Alpha-fetoprotein Changing And Tumor Recurrence After Liver Transplantation For Patients With Hepatocellular Carcinoma

BackgroundsHepatocellular carcinoma (HCC) is the most common primary malignant tumor in liver worldwide, which ranks fifth in overall frequency, and around 372 000 new cases of HCC are diagnosed and about 1.25 million HCC patients die worldwide annually. And it is estimated conservatively that there are 400 million persistent carriers of HBV worldwide, 25% of whom have chronic liver disease and cirrhosis, which could progess to hepatocellular carcinoma. In China, there are also 120 million persistent carriers of HBV and 30 million Chronic Hepatitis B patients. HCC is the second common cause of cancer death in China, where its mortality rate is 20.37/100 thousand. HCC usually occurs in the female residents, who are with the average age of 30 to 50 years old, by the sea in Southeast China. 70% to 90% of HCC cases occur in the background setting of cirrhosis, thereby requiring thetreatment of both diseases simultaneously.Because of the lacky of the early diagnosis of HCC, the ablation rate and the long-survival after resectation are still low. As an effective treatment, LT has been accepted as the only potentially curative option for patients with HCC. The long-term survival of HCC LT has exceed the radical resection in small HCC (diameter <3cm). However, recurrence of disease is the most predictive clinical prognostic indicator for all HCC patients. Long-term survival (at 3-5 years) remains <40% due to the high incidence of recurrence (25%-67%) in HCC patients treated with LT. Given the growing organs shortage and the risk of aggressive recurrence, selection of candidates for LT is a crucial factor and still a debate. Efforts are focused on identifying tumor characters improving predictive power of recurrence and establishing optimal recipients selection criteria that can define a subset of HCC patients that stand to benefit from LT.Alpha fetoprotein (AFP) is a fetal specific glycoprotein produced primarily by the fetal liver. Normally, its serum concentration falls rapidly after birth and its synthesis in adult life is repressed. However, greater than 70% of HCC patients have a high serum concentration of AFP because of the tumor excretion. The positive rate of AFP in HCC is about 75.8%-78. 8%. Forty years after its discovery, serum AFP remains a most useful tumor marker in screening HCC patients, because the serum AFP is elevated in HCC sensitivity, which is useful in early diagnosis of HCC especially combined by the B type Doppler Ultrasonography. The serum concentration of 20ng/ml is the most commonly used cut-off value to differentiate HCC patients from healthy adults in clinical researches. The persistent high serum AFP (>400 ng/ml) excluded chronic hepatitis, pregnancy and embryoma usually is the effect indication in clinical diagnosis of HCC. And the HCC patients with a high AFP concentration (400 ng/ml) tend to have greater tumor size, bilobar involvement, massive or diffuse types, portal vein thrombosis, and a lower median survival rate. After surgical resection, it is gradualness that serum AFP concentration reduces to the normal range. Most time serum AFP concentration will become normal post-operation. Furthermore the persistent high AFP levels or the long time that serum AFP reduces to normal range may indicates the intra- or extrahepatic cancer spread and be associated with poor prognosis. The measure of serum AFP is simple, continuous and convenient for the post-operation follow-up and curative effect evaluation. The further study that the relation of the dynamic post-LT AFP levels and the HCC recurrence may be useful to a predictive prognostic indicator for the HCC recurrence post-LT.Patients and MethodsThe clinical and follow-up data of 97 patients receiving consecutive liver transplantation in our center for hepatocellular carcinoma from Feb. 2004 to Dec. 2006 were retrospectively reviewed. All 97 HCC patients have been diagnosed by pathology, 26 patients of whom with portal vein thrombosis and 37 patients' cancerfocus diameter < 3cm. There are 87 male patients and 10 female with the average age of 47.89 ±9.9 years old, included 77 patients who have HBV hepatocirrhosis background before LT. There are 11 patients who received the surgical resection and 9 patients who received trans-arterial chemotherapy and embolization (TACE) before LT. 32 patients received Orthotopic Liver Transplantation (OLT) and 65 patients received the improved Piggyback Liver Transplantation. Immunosuppressive regimens after LT were based on a standardized protocol using prednisone, Mycophenolate Mofetil (MMF), Cyclosporine A (CsA) or Tacrolimus (FK506).A. All 97 patiens were divided into three goups according to the pre-LT serum AFP levels.Group A was defined as the pre-LT serum AFP levels lower than 20ng/ml (n=28).Group B was defined as the pre-LT serum AFP levels higher than 20ng/ml but not higher than 400 ng/ml (n=27).Group C was defined as the pre-LT serum AFP levels higher than 400ng/ml (n=42).B. The 69 patiens who had the serum AFP higher 20ng/ml (Group B and Group C) were divided into another three sub-groups according to the decreasing degree of the serum AFP levels after LT.Group BC1 was defined as the serum post-LT AFP levels rapidlly decreased tolower than 20ng/ml within two weeks (n=14).Group BC2 was defined as the serum post-LT AFP levels slowly decreased to lower than 20ng/ml within two months (n=25).Group BC3 was defined as the serum post-LT AFP levels didn't decreased to lower than 20ng/ml within two months (n=29).C. The patients were followed up closely at the outpatient clinic, and tumor recurrence or metastasis was monitored by AFP, B-Ultrasonography, chest X-ray, and Emission Computed Tomography every 3 months for the first 2 years and semiannually thereafter.D. The data were analyzed statistically using the software SPSS, version 13.0 (SPSS Inc, Chicago, IL). Chi-square analysis and t test were performed to evaluate the categorical variable and quantitative variable respectively. A P value less than 0.05 was considered statistically significant.ResultsThe mean follow-up of the 97 patients was 17.1 months (range 1.6-39.1 months), among whom, overall 32 (32.9%) had been histologically proven HCC recurrence and metastasis with the mean tumor-free survival time 7.1 months. The common location of the reccucence lesions was liver (23.7%), lung (19.6%) and bone (7.2%).A. Serum AFP Pre-LT and the HCC recurrence post-LT.The follow-up data showed that 4 (14.3%), 6 (22.2%) and 22 (52.4%) patients had been histologically proven HCC recurrence post-LT respectively in Group A, Group B and Group C. Compared to patients in Group A and Group B, patients in Group C had a significant higher recurrence and metastasis rate (52.4% vs 14.3%, P=0.001 and 52.4% vs 22.2%, P=0.013, respectively).And there is no significant difference between Group A and Group B (14.3% vs 22.2%, P>0.05).The intrahepatic HCC recurrence rate was statistically significant different among three groups (P=0.003), but no significant difference for the lung and bone metastasis post-LT.B. Dynamic serum AFP levels post-LT and the HCC recurrence.The pre-LT serum AFP levels were no significant difference between Group BC1 and Group BC2 (P>0.05). Compared to patients in Group BC1 and Group BC2, patients in Group BC3 had a significant higher per-LT serum AFP levels (P=0.004 and P<0.001, respectively).The follow-up data showed that patients in Group BC3 had a significant higher recurrence rate (63.3% vs 28.6%, P=0.032 and 63.3% vs 20.0%, P=0.001, respectively), compared to patients in Group BC1 and Group BC2. And there is no significant difference between the recurrence and metastasis rate of Group A and Group B (28.6% vs 20.0%, P>0.05).The intrahepatic HCCrecurrence was statistically significant different among three sub-groups (P=0.007), but no significant difference for the lung and bone metastasis post-LT.ConclusionsThe pre- and post-LT serum AFP levels are significantly related with the HCC recurrence and metastasis after LT. The rate of HCC recurrence and metastasis after LT was higher in patients whose pre-LT AFP levels were >400ng/ml or post-LT AFP levels could not decrease to ≤20ng/ml within 2 months.The pre-LT serum AFP levels may be useful to construct the criterion of LT for HCC patients. And the dynamic changes of AFP after LT were valuable in predicting recurrence of HCC. If the post-LT serum AFP retains high levels after two months, the recipients had better been attentively followed up by B-Ultrasonography, chest X-ray, and Emission Computed Tomography (ECT), in order to find the recurrence and metastasis focus early and treat it in time.