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Patterns of Discordance Between Pretransplant Imaging Stage of Hepatocellular Carcinoma and Posttransplant Pathologic Stage

A Contemporary Appraisal of the Milan Criteria

Ecker, Brett L., MD1; Hoteit, Maarouf A., MD2; Forde, Kimberly A., MD, MHS2,3; Hsu, Christine C., MD2; Reddy, K. Rajender, MD2; Furth, Emma E., MD4; Siegelman, Evan S., MD5; Habibollahi, Peiman, MD5; Ben-Josef, Edgar, MD6; Porrett, Paige M., MD, PhD1; Abt, Peter L., MD1; Shaked, Abraham, MD, PhD1; Olthoff, Kim M., MD1; Levine, Matthew H., MD, PhD1

doi: 10.1097/TP.0000000000002056
Original Clinical Science—Liver

Background Patients with hepatocellular carcinoma (HCC) exceeding Milan criteria on explant pathology are at increased risk of recurrence and death. Discordance between contemporary magnetic resonance imaging (MRI) and explant pathology, and preoperative characteristics predictive of discordance are not well understood.

Methods Patients who underwent orthotopic liver transplantation for HCC after preoperative MRI were identified in a prospectively collected institutional database (January 2003 to December 2013). Patients were dichotomized to “within” or “outside” Milan criteria by both imaging and explant pathologic evaluation. Binary logistic regression and Kaplan-Meier methodology were used to identify independent predictors of imaging/pathologic discordance and its impact on posttransplant survival.

Results Of 318 patients with HCC meeting Milan criteria by MRI at the time of orthotopic liver transplantation, 248 (78.0%) remained within a pathological correlate of Milan criteria on explant examination. Understaging was associated with worse median recurrence-free survival (64.0 months vs 140.0 months, P = 0.002) and overall survival (96.0 months vs 143.0 months, P = 0.005), and did not vary between patients exceeding criteria due to tumor explant greater than 5 cm, more than 3 tumor foci, or a tumor greater than 3 cm in the setting of multifocality. Discordance was independently associated with an increasing serum alpha fetal protein level (odds ratio, 2.82; 95% confidence interval, 1.37-5.79; P = 0.005).

Conclusions Underestimating HCC burden before liver transplant remains frequent despite contemporary imaging technologies. Patients with an increasing alpha fetal protein before transplantation may benefit from more frequent testing or novel neoadjuvant therapies.

Understaging is the Achilles heel of liver transplantation for HCC. As might be expected, the authors show that understaging is associated with worse outcomes, but identify AFP as a potentially useful predictor of this higher risk group that could be targeted for interventions.

1 Division of Transplant Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA.

2 Division of Hepatology, Department of Gastroenterology, University of Pennsylvania, Philadelphia, PA.

3 Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA.

4 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.

5 Department of Radiology, University of Pennsylvania, Philadelphia, PA.

6 Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA.

Received 20 July 2017. Revision received 24 October 2017.

Accepted 27 October 2017.

The authors declare no funding or conflicts of interest.

B.L.E., M.A.H., A.S., K.M.O., M.H.L. participated in the conception design. B.L.E. participated in the acquisition of data. All authors participated in the analysis interpretation of data. B.L.E., M.H.L. participated in the drafting. All authors participated in revising. All authors gave their final approval of the version to be published.

Correspondence: Matthew H. Levine, MD, PhD, 3400 Spruce Street, 1 Founders, University of Pennsylvania, Philadelphia, PA 19104. (

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