Mucinous cystic neoplasms of the liver and pancreas: Relationship between KRAS driver mutations and disease progression

Abstract

Aims

To compare the oncogenic mutation status among mucinous cystic neoplasms (MCNs) of different histological grades and between liver and pancreatic MCNs.

Methods and Results

KRAS, GNAS, RNF43 and PIK3CA were sequenced in 25 surgical cases of hepatopancreatic MCNs. Molecular features were correlated with clinicopathological and immunohistochemical findings. KRAS mutations were identified in 5 cases (20%), while GNAS, RNF43 and PIK3CA were the wild-type in all cases. KRAS mutations were uncommon in cases of low-grade dysplasia (1/20, 5%), while KRAS was mutated in all cases of higher grades, except for one liver MCN with intermediate-grade dysplasia (4/5, 80%; p=0.002). This genetic alteration was slightly more frequent in the pancreas than in the liver (4/17 [24%] vs. 1/8 [13%], p=NS). KRAS-mutated MCNs more commonly showed a multilocular cystic appearance (p=0.040) and the expression of MUC1 (p=0.040), MUC2 (p=0.016), and MUC5AC (p=0.015) than KRAS-wild-type tumours. In cases of KRAS-mutated MCNs with intermediate- or high-grade dysplasia, identical mutations were also detected in areas of adjacent low-grade dysplasia.

Conclusions

KRAS mutations appear to be a major driver genetic alteration in both liver and pancreatic MCNs. Since identical KRAS mutations were present in low- and higher-grade areas in individual cases, KRAS mutations occurring in low-grade MCNs may lead to tumour progression. Thus, preoperative KRAS testing may contribute to estimations of malignant potential. The lower incidence of KRAS mutations in liver MCNs may also explain why the risk of malignant transformation in liver MCNs is lower than that in pancreatic MCNs.

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