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Pancreatic cysts are a complex group of benign, malignant, and premalignant lesions with diverse clinical, radiologic, and pathologic features.1, 2 It is no longer believed that the vast majority of pancreatic cysts are pseudocysts, inclusion cysts, or benign neoplastic cysts that do not require follow-up. Our knowledge and understanding of neoplastic pancreatic cysts in general, and mucinous pancreatic cysts in particular, has grown exponentially since the 1980s when intraductal papillary mucinous neoplasm (IPMN) was recognized as a distinct entity from mucinous cystic neoplasm (MCN).3 Our realization that all neoplastic mucinous cysts have malignant potential has led to intensive evaluation of patients with both symptomatic and asymptomatic pancreatic cysts to determine the nature of the cyst and, thus, the possible need for resection.

Now that we are looking closely, we know that pancreatic cysts are extremely common lesions. Approximately 2.6% of asymptomatic adults and >8% of adults aged >80 years who undergo abdominal imaging have a pancreatic cyst.4 The majority of these cysts are incidental cysts, and most are mucinous, but most are not malignant.1, 5, 6 Surgical resection of all pancreatic mucinous cysts is logistically impossible. Imaging may be very helpful for differentiating mucinous from nonmucinous cysts, but nearly 20% of serous cystadenomas are macrocystic with few septations, mimicking a mucinous cyst, whereas IPMNs can cause pancreatitis and simulate the appearance of a pseudocyst.7-9 In addition, imaging is not at all helpful in accurately differentiating low-grade from high-grade dysplastic or even malignant mucinous cysts.10, 11

The current paradigm of preoperative diagnosis uses clinical, radiologic, and pathologic methods to determine high-risk features of malignancy.12-19 One of the first questions to answer in cyst fluid analysis is whether the cyst is mucinous or nonmucinous. Most nonmucinous cysts are serous cysts. Just a few years ago, this distinction alone was sufficient to determine the need for surgery.20 Although serous cysts were resected primarily to relieve symptoms, all mucinous cysts, regardless of type, were resected because of the concern for malignant progression. What became clear from clinicopathologic analysis of these resected mucinous neoplasms was that there were distinct types of mucinous cysts, distinguished by sex, age, location in the pancreas, association with the pancreatic ducts, pathologic features, and likelihood of progression to cancer.1, 5, 7, 21, 22

Most MCNs are usually low-grade neoplasms that do not involve the main pancreatic duct. They are typically large, multiloculated cysts that occur primarily in the body or tail of the pancreas of young to middle-aged women.1, 23, 24 The current recommendation is to resect all MCNs regardless of grade, because intervention at diagnosis avoids long-term, expensive, annual surveillance.6

In contrast, IPMNs are a heterogeneous group of neoplastic cysts arising from the pancreatic ducts. These cysts generally develop in the elderly, and men and women are almost equally affected. IPMNs are distinguished by main-duct versus branch-duct involvement, cyst lining epithelial cell type, and grade of dysplasia.1, 5, 7, 21, 25 Because of the typically older age at diagnosis, patients with IPMNs often have comorbid conditions and require careful consideration of the risk of surgical resection against the risk of malignancy. Branch-duct IPMNs are most often located in the pancreatic head or uncinate process and have a low risk of malignancy that does not justify the morbidity of a Whipple resection, especially in a high-risk surgical candidate. Surgical management guidelines (also called the “Sendai guidelines”) have evolved from the numerous studies that examined the relative risk of malignancy associated with symptoms, cyst size, the presence of a dilated main pancreatic duct as surrogate marker for main duct involvement, the presence of a mural nodule, and cytologic evidence of malignancy.6 The relative risk of malignancy is greater in main-duct IPMNs compared with branch-duct IPMNs, in part because of the greater risk of malignancy associated with the more common intestinal-type cyst lining of main-duct IPMN compared with the more common gastric-type cyst lining of branch-duct IPMN.5, 7, 25 So now, in addition to the challenge of distinguishing mucinous from nonmucinous cysts preoperatively, there is the challenge of accurately subclassifying mucinous cysts and determining the risk of malignancy from preoperative features.

Like any clinical diagnostic test, the analysis of pancreatic cyst fluid should add value in the decision-making process of patient management. In this issue of Cancer (Cancer Cytopathology), Chai et al26 demonstrate that cyst fluid is a vital component of the multimodal approach to the preoperative diagnosis of pancreatic cysts. They provide a volume-based protocol using minimal cyst fluid volumes for the analysis of carcinoembryonic antigen (CEA), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) analysis, and cytology, thus optimizing the use of the often scant cyst fluid volumes obtained during aspiration. This multimodal approach to the preoperative diagnosis of pancreatic cysts has been espoused for years,16, 27 but these authors are the first to demonstrate that supernatant fluid is comparable to the neat fluid and cell block preparation of the cell button for CEA and KRAS testing. Their data confirm prior studies that have established CEA as the most sensitive test for the detection of mucinous cysts.10, 28 KRAS testing of the cyst fluid is valuable when the CEA level is low, because the presence of a KRAS mutation supports the presence of a mucinous cyst.29, 30 In the study cohort reported by Chai et al, 2 of 25 patients were diagnosed with a mucinous cyst in which CEA and cytology were noncontributory. Thus, in these 2 patients, the KRAS test turned a nondiagnostic test into a test that was diagnostic of a mucinous cyst, precluding the need for a repeat biopsy. The authors correctly note, however, that the added value of molecular testing can be small compared with the combination of cytology and CEA testing. It is an expensive test and, as a single positive or negative test, does not add value to determining that a cyst is mucinous over an elevated CEA level ≥192 ng/mL. In addition, a negative test, which may well be falsely negative due to insufficient and possibly nonrepresentative DNA, does not exclude a neoplastic mucinous cyst. A KRAS mutation is helpful in supporting the presence of an IPMN or MCN when the CEA level is not elevated. A recent study has demonstrated that guanine nucleotide protein, alpha stimulating (GNAS) mutations differentiate MCN from IPMN.31 Although, like KRAS, GNAS does not distinguish benign from malignant cysts, this finding may be helpful in patient management, because MCNs are generally resected regardless of grade.

In their report, Chai et al note that the weakness of their study is in the very low histology follow-up confirming the clinicopathologic diagnoses. Only 7 of their 53 patients underwent resection for 4 mucinous cysts and 3 nonmucinous cysts. The 4 mucinous cysts included 2 MCNs and 2 IPMNs, all with low-grade or intermediate-grade dysplasia. The authors do not address the cytologic diagnoses of dysplasia in noninvasive mucinous cysts, which, aside from determining whether a cyst is mucinous or not, is the second challenge for cyst fluid analysis, because it directly impacts patient management. Although imaging can highlight features that correlate with malignancy,11, 28, 32-38 imaging features alone are insensitive for the detection of high-grade (preinvasive) tumors and for distinguishing these from lower grade neoplasms.10, 28 Cytology is the most sensitive test for determining malignancy in pancreatic cysts10; in addition, the specificity for detecting malignancy at the threshold of “positive” for malignancy is extremely high. This high specificity, however, comes at the expense of sensitivity.12, 14 Studies have demonstrated that, despite the scant cellularity of many cyst aspirates, cyst fluids may contain cells that are atypical to suspicious for malignancy.14, 15, 39 Cytologic detection of high-grade dysplasia is the optimal detection point for providing early intervention, either surgically or with cyst ablation therapy.12, 14 Distinguishing intermediate-grade dysplasia (eg, moderate dysplasia or borderline malignancy) from high-grade dysplasia (eg, carcinoma in situ) is not only a challenge for histologic analysis, but it is especially a challenge for cytologic analysis.40 The heterogeneity of the cyst lining typical of most mucinous cysts may cause the cells in the cyst fluid to underestimate the final histologic grade,39 and cellular degeneration coupled with a lack of standardized criteria and pathologist's experience with these types of specimens contributes to the poor performance of cytologic analysis for a “positive” diagnosis. That said, the recognition of high-grade atypia as a whole (at least moderate dysplasia but, more likely than not, high-grade dysplasia or invasive carcinoma)14 is a powerful and more sensitive finding that other high-risk imaging features like mural nodule or dilated main pancreatic duct for the early detection of cancer.12

While further development of more specific markers of cyst type and biologic behavior is awaited, imaging and cyst fluid analysis currently offers the best means of accurately assessing pancreatic cysts preoperatively. This cyst fluid needs proper tissue management and triage for optimal patient care. Chai et al26 offer a protocol for efficient use of the often scant fluid. If cyst fluid analysis does not support a mucinous etiology on the one hand or high-grade dysplasia in a mucinous cyst on the other, then conservative patient management is a viable alternative in asymptomatic patients without high-risk imaging features, especially in poor surgical candidates.

FUNDING SOURCES

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No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

REFERENCES

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  3. REFERENCES
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