Sonic Hedgehog (SHH) Expression in Biliary Intraepithelial Neoplasia (BilIN), Peribiliary Glands, and Intrahepatic Cholangiocarcinomas.
Maylee Hsu, Motoko Sasaki, Kenichi Harada, Saya Igarashi, Yasuni Nakanuma. Kanazawa University Graduate School of Medicine, Japan
Background: SHH is aberrantly activated in pancreatic ductal adenocarcinomas (PDACs) and in the precursor lesion, pancreatic intraepithelial neoplasia (PanIN). The recently characterized pancreatic duct gland (PDG) has also been shown to undergo injury-induced, SHH-mediated mucinous metaplasia and may serve as a possible link between chronic injury and pancreatic duct neoplasia. Similar to the PanIN-PDAC sequence model, cholangiocarcinoma (CC) follows a stepwise carcinogenesis process and arises from the precursor lesion BilIN, graded as BilIN-1, 2, and 3 (mild, moderate, and severe dysplasia). Additionally, analogous to reactive PDGs, florid reactive peribiliary glands (PBGs) are often seen preceding the development of CC, in particular in cases of hepatolithiasis (HL). Due to the similarities between the precursor and background lesions involved in PDAC and CC, the role of the hedgehog pathway was investigated in BilIN, PBGs, and CCs in the setting of HL.
Design: Immunohistochemical expression of SHH was evaluated in lesions with HL: normal bile duct (BD) (20), reactive BD (33), BilIN-1 (24), BilIN-2 (21), BilIN-3 (20), intrahepatic CC (ICC) (30), normal/reactive PBG (13), and atypical PBG, identified as those displaying nuclear atypia beyond reactive changes (15). Also for comparison, PDAC (36), normal BD without HL (28) and ICC without HL (58) were stained for SHH. Expression was evaluated as follows: no staining (0), weak (1), moderate (2), and strong (3), present in ≥25% of the lesion. Immunohistochemical staining for smoothened (Smo), a hedgehog pathway mediator, was also preformed and scored as: negative, present in lesion, or present in the adjacent stromal cells.
Results: In cases with HL, a higher percentage of 2 to 3+ SHH staining, which increased with grade, was identified in ICC (70%), BilIN-3 (85%), BilIN-2 (66.7%), BilIN-1 (37.5%), and reactive BD (27.3%) as compared to normal BD (5%). In cases without HL, 69% of ICCs, as compared to 7.1% of normal BD, and 50% of PDAC had 2 to 3+ SHH staining. Normal PBGs did not stain for SHH, and no correlation was identified among atypical and normal/reactive PBGs. Predominately stromal Smo staining was present in 37.5% of ICCs without HL and 51.2% of PDAC, and no significant Smo staining was found in cases with HL.
Conclusions: SHH is frequently aberrantly expressed in ICC and correlates with increasing grade of BilIN, however, may not be involved in reactive PBG proliferation. Similar to PDAC, the hedgehog pathway appears to play a key role in the development of ICC.
Category: Liver & Pancreas
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 201, Wednesday Morning