Key words : Cancer recurrence, Interventional radiology methods, Liver transplant

Introduction

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the second most common cause of cancer mortality worldwide.¹ Liver transplant (LT) is considered the optimal therapy for HCC in patients whose tumors cannot be surgically resected. However, posttransplant recurrence and distant metastasis occur in 10% to 15% of these LT recipients.² Here, we evaluated treatment methods and long-term outcomes in LT recipients with posttransplant HCC recurrence and/or distant metastasis.

Materials and Methods

From December 1988 to January 2021, we performed 683 LT procedures at Baskent University; 72 of these LT patients had been previously diagnosed with HCC. Before transplant, all patients had been evaluated according to Baskent crieteria3 and assigned to either the early diagnosis group or the late diagnosis group. According to these criteria, early diagnosis of HCC is defined as 3 or less tumors with size less than 3 cm or 1 tumor with size less than 5 cm. Patients with HCC whose tumors that did not fit these criteria are designated as having late diagnosis. At our institution, these LT criteria are routinely applied to patients regardless of tumor size and tumor number, including patients without major vascular invasion and without distant metastasis, as well as patients with negative cytology (if ascites is present).

Patients were followed up with routine laboratory tests, alpha fetoprotein tests, and ultrasonography examinations every 3 months, and computed tomog-raphy or magnetic resonance scans were performed every 6 months.

Results

We performed 72 LT procedures for patients diagnosed with HCC. There were 19 pediatric recipients (26.3%) and 53 adult recipients (73.7%). There were 31 patients (43%) in the early diagnosis group and 41 patients (57%) in the late diagnosis group. Recurrence of HCC was observed in only 7 patients (9.7%; 5 adult, 2 pediatric), including a patient in the early diagnosis group with synchronous metastasis in the lung. For treatment, we performed percutaneous radiofrequency ablation (RFA), transarterial chemoembolization (TACE), transarterial radioembolization (TARE), chemotherapy, and surgical resection. Four of 7 patients had synchronous metastasis. Metastasis was detected in lungs of 3 patients and in the abdominal wall of 1 patient. In addition, 6 patients (8.3%) had distant metastases without recurrence in the liver, with all 6 in the late diagnosis group. These distant metastases were detected in the lung (n = 3), pelvis (n = 1), humerus (n = 1), and mandible (n = 1). Patients with recurrent liver masses were treated with RFA (5 times), TACE (3 times), TARE (once), surgical resection (once), and chemotherapy (once). In patients with distant metastases without liver involvement, there were 5 total chemotherapy treatments, 4 surgical resections, and 3 RFA treatments.

The mean survival time of all patients was 137.45 ± 10 months, and the overall 1-year, 5-year, and 10-year survival rates were 90.2%, 71.7%, and 61.4%, respectively. The mean survival time of patients in the early diagnosis group was 161.46 ± 13.9 months, with 1-year, 5-year, and 10-year survival rates of 90%, 76%, and 70%, respectively. The mean survival time of patients in the late diagnosis group was 120.25 ± 13.3 months, with 1-year, 5-year, and survival rates of 90%, 68%, and 51%, respectively (Table 1). During the follow-up period, 11 patients died from recurrence and distant metastasis. The mean overall survival of these 11 patients was 37.8 months (range, 9-92 months). One of these 11 patients was in the early diagnosis group, and his mean survival was 30 months. The mean overall survival of the other 10 patients was 38.6 months (range, 9-92 months). In our study, surgical and local therapeutic treatment methods were used in patients with recurrence and/or distant metastasis, and the response rate was 84.3%.

Discussion

Hepatocellular carcinoma is the sixth most common cancer in the world and the second leading cause of mortality.⁴ Liver transplant is the most effective treatment for patients with limited HCC within the liver. With LT, especially in people with chronic liver disease, the tumor is completely eliminated by replacement of the cirrhotic liver with a healthy transplanted liver.⁵ For HCC, follow-up of patients after treatment is just as important as the primary treatment. Alpha fetoprotein, a serum tumor marker used in the diagnosis of HCC, may generate false-positive test results for some benign liver diseases, pregnancy, and some gastrointestinal stromal tumors.⁶ In addition, computed tomography and ultrasonography as tools in the radiological follow-up of patients with HCC are not sufficiently sensitive for detection of small tumors.

Studies have shown that HCC recurrence is associated with specific factors,^7,8 including tumor size and the degree of pathological differentiation. Roayaie and colleagues reported that follow-up after LT revealed earlier recurrence and metastasis in patients with tumor size greater than 5 cm and multiple lesions.⁷ Similarly, in our study, recurrence and distant metastasis were more common in the late diagnosis group versus the early diagnosis group. We attribute this observation to the fact that large and multiple tumors are more biologically aggressive, and therefore patients are susceptible to micrometastases during LT.

Surgical resection is the most effective treatment for patients with recurrence or distant metastasis after LT.⁸ In a study by Roayaie and colleagues, the 4-year survival rate for patients after surgical resection was 47%,⁷ which is nearly the same as the survival rate for a patient with no recurrence.⁹ Local therapeutic methods such as TACE, TARE, and RFA are useful in patients for whom surgical resection is contraindicated. The TACE method is an effective local therapy to treat intrahepatic metastases.¹⁰ In a study by Zhou and colleagues, the TACE method achieved partial response in 7 of 14 patients with unresectable recurrent HCC after LT.¹¹ The RFA procedure is generally effective for recurrent masses in the liver and for distant metastatic masses in the lung. Especially in patients who are not suitable for surgery, have a large amount of acid, and/or and have advanced adhesions after surgery, RFA is a treatment method with a level of safety comparable to surgery.¹⁰ The TARE method is generally used for large volume and multiple tumors, but it is also indicated for tumors that have invaded the segmental branch of the portal vein and for tumors that have not responded to TACE therapy.¹² In a study by Salem and colleagues, TACE and TARE were compared in patients with HCC, and TARE was more effective.¹³

Conclusions

Liver transplant is the unequivocal treatment option for patients with HCC. Although there is a possibility of recurrence or distant metastasis in these LT recipients, the aforementioned treatment methods have been shown to promote a posttransplant survival rate in LT recipients that is comparable with the survival rate of patients without LT. Future development of diagnosis and treatment techniques may lead to further reductions in the rates of recurrence and distant metastasis and thereby promote higher rates of posttransplant survival in patients who have received LT for treatment of HCC.

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