Grading Cytological Epithelial Atypia in Pancreatic Mucinous Cysts Predicts Patient Survival: Correlation with Histological, Molecular, and Clinical Follow-Up

M Lisa Zhang; Melanie C Kwan; Martha B Pitman

doi:10.1016/j.modpat.2024.100510

Grading Cytological Epithelial Atypia in Pancreatic Mucinous Cysts Predicts Patient Survival: Correlation with Histological, Molecular, and Clinical Follow-Up

Mod Pathol. 2024 May 3:100510. doi: 10.1016/j.modpat.2024.100510. Online ahead of print.

Authors

M Lisa Zhang¹, Melanie C Kwan², Martha B Pitman²

Affiliations

¹ Department of Pathology, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA. Electronic address: mlzhang@mgh.harvard.edu.
² Department of Pathology, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA.

PMID: 38705280
DOI: 10.1016/j.modpat.2024.100510

Abstract

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.