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Original Investigation
Pacific Coast Surgical Association
January 2017

Evaluation of Patients With Hepatocellular Carcinomas That Do Not Produce α-Fetoprotein

Author Affiliations
  • 1Dumont-UCLA (University of California, Los Angeles) Transplant Center and Liver Cancer Center, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles
  • 2Ronald Reagan UCLA Medical Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles
  • 3Department of Biomathematics, University of California, Los Angeles
JAMA Surg. 2017;152(1):55-64. doi:10.1001/jamasurg.2016.3310
Key Points

Question  What are the radiologic and pathologic features and posttransplant outcomes of hepatocellular carcinomas (HCCs) that do not produce α-fetoprotein (AFP)?

Findings  In this single-center retrospective analysis of 665 liver transplant recipients, the patients with tumors that did not produce AFP had radiographic characteristics similar to those of patients with AFP-producing tumors but significantly more favorable pathologic features and posttransplant outcomes.

Meaning  Stratifying patients with HCC by AFP status in addition to radiologic criteria may improve transplant candidate selection and prioritization.


Importance  Serum α-fetoprotein (AFP) is a biomarker for hepatocellular carcinomas (HCCs) associated with a more aggressive tumor phenotype and inferior outcomes after a liver transplant (LT). Data on the outcomes for patients with HCCs that do not produce AFP are limited.

Objective  To compare characteristics and outcomes among LT recipients with radiographically apparent HCC lesions with AFP-producing tumors or with tumors that do not produce AFP (hereafter referred to as non-AFP–producing tumors), and to identify factors influencing recurrence in LT recipients with non-AFP–producing tumors.

Design, Setting, and Participants  Retrospective analysis at a university transplant center of 665 adults with HCC who underwent an LT during the period from 1989 to 2013. Of the 665 LT recipients, 457 (68.7%) had AFP-producing tumors, and 208 (31.3%) had non-AFP–producing tumors (the maximum AFP level before an LT was ≤10 ng/mL). Dates of study analysis were from August 2015 to June 2016.

Intervention  Liver transplant.

Main Outcomes and Measures  Recurrence-free survival and recurrence rates.

Results  Patients with non-AFP–producing tumors had radiographic tumor characteristics similar to those of patients with AFP-producing tumors, but, pathologically, they had fewer lesions (25% vs 35% with >2 lesions; P = .03), smaller cumulative tumor diameters (4.2 vs 5.0 cm; P = .02), fewer microvascular (17% vs 22%) and macrovascular (2% vs 9%) invasions (P < .001), and fewer poorly differentiated tumors (15% vs 28%; P < .001). Patients with non-AFP–producing tumors also had significantly superior recurrence-free survival at 1, 3, and 5 years (88%, 74%, and 67% vs 76%, 59%, and 51%, respectively; P = .002) and lower 5-year recurrence rates (8.8% vs 22%; P < .001) than patients with AFP-producing tumors. When stratified by radiologic Milan criteria, 5-year survival was better, and recurrence lowest, among patients with non-AFP–producing tumors within the Milan criteria (71% survival and 6% recurrence), and survival was worse, and recurrence highest, for patients with AFP-producing tumors outside the Milan criteria (40% survival and 42% recurrence; P < .001). Significant predictors of recurrence among patients with non-AFP–producing tumors include radiologic (>2 tumors [HR, 4.98; 95% CI, 1.72-14.4; P = .003]; cumulative diameter [1.70 per log SD; 1.12-2.59; P < .001]; outside the Milan criteria [10.0; 3.7-33.3; P < .001) and pathologic factors (>2 tumors [4.39; 1.32-14.6; P = .02]; cumulative diameter [2.32 per log SD; 1.43-3.77; P = .001]; microvascular [3.07; 1.02-9.24; P = .05] and macrovascular invasion [8.75; 2.15-35.6; P = .002]).

Conclusions and Relevance  Nearly one-third of patients with radiographically apparent HCC have non-AFP–producing tumors that have more favorable pathologic characteristics, lower posttransplant recurrence, and superior survival compared with patients with AFP-producing tumors. Posttransplant HCC recurrence for patients with non-AFP–producing tumors is predicted by important radiologic and pathologic factors, and is negligible for patients within the Milan criteria. Stratifying patients by AFP status in addition to radiological criteria may improve the selection process for and the prioritization of transplant candidates.