Abstract:

Objective To discuss the factors related to the prognosis in the alpha fetoprotein （AFP） negative hepatocellular carcinoma （HCC） patients，and to construct the nomogram for predicting the survival time of the patients. Methods The retrospective analysis on data of 2 064 cases of AFP negative HCC patients extracted from the Surveillance， Epidemiology， and End Results （SEER） Database was conducted， and all the patients were divided into training cohort and internal validation cohort at a ratio of 7∶3， and 101 AFP negative HCC patients from the Integrated Traditional Chinese and Western Medicine Hospital in Hunan Province were regarded as the external validation cohort.The univariate Cox regression analysis results were incorporated into the multivariate analysis， and the independent risk factors for the AFP negative HCC patients were obtained by multivariate Cox analysis to build a cancer specific survival （CSS） prognosis nomogram for the AFP negative HCC patients. The predictive efficacy and clinical utility of the nomogram were evaluated by time-dependent receiver operating characteristic curve （ROC）， calibration plots， and decision curve analysis （DCA）. The total score obtained from the nomogram was used for the risk stratification to compare the degree of risk discrimination between the nomogram and the American Joint Committee on Cancer （AJCC） staging system. Results Ten independent risk factors were selected by multivariate Cox regression analysis to construct 3-year， 4-year， and 5-year CSS prognostic nomograms for the AFP negative HCC patients， including the patient’s age， pathological grade， surgical status， radiotherapy status， chemotherapy status， lung metastasis status， tumor size， tumor T stage， tumor M stage， and marital status. The area under curve （AUC） for the 3-year， 4-year， and 5-year time-dependent ROC in the training cohort were 0.807 （95% CI： 0.786－0.828）， 0.804 （95% CI： 0.782－0.826）， and 0.813 （95% CI： 0.790－0.835）， respectively. In the internal validation cohort， they were 0.776 （95% CI： 0.743－0.810）， 0.772 （95% CI： 0.737－0.808）， and 0.789 （95% CI： 0.752－0.826）， and in the external validation cohort， they were 0.773 （95% CI： 0.677－0.868）， 0.746 （95% CI： 0.620－0.872）， and 0.736 （95% CI： 0.577－0.895）. The calibration plots verified that the nomogram fitted well with the perfect line.The DCA curve revealed that the net benefit of the nomogram was significatly higer than that of the AJCC staging system at certain probability thresholds compared with AJCC staging， the nomogram had a better ability to identify high-risk individuals. Conclusion The serum AFP expression is one of the prognostic markers for the HCC patients. For those patients with AFP negative expression in serum， different considerations should be taken. The nomogram model based on multiple risk factors is a promising clinical tool for assessing the CSS in the AFP negative HCC patients.

Key words: Hepatocellular carcinoma with negative alpha fetoprotein, Nomogram, Cancer specific survival, Prediction model, Surival time