The PI3K/mTOR Pathway in Gallbladder Carcinoma
Andrea Primiani, Mohammad Shahid, Omer Yilmaz, Cristina R Ferrone, Darrell R Borger, A John Iafrate, Andrew X Zhu, Vikram Deshpande. Massachusetts General Hospital, Boston, MA
Background: Gallbladder carcinoma (GBC) is a highly aggressive malignancy. Currently, no targeted therapies are available for GBC patients as the molecular pathogenesis remains unclear. Mutations in the phosphoinositide-3 kinase (PI3K) pathway and gene amplification of human epidermal growth factor receptor 2 (Her2) have been described in a subset of GBC cases, suggesting that the PI3K pathway plays an important role in gallbladder carcinogenesis.
Design: Activation of the PI3K pathway was evaluated by using tissue microarrays containing 70 primary GBCs and 15 metastatic GBCs from a total of 82 patients. In addition, 9 gallbladders with high-grade dysplasia (HGD; 1 from a patient with concurrent GBC) were evaluated. Both primary and metastatic lesions from 5 patients were evaluated. Protein expression of pS6 and p4E-BP1 was analyzed by immunohistochemistry (IHC). Her2 amplification was evaluated by fluorescence in-situ hybridization (FISH) in 91 cases. Genotypic analysis of PI3K was performed in 23 cases by using a multiplex PCR platform. Survival was compared using the Kaplan-Meier analysis.
Results: Twenty-eight (35%) GBC were negative for p4E-BP1, while 52 (65%) showed nuclear and cytoplasmic reactivity. Sixteen (20%) GBC were negative for pS6, while 63 (80%) showed cytoplasmic reactivity for this marker. The mean survival of patients with p4E-BP1-negative GBC and p4E-BP1-positive GBC was 42.8 months and 11.33 months, respectively (log rank test 0.06). There was no association between tumor stage and p4E-BP1 expression. The mean survival of patients with pS6-negative GBC and pS6-positive GBC was 35 months and 20 months, respectively. (log rank test 0.6). Her2 amplification was detected in specimens from 4 of 82 (5%) patients with GBC. One case with Her2 amplification was negative for both p4E-BP1 and pS6 while the rest showed both p4E-BP1 and pS6 expression. PI3K mutations were identified in 3 of 23 (13%) GBC cases, all of which were negative for Her2 amplification and pS6 expression. One of the PI3K-mutant cases showed expression of p4E-BP1. Her2 amplification was not seen in any HGD cases. Among the HGD cases, 8 (89%) and 7 (78%) showed expression for p4E-BP1 and pS6, respectively.
Conclusions: The presence of Her2 amplification (5% of GBCs) and PI3K mutations (13% of GBC), which were mutually exclusive genetic abnormalities in this cohort, and the shorter survival of tumors expressing activating markers of mTOR pathway suggest that the PI3K/mTOR pathway is a critical (and potentially addictive) pathway in GBC tumorigenesis. We hypothesize that PI3K/mTOR inhibition may have significant therapeutic effect in these tumors.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 111, Monday Morning