GNAS Codon 201 mutations are uncommon in Intraductal Papillary Neoplasms of the Bile Duct

Aims: Activating point mutations of GNAS at codon 201 have recently been detected in approximately two-thirds of Intraductal Papillary Mucinous Neoplasms (IPMNs) of the pancreas. Intraductal papillary neoplasms of the bile ducts (IPNBs) morphologically resemble pancreatic IPMNs. Thus, we sought to assess the mutational status of GNAS at codon 201 in IPNBs.

Methods: Thirty-four patients from three institutions were included and DNA from microdissected IPNBs was subjected to a sensitive PCR/ligation method for the detection of GNAS mutations at codon 201 and of KRAS mutations at codon 12. Mutational status was compared with clinical and pathologic data.

Results: The IPNBs had a median diameter of 3.5cm and were located intrahepatic (N=6), extrahepatic (N=13), both intra- and extrahepatic (N=4), or in the gallbladder (intracystic papillary neoplasms, N=11). Most exhibited pancreatobiliary differentiation (N=20), had high-grade dysplasia (N=26), and an associated adenocarcinoma (N=20). Analysis of GNAS codon 201 identified only one mutant sample in a multifocal intestinal subtype intrahepatic IPNB with high-grade dysplasia. Six lesions harbored a KRAS codon 12 mutation.

Discussion: GNAS codon 201 mutations are uncommon in IPNBs, in contrast to pancreatic IPMNs. This finding might be important for biomarker applications in order to distinguish IPNBs from IPMNs – for example in the ampullary region where both entities may be located. A more comprehensive molecular profiling is needed to uncover the pathways involved in IPNB development.

Table 1: Clinical and pathological summary of 34 IPNBs

		All patients (N=34)
Median age (years)		65 (range, 54–76)
Gender	Male	20
	Female	14
Surgery	Hepatectomy	7
	Segmental bile duct resection	3
	Hepatectomy and segmental bile duct resection	5
	Tumor cholecystectomy	11
	Orthotopic liver transplantation	1
	Pancreatoduodenectomy (Whipple's procedure)	7
R-Status	0	28
	1	2
	unknown	4
Location	Intrahepatic bile ducts	6
	Extrahepatic bile ducts	13
	Intra- and extrahepatic bile ducts	4
	Gallbladder	11
Median size (cm)		3.5 (range, 0.7–21.1)
Subtype	Gastric	10
	Intestinal	2
	Pancreatobiliary	20
	Oncocytic	2
Grade of dysplasia	Low	3
	Intermediate	5
	High	26
Associated invasive cancer	Yes	20
T classification	NA	14
	T1	4
	T2	6
	T3	9
	T4	1
Lymph node metastases	NA	14
	N0	13
	N1	3
	NX	4
KRAS	mutation detected	6
GNAS	mutation detected	1