RESUMEN
Cytological examination of epithelial cells in cyst fluids from pancreatic mucinous cysts is the optimal method for identifying high-grade atypia (HGA), which may represent histological high-grade dysplasia (HGD) or invasive carcinoma, and thereby classify the cyst as high-risk, warranting surgical resection. Cytological features of HGA were previously described at our institution in 2013 and implemented thereafter, but performance of grading with these criteria has not yet been reported. 1322 pancreatic cyst fluid specimens (2014-2021) were identified; all pathology reports and relevant clinical data were reviewed in detail. 230 unique cysts (217 patients) contained neoplastic mucinous epithelium. Of the 230 cysts, 178 had low-grade atypia (LGA), and 52 had HGA. 97 cysts had histologic follow-up: 77 (79%) were resections and 20 (21%) were diagnostic surgical biopsies only. 92 (95%) were confirmed neoplastic mucinous cysts, 3 were adenocarcinomas, and 2 were benign entities. Among histologically confirmed neoplastic mucinous cysts, 58 had low-grade dysplasia (LGD); 34 had HGD, of which 14 also had invasive carcinoma. A significantly higher proportion of cysts with HGA (63%) demonstrated at least HGD on follow-up compared to those with LGA (26%, p<0.001). The sensitivity and specificity of HGA for accurately classifying a high-risk cyst were 54% and 81%, respectively. 146/230 (64%) cysts had corresponding next-generation sequencing results. 31% of HGA cysts harbored a high-risk mutation (TP53, CDKN2A, and/or SMAD4) vs. 7% of LGA cysts (p<0.001). Among cysts without histologic confirmation, 25% of HGA cysts had a high-risk mutation vs. 7% of LGA cysts. The grade of cytological atypia was predictive of overall survival and recurrence-free survival (p<0.001 and p=0.020, respectively). Implementation of cytological criteria for HGA in pancreatic mucinous cysts has relatively low sensitivity but modest specificity for classifying a high-risk cyst. Though high-risk mutations were more commonly found in cysts with HGA, their frequency is overall low. Thus, evaluating the degree of cytologic atypia, which is predictive of patient survival, provides significant value and informs patient outcomes.
RESUMEN
OBJECTIVE: Elevated pancreatic cyst fluid carcinoembryonic antigen (CEA) has been routinely used to classify mucinous cysts. This study incorporates original data that established the CEA ≥192 ng/mL threshold with over 20 years of additional data and reassesses the diagnostic performance of CEA for differentiating mucinous from non-mucinous cysts. DESIGN: 1169 pancreatic cysts (1999-2021) with CEA results were identified. 394 cases had histological confirmation as the diagnostic standard. Additionally, 237 cysts without histological confirmation demonstrated KRAS, GNAS, or RNF43 mutations by molecular testing and were combined with the histologically confirmed cysts for separate analysis on a total cohort of 631 cysts. RESULTS: Median CEA was significantly higher in mucinous cysts (323.9 ng/mL, n=314) versus non-mucinous cysts (204.6 ng/mL, n=80) (p<0.001). Receiver operating characteristic curve analysis demonstrated an optimal CEA cut-off of 20 ng/mL (area under the curve: 80%), though the specificity was lower than desired (sensitivity 89%, specificity 64%). At the previously established threshold of 192 ng/mL, sensitivity and specificity were 56% and 78%, respectively. To achieve a specificity of 85% as originally reported, a CEA threshold of 250 ng/mL was needed; the 13 false positive cases at this threshold included 4 benign simple cysts, 2 squamoid cysts, 1 serous cystadenoma, 1 lymphoepithelial cyst and 5 more uncommon entities. All results remained similar within the total cohort after including additional cases with KRAS/GNAS/RNF43 mutations only. CONCLUSION: Cyst fluid CEA continues to be a useful test in the diagnosis of mucinous pancreatic cysts but does not appear as specific as previously reported. Raising the CEA threshold to 250 ng/mL to maintain specificity for differentiating mucinous from non-mucinous cysts may be considered.
