Molecular Divergence within Synchronous and Metachronous Intraductal Papillary Mucinous Neoplasms
L Stoll, JK Ryu, E Chen, S Egawa, M Ishida, M Akada, F Motoi, M Unno, RD Schulick, T Furukawa, RH Hruban, A Maitra. Johns Hopkins University, Baltimore; Tohoku University Graduate School of Medicine, Sendai, Japan; Tokyo Women's Medical University, Tokyo, Japan
Background: Intraductal papillary mucinous neoplasms (IPMNs) are cystic precursor lesions of pancreatic adenocarcinoma, and demonstrate a propensity for multifocality. This can present as either synchronous or metachronous IPMNs. The molecular basis for multifocality is poorly defined.
Design: We evaluated a series of six synchronous and five metachronous cases of IPMNs collated from the United States and Japan. In addition to assessment of clinico-pathological features, expression of p53 and Dpc4 was analyzed by immunohistochemistry, and KRAS2 gene sequencing was performed on laser microdissected tissue obtained from one multifocal synchronous and two metachronous IPMNs.
Results: The average age of patients with synchronous IPMNs at presentation was 70 years (61-83 years), with a female predominance (66%). In contrast, the average age at presentation of first metachronous lesion was 66 years (50-75 years), and all patients were male in this series. The pathology of synchronous IPMNs included moderate dysplasia (66%), high-grade dysplasia (carcinoma-in-situ) (17%), and IPMN with invasive carcinoma (17%). The pathology of metachronous IPMNs at first presentation were moderate dysplasia (40%) and high-grade dysplasia (60%); at recurrence, the lesions demonstarted moderate dysplasia (20%), high-grade dysplasia (20%), and IPMN with invasive carcinoma (60%). Neither aberrant loss of Dpc4 expression nor nuclear accumulation of p53 was observed in any of the non-invasive synchronous or metachronous IPMNs. In one metachronous IPMN pair, identical KRAS2 mutations were seen in the primary and its recurrence, while in another metachronous pair, a de novo mutation was observed only in the recurrent lesion. In a multifocal synchronous IPMN, DNA from independently microdissected cysts demonstrated distinct codon 12 mutations (GGT-GAT or GGT-GTT), consistent with independent genetic hits in the same carcinogenic field.
Conclusions: Multifocal IPMN lesions likely represent independent clones of cystic neoplasia in the pancreas, further underscoring the need for continued follow up even in patients with resected non-invasive lesions.
Category: Liver & Pancreas
Wednesday, March 11, 2009 9:30 AM
Poster Session V # 243, Wednesday Morning