth rate >5 mm/2 years) and “high-risk stigmata” (including (i) obstructive jaundice in a patient with cystic lesion of the head of the pancreas, (ii) enhancing mural nodule >5 mm, (iii) main pancreatic duct >10 mm) to select patients at risk who require surgeries.
MCNs represent 25% of all resected PCNs and defined by the presence of ovarian stroma, with common locations in the pancreatic body and tail.[5,19] MCNs harbor a risk of malignancy, with estimates ranging from 10% to 50%. Since the natural history of MCNs still remains poorly understood, surgical resection is recommended for all surgically fit patients in previous guidelines.[20,21] However, a multicenter study doubted this aggressive recommendation. And the European Study Group on Cystic Tumors of the Pancreas suggested that resection is recommended for MCNs ≥ 40 mm, MCNs which are symptomatic or have risk factors (e.g., mural nodule) irrespective of the size.
SPNs are relatively rare in PCNs on a worldwide scale. While in a Chinese study, SPNs represent 31.7% of 2251 resected PCNs, becoming the most common subtype of PCN in China. Previous studies showed SPNs have female dominance with a ratio of 10 : 1 and a mean age of 22 years old. SPNs have a relatively favorable prognosis and usually have low malignant potential in young females while appear more aggressive and with a higher malignant risk in older patients, especially in males. In 2010, WHO classified SPNs as potentially malignant neoplasms. Surgery is recommended for all surgically fit patients when diagnosis is made.
There are other rare types of PCNs such as cystic neuroendocrine carcinoma, cystic ductal adenocarcinoma. More cases and years of fellow-up need to be collected to know more about these uncommon PCNs.
Differential diagnosis is the key to identify patients at risk
Making an accurate diagnosis of PCNs is important because different types of PCNs have distinct possibility of malignant transformation. Some of them may even develop pancreatic ductal adenocarcinoma. Thus, a correct diagnosis of PCNs offers a potential opportunity for the prevention or early detection of pancreatic cancer. Meanwhile, the accuracy of diagnosis is critical since different types of PCNs are treated differently. However, the diagnosis of PCNs is intricate, and the accuracy reported in previous studies varies greatly among different centers, although it was quite low. The general accuracy of diagnosis in 16 top pancreatic centers in China was only 33%, with MCNs and SCNs as low as 15%. One previous study reported a misdiagnosis rate of 53%, of which 27% was truly clinical mistakes. In addition, even an accurate diagnosis is finally made, it is still controversial whether patients require additional analysis, surgery, or surveillance.
Although different imaging features and molecular features have been identified and summarized, some features have low specificity, leading to a dilemma to distinguish among the types. The accuracy of diagnosis of SCNs was reported relatively low among the 4 types in resected cases.[26,27] Mainly because they were misdiagnosed as IPMNs or MCNs according to the imaging studies, which led to inappropriate surgeries. While the accuracy of preoperative diagnosis is relatively high in patients with SPNs and IPMNs.
Besides the accurate preoperative diagnosis, it is also necessary to identify the risk features of malignancy, such as “worrisome features” and “high-risk stigmata” of IPMNs. Since only a part of PCNs will ultimately develop into invasive PDAC, this can help make better discussions on management.
Current experience and evidence in selecting PCN patients at risk
Currently, most physicians follow guidelines for selection of high-risk PCN patients. The parameters usually under consideration include imaging features, tumor size, main pancreatic duct (MPD) diameter, tumor markers (serum or cyst fluid), symptoms, and cytology. In some reports, even age, tumor location, diabetes, and weight loss were included.[28,29] These parameters, no matter was used alone or in combination, showed high inaccuracy or under debate in selecting PCN patients at risk. Even the clinical guidelines for PCNs are inconsistent in predicting malignancy. For instance, the Sendai consensus guideline showed high sensitivity (87%) and low specificity (28%), while the Fukuoka consensus guideline showed low sensitivity (40%) but extremely high specificity (96%) for prediction of malignant mucinous PCNs. Combination of the 2 guidelines, as well as CA19-9 incorporation may generate an improved model with both clinically accepted sensitivity and specificity for identification of malignant PCNs.
Cyst fluid analysis, especially amylase and tumor markers (e.g., CA19-9 and carcinoembryonic antigen [CEA]) is still prevalent in making differential diagnosis and risk prediction. People believe IPMNs are communicable with pancreatic ducts and should demonstrate a high level of amylase in cyst fluid. Unfortunately, evidence clearly showed that the amylase levels are similar between IPMNs and MCNs.[31,32] Up to 7% of MCNs communicate with the pancreatic duct because of a fistula between cysts and the pancreatic ducts.[33,34] More tiny and MRI-invisible fistulas may exist between non-IPMNs and the pancreatic ducts. Our group also found 2 cases of SCNs communicating with main pancreatic duct. Pancreatic cancer and pancreatic neuroendocrine tumor (PNET) can also manifest considerably high levels of amylase, and importantly, there is no clear threshold of the amylase level for differentiating any types of PCNs.[33,34] On the other hand, IPMNs can also have a low level of cyst fluid amylase. Therefore, amylase test in cyst fluid can only suggest possible communication between cysts and the pancreatic ducts but has very limited value in defining the type of PCNs. Tumor markers may support the warning of malignant or potentially malignant PCNs; however, a low level of tumor markers cannot exclude malignancy.
Much attention has been paid to the size of cysts/tumors since some evidence indicated that large or fast-growing cysts/tumors were more likely to be malignant or become malignancy in near future. Typically, 3 retrospective studies from France, South Korea, and the United States supported that cyst growth rate was associated with increased risk of malignancy in BD-IPMNs, although the criteria of cyst growth rate varied.[35–37] In contrast, another 2 reports also from South Korea and the United States argued that cyst growth rate itself was not a reliable predictor of malignancy.[38,39] These retrospective researches had bias and the volume was relatively small. Recently, 2 large-scale, long-term follow-up, prospective studies suggested that cyst growth was an independent risk factor of malignancy in IPMN.[40,41] Therefore, large or fast-growing IPMNs should be treated with cautiousness. For SCNs, however, although they can grow especially after 7 years postdiagnosis, there is no evidence that large SCNs have higher malignant potential.
In summary, worrisome features in imaging and tumor markers in cyst fluid are commonly used for identifying PCN patients at risk in current clinical practice. However, the misdiagnostic rate is very high, and thus, novel modalities are urgently needed.
Promising approaches to change the current modality to select high-risk PCN patients
Due to the unsatisfying accuracy of identifying high-risk PCN patients using the current methods, many novel approaches have been developing. The strategies ranged from peripheral blood test, imaging, and biochemical tests of cystic fluid to the next-generation sequencing (NGS). Taking advantage of many clinical parameters, Masica et al using the Multivariate Organization of Combinatorial Alterations algorithm to test millions of feature combinations in a large cohort with more than 1000 PCN patients, and found several composite markers much better than current guidelines. Lan et al, considering that high-risk PCNs could induce inflammatory like malignant tumors, revealed that neutrophil-to-lymphocyte ratio (NLR) higher than 1.976 was an independent risk factor for malignant PCNs. An accuracy of 86.1% was acquired when a combination of NLR, CA19-9 and presence of enhanced solid component was used. Permuth et al analyzed circulating long non-coding RNAs (lncRNAs) in PCN patients’ plasma and developed an 8-lncRNA signature with greater accuracy than standard clinical and radiologic features in selecting malignant IPMNs. The area under curve (AUC) was as high as 0.924 when using a combined model containing the 8-lncRNA signature and conventional clinical features such as jaundice and radiomics.
Tests of cyst fluid make more sense but needs an invasive procedure, typically endoscopic ultrasonography (EUS). EUS with or without fine needle aspiration was much more popular in the Western countries than China. Endoscopic Ultrasonography guided fine-needle aspiration (EUS-FNA) is limited in use becasue of the risk of bleeding, dissemination and fluid spillage. Since tumor markers like CA19-9 and CEA are not accurate enough to differentiate high-risk patients, many other molecules were evaluated by investigators. The most promising molecules are glucose and vascular endothelial growth factor A (VEGFA). The glucose level in cyst fluid is significantly lower in MCNs, IPMNs, and pancreatic ductal adenocarcinoma than that in other PCNs including SCNs, cystic neuroendocrine tumor (NET), pseudocyst, and SPNs. The glucose level itself has an accuracy of 90%, however, when combined with the CEA level, it has an accuracy of 93% with AUC of 0.95 to identify MCN and IPMN. The decreased level of glucose may be because the increased glycolytic activity in potentially malignant PCNs. Since most mucinous pancreatic cysts are malignant or potentially malignant PCNs, researchers found that specific glycoforms of MUC5AC and endorepellin in cyst fluid was capable of distinguishing mucinous cysts from nonmucinous cysts, with an accuracy of 87% to 96%.[46,47] Unfortunately, the detection method is somewhat complicated. Surprisingly, interrogators found that the level of VEGFA was dramatically higher in SCNs than other PCNs, although the underlying reasons were unclear. When combined with CEA, the sensitivity and specificity of VEGFA for SCNs are 95.5% and 100%, respectively, with an astonishing AUC of 0.993. Most importantly, the cutoff value (8500 pg/mL) of VEGFA to differentiate SCN is very clear and is convenient for clinical practice. In addition, VEGFA is very easy to be tested, with low cost.
PCNs have special genetic mutations, nearly all of which are related to the E3 ubiquitin pathway. In detail, SPNs typically harbor mutated CTNNB1, and SCNs normally have VHL gene alterations. While IPMNs and MCNs are frequently associated with KRAS and RNF43 mutations, IPMNs have additional GNAS mutations. KRAS, RNF43, and GNAS are all frequently mutated genes in pancreatic cancer, consistent with the fact that IPMNs and MCNs are more malignant than SCNs and SPNs. Therefore, detection of these genetic mutations is reasonable to differentiate types of PCNs and find high-risk patients. For PCN differential diagnosis, NGS perfectly beat convectional modalities, demonstrating 100% sensitivity and 100% specificity for selecting IPMNs with advanced neoplasia. The performance (89% sensitivity and 100% specificity) was also quite good to identify both IPMNs and MCNs with advanced neoplasia. However, the test costs $750 for each patient and needs special facilities. Thus, this approach, although useful, is uneasy to be generalized to a great extent in real-world conditions.
For a certain type of PCNs, somatic mutations may select high-risk patients by predicting prognosis, but this is still under debate. For example, IPMNs with GNAS rather than KRAS/NRAS/HRAS mutations are associated with a better prognosis. While some authors found no association between GNAS and IPMN prognosis, the high expression of phosphorylated substrates of protein kinase A (PKA), which was activated by GNAS-activating mutations, predicts a poor prognosis.[53,54] Similarly, KRAS mutations in IPMNs do not correlated with dysplasia grade, invasion, or survival. In MCNs, however, recurrent KRAS alterations suggest high-risk lesions since mutant KRAS was detected in nearly all (>80%) high-grade dysplasia MCNs and in only 5% to 19% of low-grade dysplasia MCNs.[56–58] Thus, the roles of certain gene mutations in risk screening in PCN patients are context-dependent.
These promising approaches shed light on the future of differential diagnosis and risk classification of PCNs, although most of them need further validation using independent, large-volume cohorts.
The correct approach to efficiently select patients at risk
To identify high-risk PCN patients efficiently, a good clinical strategy and high-performance methods are both warranted. We proved that multidisciplinary team (MDT) discussion greatly improved the accuracy of diagnosis of PCNs. Based on MDT, the general accuracy of diagnosis could be increased from 20.8% to 71.7%. Our experience suggest that MDT is an independent way to increase accurate diagnosis since no special approaches were used in our study. Given the significantly improved sensitivity and specificity of novel approaches, the effects of MDT can be further highlighted. Therefore, we appeal to academic centers to verify and use the upmentioned or other novel approaches for assistance of differential diagnosis based on their conditions and preference, and regularly perform MDT discussion for PCN diagnosis and high-risk patient identification.
Identification of high-risk PCN patients is critical for PCN management, and differential diagnosis is the footstone for risk classification. Novel approaches have been developing with quite good sensitivity and specificity for selecting high-risk patients. MDT combined with novel approaches is the promising way to the best PCN management.
QZ and YC have contributed equally to the article.
Conflicts of interest
The authors declare no conflicts of interest.
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